‘3-D’ test could reduce reliance on animals for testing asthma and allergy medications

To determine whether new medicines are safe and effective for humans, researchers must first test them in animals, which is costly and time-consuming, as well as ethically challenging. In a study published in ACS’ journal Molecular Pharmaceutics, scientists report that they’ve developed a simple, “3D” laboratory method to test asthma and allergy medications that mimics what happens in the body, which could help reduce the need for animal testing.Amir Ghaemmaghami and colleagues note that respiratory conditions, such as asthma and allergies, are becoming more common. These conditions affect the lungs and the airway leading to the lungs, making it difficult to breathe. Every year, respiratory symptoms lead to expensive hospital visits, as well as absences from work and school. Better drugs could provide relief, but before giving new medicines to people, researchers must first test them in animals — a costly and laborious process. Sometimes, researchers will use “2D” tests in which they apply the drug to a layer of human cells in a lab dish instead, but this isn’t an adequate way to tell how a medicine will work in a whole animal or a whole person. So, Ghaemmaghami’s team developed a new, 3D alternative.Their test includes three types of human cells that are typically in a person’s airway. In the body, these cells are close together and are involved in the development of respiratory conditions. The 3D “model” reacted just like a real person’s airway when they exposed it to allergens and bacterial extract. They say that the model has the potential of reducing the need for some animal testing of new drugs for respiratory conditions.Story Source:The above story is based on materials provided by American Chemical Society. …

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Eleven new genes affecting blood pressure discovered

New research from Queen Mary University of London has discovered 11 new DNA sequence variants in genes influencing high blood pressure and heart disease.Identifying the new genes contributes to our growing understanding of the biology of blood pressure and, researchers believe, will eventually influence the development of new treatments. More immediately the study highlights opportunities to investigate the use of existing drugs for cardiovascular diseases.The large international study, published today in the American Journal of Human Genetics, examined the DNA of 87,736 individuals to discover genetic variants associated with blood pressure traits. Validation of these sequence variants was performed in a further 68,368 individuals. This analysis led to the identification of 11 new genes.Worldwide, raised blood pressure is estimated to cause 7.5 million deaths, about 12.8% of the total of all deaths. Genes and lifestyle factors (e.g., salt intake and obesity) are both known to be important risk factors.Patricia Munroe, Professor of Molecular Medicine at Queen Mary University of London, comments: “Discovering these new genetic variants provides vital insight into how the body regulates blood pressure. With further research, we are hopeful it could lead to the development of new treatments for treating blood pressure and heart disease — a leading cause of death worldwide.”Michael Barnes, Director of Bioinformatics, Barts and The London NIHR Cardiovascular Biomedical Research Unit, Queen Mary University of London, comments:”By highlighting several existing drugs that target proteins which influence blood pressure regulation, our study creates a very real opportunity to fast-track new therapies for hypertension into the clinic.”Story Source:The above story is based on materials provided by Queen Mary, University of London. Note: Materials may be edited for content and length.

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Mechanism of crude oil heart toxicity on fish revealed from oil spill research

Scientists from Stanford University and the National Oceanic and Atmospheric Administration (NOAA) have discovered that crude oil interferes with fish heart cells. The toxic consequence is a slowed heart rate, reduced cardiac contractility and irregular heartbeats that can lead to cardiac arrest and sudden cardiac death.The research, published in the Feb. 14 issue of Science, is part of the ongoing Natural Resource Damage Assessment of the April 2010 Deepwater Horizon oil spill.While crude oil is known to be cardiotoxic to developing fish, the physiological mechanisms underlying its harmful effects were unclear. Stanford and NOAA scientists studying the impact of crude oil from the Deepwater Horizon spill on tuna discovered that it interrupts the ability of fish heart cells to beat effectively.Crude oil is a complex mixture of chemicals, some of which are known to be toxic to marine animals. Past research has focused in particular on “polycyclic aromatic hydrocarbons” (PAHs), which can also be found in coal tar, creosote, air pollution and stormwater runoff from land. In the aftermath of an oil spill, PAHs can persist for many years in marine habitats and cause a variety of adverse environmental effects.The researchers report that oil interferes with cardiac cell excitability, contraction and relaxation — vital processes for normal beat-to-beat contraction and pacing of the heart.Their tests revealed that very low concentrations of crude oil disrupt the specialized ion channel pores — where molecules flow in and out of the heart cells — that control heart rate and contraction in the cardiac muscle cell.This cyclical signaling pathway in cells throughout the heart is what propels blood out of the pump on every beat. The protein components of the signaling pathway are highly conserved in the hearts of most animals, including humans.The researchers found that oil blocks the potassium channels distributed in heart cell membranes, increasing the time to restart the heart on every beat. This prolongs the normal cardiac action potential, and ultimately slows the heartbeat. The potassium ion channel impacted in the tuna is responsible for restarting the heart muscle cell contraction cycle after every beat, and is highly conserved throughout vertebrates, raising the possibility that animals as diverse as tuna, turtles and dolphins might be affected similarly by crude oil exposure. Oil also resulted in arrhythmias in some ventricular cells.”The ability of a heart cell to beat,” explained Barbara Block, a professor of marine sciences at Stanford, “depends on its capacity to move essential ions like potassium and calcium into and out of the cells quickly. …

