Olfactory receptors in the skin: Sandalwood scent facilitates wound healing, skin regeneration

Skin cells possess an olfactory receptor for sandalwood scent, as researchers at the Ruhr-Universitt Bochum have discovered. Their data indicate that the cell proliferation increases and wound healing improves if those receptors are activated. This mechanism constitutes a possible starting point for new drugs and cosmetics. The team headed by Dr Daniela Busse and Prof Dr Dr Dr med habil Hanns Hatt from the Department for Cellphysiology published their report in the Journal of Investigative Dermatology.The nose is not the only place where olfactory receptors occurHumans have approximately 350 different types of olfactory receptors in the nose. The function of those receptors has also been shown to exist in, for example spermatozoa, the prostate, the intestine and the kidneys. The team from Bochum has now discovered them in keratinocytes — cells that form the outermost layer of the skin.Experiments with cultures of human skin cellsThe RUB researchers studied the olfactory receptor that occurs in the skin, namely OR2AT4, and discovered that it is activated by a synthetic sandalwood scent, so-called Sandalore. Sandalwood aroma is frequently used in incense sticks and is a popular component in perfumes. The activated OR2AT4 receptor triggers a calcium-dependent signal pathway. That pathway ensures an increased proliferation and a quicker migration of skin cells — processes which typically facilitate wound healing. In collaboration with the Dermatology Department at the University of Mnster, the cell physiologists from Bochum demonstrated that effect in skin cell cultures and skin explants.Additional olfactory receptors in skin detectedIn addition to OR2AT4, the RUB scientists have also found a variety of other olfactory receptors in the skin, the function of which they are planning to characterise more precisely. …

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Tumor suppressor gene linked to stem cells, cancer biologists report

Just as archeologists try to decipher ancient tablets to discern their meaning, UT Southwestern Medical Center cancer biologists are working to decode the purpose of an ancient gene considered one of the most important in cancer research.The p53 gene appears to be involved in signaling other cells instrumental in stopping tumor development. But the p53 gene predates cancer, so scientists are uncertain what its original function is.In trying to unravel the mystery, Dr. John Abrams, Professor of Cell Biology at UT Southwestern, and his team made a crucial new discovery — tying the p53 gene to stem cells. Specifically, his lab found that when cellular damage is present, the gene is hyperactive in stem cells, but not in other cells. The findings suggest p53’s tumor suppression ability may have evolved from its more ancient ability to regulate stem cell growth.”The discovery was that only the stem cells light up. None of the others do. The exciting implication is that we are able to understand the function of p53 in stem cells,” said Dr. Abrams, Chair of the Genetics and Development program in UT Southwestern’s Graduate School of Biomedical Sciences. “We may, in fact, have some important answers for how p53 suppresses tumors.”The findings appear online in the journal eLife, a joint initiative of the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust.p53 is one of the hardest working and most effective allies in the fight against cancer, said Dr. Abrams. …

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Plant growth enhanced through promotion of pore opening