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Scientists identify gene linking brain structure to intelligence

For the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study is published today in Molecular Psychiatry and may help scientists understand biological mechanisms behind some forms of intellectual impairment.The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified.An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence.Dr Sylvane Desrivires, from King’s College London’s Institute of Psychiatry and lead author of the study, said: “We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity — how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.”She adds: “It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.”The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate.To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. …

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Longevity mutation found in flies far and wide

To date, evidence that mutations in a gene called Indy could increase life span in flies and mimic calorie restriction in mammals has come only from experiments in the lab. A new study finds that the same benefit is present in naturally Indy-mutated flies descended from flies collected in the wild all over the world and going back decades.For years, researchers have been investigating how mutations of a gene called Indy (for “I’m Not Dead Yet”) affect metabolism, life span, and reproductive fitness in both mammals and fruit flies. So far mutations in Indy have been studied experimentally only in the lab. No longer. A new study reports that a particularly important variation of the gene with much the same life-governing consequences has actually been widespread among fruit flies, judging by lines gathered from the wild across the entire globe for 60 years.The naturally occurring variation is the insertion of a transposable element — an invasive snippet of DNA — at a specific position on Indy. Researchers, including Brown University biology professors Stephen Helfand and Robert Reenan, found that the transposable element, called Hoppel, was present to varying extents in 17 of 22 fruit fly lines gathered from all over the world as far back as the middle of last century. Hoppel was present in 100 percent of a captive fly line started in 2006 in Mumbai, India, for example, and 55 percent of flies descended from those gathered in Oahu, Hawaii, in 1955.Helfand recalled that in 2000 when he first published a paper in Science demonstrating the effect of Indy on life span, a couple of reporters asked him why a mutation that conveyed such advantages wasn’t found in the wild.Indeed, 14 years later the prevalence of Hoppel insertion suggests that it has been beneficial to flies in the wild and therefore persisted during their evolution, said Helfand, of Brown’s Department of Molecular Biology, Cellular Biology, and Biochemistry.”It’s kind of remarkable that just the Hoppel in Indy should affect fertility and life span because these flies from around the world are from such differing genetic backgrounds,” said Helfand. “This suggests that we are correct that Indy does play a role in longevity. If it does it in the lab, that’s great, but now we can show that it does it in the wild.”In the study, published online Jan. 31 in the journal Aging, the researchers, led by postdoctoral scholar Chen-Tseh Zhu, describe experiments that confirm that the Hoppel transposon’s presence positively affected life span and fertility in the flies. …

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The role of ‘master regulators’ in gene mutations and disease

Oct. 13, 2013 — Researchers at the University of California, San Diego School of Medicine have developed a new way to parse and understand how special proteins called “master regulators” read the genome, and consequently turn genes on and off.Writing in the October 13, 2013 Advance Online Publication of Nature, the scientists say their approach could make it quicker and easier to identify specific gene mutations associated with increased disease risk — an essential step toward developing future targeted treatments, preventions and cures for conditions ranging from diabetes to neurodegenerative disease.”Given the emerging ability to sequence the genomes of individual patients, a major goal is to be able to interpret that DNA sequence with respect to disease risk. What diseases is a person genetically predisposed to?” said principal investigator Christopher Glass, MD, PhD, a professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego.”Mutations that occur in protein-coding regions of the genome are relatively straight forward, but most mutations associated with disease risk actually occur in regions of the genome that do not code for proteins,” said Glass. “A central challenge has been developing a strategy that assesses the potential functional impact of these non-coding mutations. This paper lays the foundation for doing so by examining how natural genetic variation alters the function of genomic regions controlling gene expression in a cell specific-manner.”Cells use hundreds of different proteins called transcription factors to “read” the genome, employing those instructions to turn genes on and off. These factors tend to be bound close together on the genome, forming functional units called “enhancers.” Glass and colleagues hypothesized that while each cell has tens of thousands of enhancers consisting of myriad combinations of factors, most enhancers are established by just a handful of special transcription factors called “master regulators.” These master regulators play crucial, even disproportional, roles in defining each cell’s identity and function, such as whether it will be a muscle, skin or heart cell.”Our main idea was that the binding of these master regulators is necessary for the co-binding of the other transcription factors that together enable enhancers to regulate the expression of nearby genes,” Glass said.The scientists tested and validated their hypothesis by looking at the effects of approximately 4 million DNA sequence differences affecting master regulators in macrophage cells in two strains of mice. Macrophages are a type of immune response cell. They found that DNA sequence mutations deciphered by master regulators not only affected how they bound to the genome, but also impacted neighboring transcription factors needed to make functional enhancers.The findings have practical importance for scientists and doctors investigating the genetic underpinnings of disease, said Glass. “Without actual knowledge of where the master regulator binds, there is relatively little predictive value of the DNA sequence for non-coding variants. Our work shows that by collecting a focused set of data for the master regulators of a particular cell type, one can greatly reduce the ‘search space’ of the genome in a particular cell type that would be susceptible to the effects of mutations. …

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Cell growth discovery has implications for targeting cancer

Oct. 11, 2013 — The way cells divide to form new cells — to support growth, to repair damaged tissues, or simply to maintain our healthy adult functioning — is controlled in previously unsuspected ways UC San Francisco researchers have discovered. The findings, they said, may lead to new ways to fight cancer.The steps leading a quiet cell to make and divvy up new parts to form daughter cells rely on some of the cell’s most complex molecular machines. Different machines play key roles at different stages of this cell cycle. Each of these cellular machines consists of many proteins assembled into a functioning whole. They carry out such tasks as repairing DNA in the newly replicated gene-bearing chromosomes, for instance, or helping pull the chromosomes apart so that they can be allocated to daughter cells.In a study published online on October 10, 2013 in the journal Molecular Cell, UCSF researchers led by molecular biologist Davide Ruggero, PhD, associate professor of urology, and computational biologist Barry Taylor, PhD, assistant professor of epidemiology and biostatistics, found that the production of entire sets of proteins that work together to perform such crucial tasks is ramped up together, all at once — not due to the transcription of genes into messenger RNA, a phenomenon scientists often study to sort out cellular controls — but at a later stage of gene expression that occurs within the cell’s protein-making factories, called ribosomes.”We have found that these proteins are regulated specifically and exquisitely during the cell cycle,” Ruggero said. When this regulation falters, it wreaks havoc in the cell, he added. “Cell-cycle control is a process that is most often misregulated in human disease,” he said.More specifically, the researchers found that this coordinated timing of protein production during the cell cycle is largely governed at the tail end of gene expression, within the ribosome, where cellular machinery acts on messenger RNA to churn out the chains of amino acids that eventually fold into functional form as proteins.In 2010 Ruggero reported key evidence suggesting that this stage of protein production, called “translation,” might be an often-neglected process in many tumors, ranging from lymphomas, multiple myeloma and prostate cancer.In the new study, the researchers examined translation of messenger RNA into protein at the classic phases of the cell cycle, before the cell actually divides. These are the G1 phase, when cells grow and make lots of proteins before replicating their DNA; the S phase, when cells replicate their DNA; and the G2 phase, when cells make internal components known as organelles, which they divvy up along with the chromosomes when the cell actually divides during mitosis.The scientists used a technique know as ribosome profiling, originally developed for yeast cells in the lab of Jonathan Weismann, PhD, Howard Hughes Investigator at UCSF and professor of cellular and molecular pharmacology, to figure out which messenger RNA was being translated into protein by the ribosome during human cell division. They then used computational techniques developed by Taylor’s lab team along with the lab team of Adam Olshen, PhD, professor of epidemiology and biostatistics, to better quantify which genes had been translated into proteins.By conducting a genome-wide investigation of translation and interrogating the data with sophisticated computer algorithms, the researchers discovered that different groups of protein were made in abundance at a particular phase, only to be quieted during another phase of the cell cycle. …

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Alzheimer’s patients show striking individual differences in molecular basis of disease

Sep. 12, 2013 — Alzheimer’s disease is thought to be caused by the buildup of abnormal, thread-like protein deposits in the brain, but little is known about the molecular structures of these so-called beta-amyloid fibrils. A study published by Cell Press September 12th in the journal Cell has revealed that distinct molecular structures of beta-amyloid fibrils may predominate in the brains of Alzheimer’s patients with different clinical histories and degrees of brain damage. The findings pave the way for new patient-specific strategies to improve diagnosis and treatment of this common and debilitating disease.Share This:”This work represents the first detailed characterization of the molecular structures of beta-amyloid fibrils that develop in the brains of patients with Alzheimer’s disease,” says senior study author Robert Tycko of the National Institutes of Health. “This detailed structural model may be used to guide the development of chemical compounds that bind to these fibrils with high specificity for purposes of diagnostic imaging, as well as compounds that inhibit fibril formation for purposes of prevention or therapy.”Tycko and his team had previously noticed that beta-amyloid fibrils grown in a dish have different molecular structures, depending on the specific growth conditions. Based on this observation, they suspected that fibrils found in the brains of patients with Alzheimer’s disease are also variable and that these structural variations might relate to each patient’s clinical history. But it has not been possible to directly study the structures of fibrils found in patients because of their low abundance in the brain.To overcome this hurdle, Tycko and his collaborators developed a new experimental protocol. They extracted beta-amyloid fibril fragments from the brain tissue of two patients with different clinical histories and degrees of brain damage and then used these fragments to grow a large quantity of fibrils in a dish. They found that a single fibril structure prevailed in the brain tissue of each patient, but the molecular structures were different between the two patients.”This may mean that fibrils in a given patient appear first at a single site in the brain, then spread to other locations while retaining the identical molecular structure,” Tycko says. “Our study also shows that certain fibril structures may be more likely than others to cause Alzheimer’s disease, highlighting the importance of developing imaging agents that target specific fibril structures to improve the reliability and specificity of diagnosis.”Share this story on Facebook, Twitter, and Google:Other social bookmarking and sharing tools:|Story Source: The above story is based on materials provided by Cell Press, via EurekAlert!, a service of AAAS. …