By inducing the pore opening of leaves, researchers at Nagoya University’s ITbM developed a strategy for enhancing photosynthesis and plant growth, which may be applied to crops and fuel plants to support global food production and a sustainable low-carbon society.By determining the key factor in regulating photosynthesis and plant growth, Professor Toshinori Kinoshita, Dr. Yin Wang and co-workers at Nagoya University’s Institute of Transformative Bio-Molecules (WPI-ITbM) have succeeded in developing a method to increase photosynthesis (carbon dioxide uptake) and plant growth through the promotion of stomatal opening. The study was recently published in the Proceedings of the National Academy of Sciences (PNAS), is expected to contribute to the promotion of plant production and towards the development of a sustainable low-carbon society.Stomata are small pores located on the surface of leaves that control gas exchange with the external environment, and are the primary inlet for the uptake of carbon dioxide. “Stomatal resistance, which suppresses gas exchange through the stomata, is considered to be the major limiting factor for carbon dioxide uptake by plants during photosynthesis,” explains Professor Kinoshita, “very few reports have existed focusing on the induction of stomatal opening. Therefore, we decided to develop a method to manipulate stomatal opening in view of increasing photosynthesis (carbon dioxide uptake) and plant production.”Kinoshita’s group has already revealed some of the key factors that mediate stomatal opening. The plasma membrane proton (H+)-ATPase or proton pump, an enzyme creating electrochemical gradients in the cell membranes of plants, has been identified as one of the key components. “An increase in photosynthesis (carbon dioxide uptake) by approximately 15% and a 1.4~1.6 times increase in plant growth of Arabidopsis plants was observed by enhanced stomatal opening achieved through overexpression of the proton pump in guard cells that surround the stomata pore,” elaborates Professor Kinoshita.Professor Kinoshita and his co-workers envisage that application of this method will contribute to the increase in the production of crops and fuel plants as well as towards the reduction of carbon dioxide in the atmosphere. Professor Kinoshita states, “Identifying that the manipulation of stomatal opening is the key limiting factor in photosynthesis and plant growth enables us to consider strategies to solve current issues in food production and carbon emissions.”Story Source:The above story is based on materials provided by Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University. Note: Materials may be edited for content and length.

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Proteins that control energy use necessary to form stem cells

Two proteins that control how cells break down glucose play a key role in forming human stem cells, University of Washington researchers have found. The finding has implications for future work in both regenerative medicine and cancer therapy.A report on this research appears online March 20 in the CELL journal Stem Cell. The paper’s lead authors are Julie Mathieu, a postdoctoral fellow at the UW, and Wenyu Zhou, a former graduate student at UW and now a postdoctoral scholar at Stanford University. Hannele Ruohola-Baker, UW professor of biochemistry, is the paper’s senior author.The researchers changed mature human cells to an earlier stem cell-like state by inserting genes for four proteins. This technique is called reprogramming.These reprogrammed cells have the extraordinary ability to develop into any type of cell in the human body, a capacity called pluripotency. It is hoped that pluripotent stem cells, created from a person’s mature cells, will one day be used to form new tissues and organs to repair and replace those damaged by injury and disease.During reprogramming, the cells change gears. They shut down the metabolic pathway for generating energy from glucose. This pathway requires the presence of oxygen in mitochondria, the cell’s powerhouses. The cells then shift over to the glycolytic pathway that generates less energy but does not require the presence of oxygen.This shift may take place because, in nature, embryonic and tissue stem cells often must survive in low-oxygen conditions.This transition to a glycolytic state is of particular interest to cancer researchers as well. In many ways, cancer cells resemble stem cells. …

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Think it’s safe to type a quick text while walking? Think again

Texting and walking is a known danger, but Dietrich Jehle, professor of emergency medicine at the University at Buffalo, says distracted walking results in more injuries per mile than distracted driving.Consequences include bumping into walls, falling down stairs, tripping over clutter or stepping into traffic. The issue is so common that in London, bumpers were placed onto light posts along a frequented avenue to prevent people from slamming into them.”When texting, you’re not as in control with the complex actions of walking,” says Jehle, MD, who is also an attending physician at Erie County Medical Center, a regional trauma center in Western New York. “While talking on the phone is a distraction, texting is much more dangerous because you can’t see the path in front of you.”Though injuries from car accidents involving texting are often more severe, physical harm resulting from texting and walking occurs more frequently, Jehle says.Jehle explains that pedestrians face three types of distraction: manual, in which they are doing something else; visual, where they see something else; and cognitive, in which their mind is somewhere else.In his practice, Jehle has seen, first-hand, the rise of cell phone-related injuries.Tens of thousands of pedestrians are treated in emergency rooms across the nation each year, and Jehle believes as many as 10 percent of those visits result from accidents involving cell phones. He says the number of mishaps involving texting and walking is likely higher than official statistics suggest, as patients tend to underreport information about themselves when it involves a behavior that is embarrassing.Historically, pedestrian accidents affected children, the intoxicated or the elderly, says Jehle. However, cell phone related injuries have skyrocketed over the past 10 years, coinciding with the rise of smartphones.And with social media so pervasive, texting isn’t the only concern. It’s not uncommon to find a person walking, head down, scrolling through their Twitter feed or checking email.A study from Ohio State University found that the number of pedestrian ER visits for injuries related to cell phones tripled between 2004 and 2010 — even though the total number of pedestrian injuries dropped during that period.The study also found that the age group most at risk for cell-phone related injuries while walking are adults under 30 — chiefly those between the ages of 16 and 25.Laws discouraging texting and walking have been written up, but are strongly voted down, says Jehle. His suggestion: mobile applications that text via voice command or use the phone’s camera to display the approaching streetscape while pedestrians text.Although Jehle prefers that pedestrians keep their eyes off of their phones until they reach their destination, he says the apps are better than nothing at all.Story Source:The above story is based on materials provided by University at Buffalo. The original article was written by Marcene Robinson. Note: Materials may be edited for content and length.