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How chromosome ends influence cellular aging

Sep. 11, 2013 — By studying processes that occur at the ends of chromosomes, a team of Heidelberg researchers has unravelled an important mechanism towards a better understanding of cellular aging. The scientists focused on the length of the chromosome ends, the so-called telomeres, which can be experimentally manipulated. Their research, which was conducted at the Center for Molecular Biology of Heidelberg University (ZMBH), allows for new approaches in the development of therapies for tissue loss and organ failure associated with senescence (cellular aging). The research results may also be significant for cancer treatment. They were recently published in the journal Nature Structural & Molecular Biology.Share This:Each cell contains a set of chromosomes in which the vast majority of our genetic information is stored in the form of DNA. This information must be protected to ensure the proper functioning of the cell. To achieve this, the very ends of the chromosomes, the telomeres, play an important role in protecting the chromosomal DNA from being degraded. “We can imagine that telomeres are analogous to the plastic caps at the ends of our shoelaces. Without them, the ends of the laces get frayed and eventually the entire shoelace does not function properly,” explains Dr. …

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Organic molecules found in Sutter’s Mill meteorite, not previously found in any meteorites

Sep. 10, 2013 — An important discovery has been made concerning the possible inventory of molecules available to the early Earth. Scientists led by Sandra Pizzarello, a research professor in ASU’s Department of Chemistry and Biochemistry, found that the Sutter’s Mill meteorite, which exploded in a blazing fireball over California last year, contains organic molecules not previously found in any meteorites. These findings suggest a far greater availability of extraterrestrial organic molecules than previously thought possible, an inventory that could indeed have been important in molecular evolution and life itself.Share This:The work is being published in this week’s Proceedings of the National Academy of Sciences. The paper is titled “Processing of meteoritic organic materials as a possible analog of early molecular evolution in planetary environments,” and is co-authored by Pizzarello, geologist Lynda Williams, NMR specialist Gregory Holland and graduate student Stephen Davidowski, all from ASU.Coincidentally, Sutter’s Mill is also the gold discovery site that led to the 1849 California Gold Rush. Detection of the falling meteor by Doppler weather radar allowed for rapid recovery so that scientists could study for the first time a primitive meteorite with little exposure to the elements, providing the most pristine look yet at the surface of primitive asteroids.”The analyses of meteorites never cease to surprise you … and make you wonder,” explains Pizzarello. “This is a meteorite whose organics had been found altered by heat and of little appeal for bio- or prebiotic chemistry, yet the very Solar System processes that lead to its alteration seem also to have brought about novel and complex molecules of definite prebiotic interest such as polyethers.”Pizzarello and her team hydrothermally treated fragments of the meteorite and then detected the compounds released by gas chromatography-mass spectrometry. The hydrothermal conditions of the experiments, which also mimic early Earth settings (a proximity to volcanic activity and impact craters), released a complex mixture of oxygen-rich compounds, the probable result of oxidative processes that occurred in the parent body. They include a variety of long chain linear and branched polyethers, whose number is quite bewildering.This addition to the inventory of organic compounds produced in extraterrestrial environments furthers the discourse of whether their delivery to the early Earth by comets and meteorites might have aided the molecular evolution that preceded the origins of life.Share this story on Facebook, Twitter, and Google:Other social bookmarking and sharing tools:|Story Source: The above story is based on materials provided by Arizona State University. …

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Potential diagnostic marker for zinc status offers insights into the effects of zinc deficiency