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3-D imaging sheds light on Apert syndrome development

Three dimensional imaging of two different mouse models of Apert Syndrome shows that cranial deformation begins before birth and continues, worsening with time, according to a team of researchers who studied mice to better understand and treat the disorder in humans.Apert Syndrome is caused by mutations in FGFR2 — fibroblast growth factor receptor 2 — a gene, which usually produces a protein that functions in cell division, regulation of cell growth and maturation, formation of blood vessels, wound healing, and embryonic development. With certain mutations, this gene causes the bones in the skull to fuse together early, beginning in the fetus. These mutations also cause mid-facial deformation, a variety of neural, limb and tissue malformations and may lead to cognitive impairment.Understanding the growth pattern of the head in an individual, the ability to anticipate where the bones will fuse and grow next, and using simulations “could contribute to improved patient-centered outcomes either through changes in surgical approach, or through more realistic modeling and expectation of surgical outcome,” the researchers said in today’s (Feb. 28) issue of BMC Developmental Biology.Joan T. Richtsmeier, Distinguished Professor of Anthropology, Penn State, and her team looked at two sets of mice, each having a different mutation that causes Apert Syndrome in humans and causes similar cranial problems in the mice. They checked bone formation and the fusing of sutures, soft tissue that usually exists between bones n the skull, in the mice at 17.5 days after conception and at birth — 19 to 21 days after conception.”It would be difficult, actually impossible, to observe and score the exact processes and timing of abnormal suture closure in humans as the disease is usually diagnosed after suture closure has occurred,” said Richtsmeier. “With these mice, we can do this at the anatomical level by visualizing the sutures prenatally using micro-computed tomography — 3-D X-rays — or at the mechanistic level by using immunohistochemistry, or other approaches to see what the cells are doing as the sutures close.”The researchers found that both sets of mice differed in cranial formation from their littermates that were not carrying the mutation and that they differed from each other. They also found that the changes in suture closure in the head progressed from 17.5 days to birth, so that the heads of newborn mice looked very different at birth than they did when first imaged prenatally.Apert syndrome also causes early closure of the sutures between bones in the face. Early fusion of bones of the skull and of the face makes it impossible for the head to grow in the typical fashion. The researchers found that the changed growth pattern contributes significantly to continuing skull deformation and facial deformation that is initiated prenatally and increases over time.”Currently, the only option for people with Apert syndrome is rather significant reconstructive surgery, sometimes successive planned surgeries that occur throughout infancy and childhood and into adulthood,” said Richtsmeier. …

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Why dark chocolate is good for your heart

It might seem too good to be true, but dark chocolate is good for you and scientists now know why. Dark chocolate helps restore flexibility to arteries while also preventing white blood cells from sticking to the walls of blood vessels. Both arterial stiffness and white blood cell adhesion are known factors that play a significant role in atherosclerosis. What’s more, the scientists also found that increasing the flavanol content of dark chocolate did not change this effect. This discovery was published in the March 2014 issue of The FASEB Journal.”We provide a more complete picture of the impact of chocolate consumption in vascular health and show that increasing flavanol content has no added beneficial effect on vascular health,” said Diederik Esser, Ph.D., a researcher involved in the work from the Top Institute Food and Nutrition and Wageningen University, Division of Human Nutrition in Wageningen, The Netherlands. “However, this increased flavanol content clearly affected taste and thereby the motivation to eat these chocolates. So the dark side of chocolate is a healthy one.”To make this discovery, Esser and colleagues analyzed 44 middle-aged overweight men over two periods of four weeks as they consumed 70 grams of chocolate per day. Study participants received either specially produced dark chocolate with high flavanol content or chocolate that was regularly produced. Both chocolates had a similar cocoa mass content. Before and after both intervention periods, researchers performed a variety of measurements that are important indicators of vascular health. …

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Brain cell activity regulates Alzheimer’s protein

Increased brain cell activity boosts brain fluid levels of a protein linked to Alzheimer’s disease, according to new research from scientists at Washington University School of Medicine in St. Louis.Tau protein is the main component of neurofibrillary tangles, one of the hallmarks of Alzheimer’s disease. It has been linked to other neurodegenerative disorders, including frontotemporal dementia, supranuclear palsy and corticobasal degeneration.”Healthy brain cells normally release tau into the cerebrospinal fluid and the interstitial fluid that surrounds them, but this is the first time we’ve linked that release in living animals to brain cell activity,” said senior author David M. Holtzman, MD. “Understanding this link should help advance our efforts to treat Alzheimer’s and other neurodegenerative disorders associated with the tau protein.The study appears online in The Journal of Experimental Medicine.Tau protein stabilizes microtubules, which are long columns that transport supplies from the center of the cell to the distant ends of the cell’s branches. Some tau in the cell is not bound to microtubules. This tau can become altered and clump together inside brain cells, forming structures called tangles. Scientists have tracked the spread of these clumps through brain networks in animal models.”In Alzheimer’s disease, you first see clumps of tau in a region called the entorhinal cortex, and then in the hippocampus, and it continues to spread through the brain in a regular pattern,” said Holtzman, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. …

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New ideas change your brain cells, research shows

A new University of British Columbia study identifies an important molecular change that occurs in the brain when we learn and remember.Published this month in Nature Neuroscience, the research shows that learning stimulates our brain cells in a manner that causes a small fatty acid to attach to delta-catenin, a protein in the brain. This biochemical modification is essential in producing the changes in brain cell connectivity associated with learning, the study finds.In animal models, the scientists found almost twice the amount of modified delta-catenin in the brain after learning about new environments. While delta-catenin has previously been linked to learning, this study is the first to describe the protein’s role in the molecular mechanism behind memory formation.”More work is needed, but this discovery gives us a much better understanding of the tools our brains use to learn and remember, and provides insight into how these processes become disrupted in neurological diseases,” says co-author Shernaz Bamji, an associate professor in UBC’s Life Sciences Institute.It may also provide an explanation for some mental disabilities, the researchers say. People born without the gene have a severe form of mental retardation called Cri-du-chat syndrome, a rare genetic disorder named for the high-pitched cat-like cry of affected infants. Disruption of the delta-catenin gene has also been observed in some patients with schizophrenia.”Brain activity can change both the structure of this protein, as well as its function,” says Stefano Brigidi, first author of the article and a PhD candidate Bamji’s laboratory. “When we introduced a mutation that blocked the biochemical modification that occurs in healthy subjects, we abolished the structural changes in brain’s cells that are known to be important for memory formation.”Story Source:The above story is based on materials provided by University of British Columbia. Note: Materials may be edited for content and length.