Aug. 29, 2013 — According to new research published in The FASEB Journal, a drop in blood zinc levels does not directly harm the blood vessel cells. Rather, zinc regulates the production of a small molecular compound, which then circulates in the blood and causes harmful blood vessel cell effects. Additionally, not only will having adequate amounts of zinc prevent the creation of this compound, but it can protect you when the compound is circulating in your blood.Share This:”Zinc deficiency afflicts two billion people worldwide and our study has revealed a zinc-regulated small compound in blood that mediates the harmful effects of zinc deprivation,” said John H. Beattie, Ph.D., a researcher involved in the work from the Rowett Institute of Nutrition and Health at the University of Aberdeen in Aberdeen, U.K. “Measurement of this compound in blood may prove very valuable, not only in assessing, for example, the risk of developing heart attack or stroke, but also as a diagnostic test for zinc status.”To make this discovery, Beattie and colleagues cultured cells from rat blood vessels and exposed them for 24 hours to the blood plasma from rats that had been given food low or adequate in zinc. Then they examined the gene expression profile to identify which genes changed when exposed to blood plasma from low zinc rats. Dramatic changes in some gene activities were found when comparing blood plasma treatments from low and adequate zinc rats. Then the scientists removed the zinc from the zinc-adequate blood plasma and saw that it had no effect on gene activity, suggesting that that there was a harmful compound produced in response to zinc deficiency and that its effects on blood vessel cells is abolished by zinc.”Most people might think of zinc as a kind of food supplement,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal, “but zinc deficiency is a serious matter. Understanding how zinc deficiency affects the body is important, not just because it can help us how to treat this deficiency, but also because it presents a new way to detect low zinc in the body that is faster and easier than current methods.”Share this story on Facebook, Twitter, and Google:Other social bookmarking and sharing tools:|Story Source: The above story is based on materials provided by Federation of American Societies for Experimental Biology, via EurekAlert!, a service of AAAS. …

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‘Mini human brains’ created: Scientists grow human brain tissue in 3-D culture system

Aug. 29, 2013 — Complex human brain tissue has been successfully developed in a three-dimensional culture system established in an Austrian laboratory. The method described in the current issue of Nature allows pluripotent stem cells to develop into cerebral organoids — or “mini brains” — that consist of several discrete brain regions.Instead of using so-called patterning growth factors to achieve this, scientists at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW) fine-tuned growth conditions and provided a conducive environment. As a result, intrinsic cues from the stem cells guided the development towards different interdependent brain tissues. Using the “mini brains,” the scientists were also able to model the development of a human neuronal disorder and identify its origin — opening up routes to long hoped-for model systems of the human brain.The development of the human brain remains one of the greatest mysteries in biology. Derived from a simple tissue, it develops into the most complex natural structure known to man. Studies of the human brain’s development and associated human disorders are extremely difficult, as no scientist has thus far successfully established a three-dimensional culture model of the developing brain as a whole. Now, a research group lead by Dr. Jürgen Knoblich at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) has just changed that.Brain Size MattersStarting with established human embryonic stem cell lines and induced pluripotent stem (iPS) cells, the group identified growth conditions that aided the differentiation of the stem cells into several brain tissues. While using media for neuronal induction and differentiation, the group was able to avoid the use of patterning growth factor conditions, which are usually applied in order to generate specific cell identities from stem cells. …

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Structure of chromosomes supported by a kind of molecular skeleton

Aug. 26, 2013 — Jan-Michael Peters and his team at the Research Institute of Molecular Pathology (IMP) found that the structure of chromosomes is supported by a kind of molecular skeleton, made of cohesin.Their discovery is published online in the current issue of the journal Nature.Every single cell in the human body contains an entire copy of the genetic blueprint, the DNA. Its total length is about 3.5 meters and all of it has to fit into the cell’s nucleus, just one-hundredth of a millimeter in diameter. Blown up in proportion, this would equal the task of squeezing a 150km long string into a soccer ball. Just how the cell manages to wrap up its DNA so tightly is still poorly understood.One way of compacting DNA is achieved by coiling it tightly around histone-proteins. This mechanism has been studied in detail and is the focus of an entire discipline, epigenetics. However, simple organisms such as bacteria have to manage their DNA-packaging without histones, and even in human cells histones probably cannot do the job on their own.A new role for an old moleculeA team of scientists at the Research Institute of Molecular Pathology (IMP) in Vienna can now present evidence for an additional mechanism involved in structuring DNA. Managing Director Jan-Michael Peters and his research group discovered that a protein-complex named cohesin has a stabilizing effect on DNA. In evolutionary terms, cohesin is very old and its structure has hardly changed over billions of years. It was present long before histones and might therefore provide an ancient mechanism in shaping DNA.Cell biologists are already familiar with cohesin and its role in cell division. …

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Celery, artichokes contain flavonoids that kill human pancreatic cancer cells

Aug. 15, 2013 — Celery, artichokes, and herbs, especially Mexican oregano, all contain apigenin and luteolin, flavonoids that kill human pancreatic cancer cells in the lab by inhibiting an important enzyme, according to two new University of Illinois studies.”Apigenin alone induced cell death in two aggressive human pancreatic cancer cell lines. But we received the best results when we pre-treated cancer cells with apigenin for 24 hours, then applied the chemotherapeutic drug gemcitabine for 36 hours,” said Elvira de Mejia, a U of I professor of food chemistry and food toxicology.The trick seemed to be using the flavonoids as a pre-treatment instead of applying them and the chemotherapeutic drug simultaneously, said Jodee Johnson, a doctoral student in de Mejia’s lab who has since graduated.”Even though the topic is still controversial, our study indicated that taking antioxidant supplements on the same day as chemotherapeutic drugs may negate the effect of those drugs,” she said.”That happens because flavonoids can act as antioxidants. One of the ways that chemotherapeutic drugs kill cells is based on their pro-oxidant activity, meaning that flavonoids and chemotherapeutic drugs may compete with each other when they’re introduced at the same time,” she explained.Pancreatic cancer is a very aggressive cancer, and there are few early symptoms, meaning that the disease is often not found before it has spread. Ultimately the goal is to develop a cure, but prolonging the lives of patients would be a significant development, Johnson added.It is the fourth leading cause of cancer-related deaths, with a five-year survival rate of only 6 percent, she said.The scientists found that apigenin inhibited an enzyme called glycogen synthase kinase-3β (GSK-3β), which led to a decrease in the production of anti-apoptotic genes in the pancreatic cancer cells. Apoptosis means that the cancer cell self-destructs because its DNA has been damaged.In one of the cancer cell lines, the percentage of cells undergoing apoptosis went from 8.4 percent in cells that had not been treated with the flavonoid to 43.8 percent in cells that had been treated with a 50-micromolar dose. In this case, no chemotherapy drug had been added.Treatment with the flavonoid also modified gene expression. “Certain genes associated with pro-inflammatory cytokines were highly upregulated,” de Mejia said.According to Johnson, the scientists’ in vitro study in Molecular Nutrition and Food Research is the first to show that apigenin treatment can lead to an increase in interleukin 17s in pancreatic cells, showing its potential relevance in anti-pancreatic cancer activity.Pancreatic cancer patients would probably not be able to eat enough flavonoid-rich foods to raise blood plasma levels of the flavonoid to an effective level. But scientists could design drugs that would achieve those concentrations, de Mejia said.And prevention of this frightening disease is another story. “If you eat a lot of fruits and vegetables throughout your life, you’ll have chronic exposure to these bioactive flavonoids, which would certainly help to reduce the risk of cancer,” she noted.

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New gene repair technique promises advances in regenerative medicine

Aug. 12, 2013 — Using human pluripotent stem cells and DNA-cutting protein from meningitis bacteria, researchers from the Morgridge Institute for Research and Northwestern University have created an efficient way to target and repair defective genes.Writing August 12 in the Proceedings of the National Academy of Sciences, the team reports that the novel technique is much simpler than previous methods and establishes the groundwork for major advances in regenerative medicine, drug screening and biomedical research.Zhonggang Hou of the Morgridge Institute’s regenerative biology team and Yan Zhang of Northwestern University served as first authors on the study; James Thomson, director of regenerative biology at the Morgridge Institute, and Erik Sontheimer, professor of molecular biosciences at Northwestern University, served as principal investigators.”With this system, there is the potential to repair any genetic defect, including those responsible for some forms of breast cancer, Parkinson’s and other diseases,” Hou said. “The fact that it can be applied to human pluripotent stem cells opens the door for meaningful therapeutic applications.”Zhang said the Northwestern University team focused on Neisseria meningitidis bacteria because it is a good source of the Cas9 protein needed for precisely cleaving damaged sections of DNA.”We are able to guide this protein with different types of small RNA molecules, allowing us to carefully remove, replace or correct problem genes,” Zhang said. “This represents a step forward from other recent technologies built upon proteins such as zinc finger nucleases and TALENs.”These previous gene correction methods required engineered proteins to help with the cutting. Hou said scientists can synthesize RNA for the new process in as little as one to three days — compared with the weeks or months needed to engineer suitable proteins.Thomson, who also serves as the James Kress Professor of Embryonic Stem Cell Biology at the University of Wisconsin-Madison, a John D. MacArthur professor at UW-Madison’s School of Medicine and Public Health and a professor in the department of molecular, cellular and developmental biology at the University of California, Santa Barbara, says the discovery holds many practical applications.”Human pluripotent stem cells can proliferate indefinitely and they give rise to virtually all human cell types, making them invaluable for regenerative medicine, drug screening and biomedical research,” Thomson says. “Our collaboration with the Northwestern team has taken us further toward realizing the full potential of these cells because we can now manipulate their genomes in a precise, efficient manner.”Sontheimer, who serves as the Soretta and Henry Shapiro Research Professor of Molecular Biology with Northwestern’s department of molecular biosciences, Center for Genetic Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, says the team’s results also offer hopeful signs about the safety of the technique.”A major concern with previous methods involved inadvertent or off-target cleaving, raising issues about the potential impact in regenerative medicine applications,” he said. “Beyond overcoming the safety obstacles, the system’s ease of use will make what was once considered a difficult project into a routine laboratory technique, catalyzing future research.”Also contributing to the study, which was supported by funding from sources including the National Institutes of Health, the Wynn Foundation and the Morgridge Institute for Research, were Nicholas Propson, Sara Howden and Li-Fang Chu from the Morgridge Institute for Research.

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Simple math sheds new light on a long-studied biological process

Aug. 7, 2013 — One of the most basic and intensively studied processes in biology — one which has been detailed in biology textbooks for decades — has gained a new level of understanding, thanks to the application of simple math to a problem that scientists never before thought could benefit from mathematics.The scientists who made the discovery, published in this week’s advance online publication of Nature, found that the process bacteria use to quickly adapt to metabolize preferred energy sources such as glucose — a process called “catabolite repression” — is controlled not just by glucose, as had long been known and taught, but just as much by other essential nutrients, such as nitrogen and sulfur, available to bacteria in their growth medium.”This is one of the most studied processes in molecular biology; it’s in every textbook,” says Terence Hwa, a professor of physics and biology at UC San Diego, who headed the team of scientists. “We showed that this process doesn’t work the way most people thought it did for the past several decades, and its purpose is different from what had generally been assumed.”The basic phenomenon, Hwa says, is analogous to a balanced diet: To reduce an individual’s sugar uptake, common wisdom is to reduce the availability of sugar. This strategy backfires on bacteria because they would increase their appetite for sugars — the process of catabolite repression would direct the bacteria to increase the production of their sugar uptake system to counteract the scarcity of sugar in the environment. However, by figuring out that catabolite repression actually works by sensing the difference between the influx of sugar and that of other essential nutrients such as nitrogen, it is possible to drastically lower the bacteria’s appetite for sugar by simply rationing the supply of nitrogen.Hwa and his team arrived at their surprising finding by employing a new approach called “quantitative biology,” in which scientists quantify biological data and discover mathematical patterns, which in turn guide them to develop predictive models of the underlying processes.”This mode of research, an iterative dialogue between data quantitation and model building, has driven the progress of physics for the past several centuries, starting with Kepler’s discovery of the law of planetary motion,” explains Hwa. “However, it was long thought that biology is so laden with historical accidents which render the application of quantitative deduction intractable.”The significance of the study, according to Hwa, is that it demonstrates that the physicists’ quantitative approach can also effectively probe and elucidate biological processes, even a classic problem that has been heavily scrutinized.”Molecular biology gives us a collection of parts and interactions,” says Hwa. “But how do you make sense of those interactions? You need to examine them in their physiological context. Quantitative patterns in physiological responses, together with mathematical analysis, provide important clues that can reveal the functions of molecular components and interactions, and in this case, also pinpoint the existence of previously unknown interactions.””It is remarkable that after so many years of studying these cells there are more fascinating things to be discovered by simple experiments and theory,” says Krastan B. Blagoev, a program director in the National Science Foundation’s Division of Physics, which jointly funded the research with the agency’s Molecular and Cellular Biology Division.Hwa and his team of physicists and biologists at UC San Diego are among the world’s leaders in quantitative biology, which is gaining an upsurge of interest and importance in the life sciences. …

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New designer compound treats heart failure by targeting cell nucleus

Aug. 1, 2013 — Researchers from Case Western Reserve University School of Medicine and the Dana-Farber Cancer Institute have made a fundamental discovery relevant to the understanding and treatment of heart failure — a leading cause of death worldwide. The team discovered a new molecular pathway responsible for causing heart failure and showed that a first-in-class prototype drug, JQ1, blocks this pathway to protect the heart from damage.In contrast to standard therapies for heart failure, JQ1 works directly within the cell’s command center, or nucleus, to prevent damaging stress responses. This groundbreaking research lays the foundation for an entirely new way of treating a diseased heart. The study is published in the August 1 issue of Cell.”As a practicing cardiologist, it is clear that current heart failure drugs fall alarmingly short for countless patients. Our discovery heralds a brand new class of drugs which work within the cell nucleus and offers promise to millions suffering from this common and lethal disease,” said Saptarsi Haldar, MD, senior author on the paper, assistant professor of medicine at Case Western Reserve and cardiologist at University Hospitals Case Medical Center.Heart failure occurs when the organ’s pumping capacity cannot meet the body’s needs. Existing drugs, most of which block hormones such as adrenaline at the cell’s outer surface, have improved patient survival. Unfortunately, several clinical studies have demonstrated that heart failure patients taking these hormone-blocking drugs still succumb to high rates of hospitalization and death. Leveraging a new approach, the research team turned their attention from the cell’s periphery to the nucleus — the very place that unleashes sweeping damage-control responses which, if left unchecked, ultimately destroy the heart.The team found that a new family of genes, called BET bromodomains, cause heart failure because they drive hyperactive stress responses in the nucleus. Prior research linking BET bromodomains to cancer prompted the laboratory of James Bradner, MD, the paper’s senior author and a researcher at the Dana-Farber, to develop a direct-acting BET inhibitor, called JQ1. …

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A roadblock to personalized cancer care?

Doctors need a way to target treatments to patients most likely to benefit and avoid treating those who will not. Tumor biomarker tests can help do this.The problem, according to a new commentary paper, is that, unlike drugs or other therapies, cancer biomarker tests are undervalued by doctors and patients. The authors say that inconsistent regulatory rules, inadequate payment and underfunded tumor biomarker research has left us in a vicious cycle that prevents development and testing of reliable biomarker tests that could be used to personalize clinical care of patients with cancer.”Right now biomarkers are not valued nearly to the extent that we see with therapeutics. But if a tumor biomarker test is being used to decide whether a patient should receive a certain treatment, then it is as critical for patient care as a therapeutic agent. A bad test is as dangerous as a bad drug,” says Daniel F. Hayes, M.D., clinical director of the breast oncology program at the University of Michigan Comprehensive Cancer Center.Hayes led a blue-ribbon panel of experts from universities, corporations, insurance and advocacy organizations to outline the issues in a commentary published today in Science Translational Medicine.Tumor biomarker tests look at the genetic or molecular make-up of a tumor to determine whether the cancer is likely to progress, and if so, if it is likely to respond to treatment. If the test is good, it can help doctors decide when a patient can safely skip further therapy, or it can be used to direct which drug might be most likely to help. The result: “personalized medicine,” which means patients get treatments that benefit them specifically and they avoid treatments — including their costs and side effects — that are not likely to make a difference for them.The regulatory process, the research funding, the reimbursement, even the standards for journal publications for tumor biomarker tests are all meager compared to the robust support for drug development, the authors say.This creates a vicious cycle in which researchers and drug companies don’t invest in tumor biomarker research, tests are not fully evaluated in clinical trials, and tests with uncertain value in terms of predicting the success of treatment are published. This in turn means that few of these tests are included in evidence-based care guidelines, leaving health care professionals unsure of whether or how to use the test, and third-party payers unsure of how much to pay for them.The authors outline five recommendations and suggest that all five must be addressed to break the vicious cycle:1. Reform regulatory review of tumor biomarker tests 2. …

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Naked mole rat’s secret to staying cancer free

July 31, 2013 — Mice and rats have long since been a standard animal model for cancer research, mainly due to their short lifespan of four years on average and high incidence of cancer. Naked mole rats however, are a mystery among mammals. This social tiny African subterranean rodent has a maximum lifespan exceeding 30 years and most surprisingly, is cancer-resistant. The fact that so far, not a single incident of cancer has been detected makes the naked mole rat a fitting model for finding novel ways to fight cancer.Recently, a team of researchers from the University of Rochester in New York and the University of Haifa found the naked mole rat’s unique mechanism to staying cancer free- a super sugar called high-molecular-mass Hyaluronan (HMM-HA). They discovered that when secreted from the naked mole rat’s cells, HMM-HA prevents cells from overcrowding and forming tumors. “Contact inhibition, a powerful anticancer mechanism, discovered by the Rochester team, arresting cell growth when cells come into contact with each other, is lost in cancer cells,” explains Prof. Eviatar Nevo, from the Institute of Evolution at the University of Haifa, “The experiments showed that when HMM-HA was removed from naked mole rat cells, they became susceptible to tumors and lost their contact inhibition.”HMM-HA is a form of Hyaluronan- a long sugar polymer, naturally present as a lubricant in the extracellular matrix of the human body. It is commonly used in the treatment of arthritis or in anti-wrinkle skin care products. According to the current results, the naked mole rat cells secrete extremely high-molecular mass HA, which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole rat tissues, owing to a more robust synthesis by a protein called HAS2 and a decreased activity of HA-degrading enzymes. …

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Statins suppress Rett syndrome symptoms in mice

July 29, 2013 — Statins, a class of cholesterol-lowering drugs found in millions of medicine cabinets, may help treat Rett Syndrome, according to a study published today in Nature Genetics. The Rett Syndrome Research Trust (RSRT) funded this work with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation.Rett Syndrome is a neurological disorder that affects girls. A seemingly typical toddler begins to miss developmental milestones. A regression follows as young girls lose speech, mobility, and hand use. Many girls have seizures, orthopedic and severe digestive problems, as well as breathing and other autonomic impairments. Most live into adulthood and require total, round-the-clock care. Rett Syndrome affects about 1 in 10,000 girls born in the U.S. each year.The new study screened for randomly induced mutations in genes that modify the effect of the Rett gene, MECP2 (methyl-CpG-binding protein 2), in a mouse model. MECP2 turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes.The challenge of treating Rett Syndrome is what drove senior author Monica Justice, Ph.D., Professor in the Departments of Molecular and Human Genetics and Molecular Physiology and Biophysics at the Baylor College of Medicine, to look beyond MECP2, hoping to find new drug targets that might improve symptoms or even reverse the course of the disease. In 2007, Adrian Bird, Ph.D., Buchanan Professor of Genetics at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, showed that symptoms in mice are reversible regardless of the age of the animal.Exploring cholesterol metabolism in neurological diseases is an emerging area, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. …

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