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Molecular ‘cocktail’ transforms skin cells into beating heart cells

The power of regenerative medicine appears to have turned science fiction into scientific reality — by allowing scientists to transform skin cells into cells that closely resemble beating heart cells. However, the methods required are complex, and the transformation is often incomplete. But now, scientists at the Gladstone Institutes have devised a new method that allows for the more efficient — and, importantly, more complete — reprogramming of skin cells into cells that are virtually indistinguishable from heart muscle cells. These findings, based on animal models and described in the latest issue of Cell Reports, offer new-found optimism in the hunt for a way to regenerate muscle lost in a heart attack.Heart disease is the world’s leading cause of death, but recent advances in science and medicine have improved the chances of surviving a heart attack. In the United States alone, nearly 1 million people have survived an attack, but are living with heart failure — a chronic condition in which the heart, having lost muscle during the attack, does not beat at full capacity. So, scientists have begun to look toward cellular reprogramming as a way to regenerate this damaged heart muscle.The reprogramming of skin cells into heart cells, an approach pioneered by Gladstone Investigator, Deepak Srivastava, MD, has required the insertion of several genetic factors to spur the reprogramming process. However, scientists have recognized potential problems with scaling this gene-based method into successful therapies. So some experts, including Gladstone Senior Investigator Sheng Ding, PhD, have taken a somewhat different approach.”Scientists have previously shown that the insertion of between four and seven genetic factors can result in a skin cell being directly reprogrammed into a beating heart cell,” explained Dr. Ding, the paper’s senior author and a professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “But in my lab, we set out to see if we could perform a similar transformation by eliminating — or at least reducing — the reliance on this type of genetic manipulation.”To that effect, the research team used skin cells extracted from adult mice to screen for chemical compounds, so-called ‘small molecules,’ that could replace the genetic factors. …

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Clutter cutter: Computer modeling used to understand how messy cells contribute to cancer

Life can be messy at all scales, requiring different organizational strategies — from cleaning the house, to removing damaged or expired cells from the body to avoid cancer progression.In a messy house, people use computers to manage paper and photo clutter; companies use computer systems to track their inventory. Now a team of researchers at Vanderbilt University in Nashville, Tenn., is taking a similar approach to cell-molecular inventory control for cancer. They have created computer models, using their programming framework (PySB), which enable them to explore the complex biochemical processes that drive cancer growth.”Our hypothesis is that understanding how the cell uses their protein inventory will lead to understanding why cells dysregulate and become carcinogenic. We expect model outputs will lead to novel, targeted cancer therapies — possibly by 2019,” explained researcher Carlos F. Lopez, who will present the work at the 58th annual Biophysical Society Meeting in San Francisco, Feb.15-19.Lopez is interested in understanding how cells in multicellular organisms engage programmed cell death — so-called “cell suicide” — for cellular removal. It is a natural part of many cells’ life cycle.When cancer cells avoid programmed cell death, uncontrolled growth fuels tumor progression. The Vanderbilt team expects their computer models to identify what goes wrong in these cases, at a speed and scale never before possible. Lopez noted: “We are bridging the nanoscale molecular-level biochemical interactions with the macroscale cancer tumor outcomes, which is a huge range in scales. Most people don’t realize this, but molecular chemical reactions at the nanometer and nanosecond level affect things that happen at the timescale level of years — nine orders of magnitude in space and time! For comparison, a nanosecond is to a second like a second is to one century.”Rather than listing the cellular biochemical reactions by hand, PySB enables the researchers to “write” the biochemical cellular processes as computer programs. …

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Tinnitus study signals new advance in understanding link between exposure to loud sounds and hearing loss

Leicester research reveals why hearing loss is correlated with auditory signals failing to get transmitted along the auditory nerve.A research team investigating tinnitus, from the University of Leicester, has revealed new insights into the link between the exposure to loud sounds and hearing loss.Their study, published this week in J Neurosci,, helps to understand how damage to myelin — a protection sheet around cells — alters the transmission of auditory signals occurring during hearing loss.The three-year study was derived from a PhD studentship funded by Action on Hearing Loss. It was led by Dr Martine Hamann, Lecturer in Neurosciences at the University’s Department of Cell Physiology and Pharmacology.Dr Hamann said: “A previous publication has shown that exposure to loud sound damages the myelin which is the protection sheet around cells. We have now shown the closer links between a deficit in the “myelin” sheath surrounding the auditory nerve and hearing loss. It becomes obvious why hearing loss is correlated with auditory signals failing to get transmitted along the auditory nerve.”Understanding cellular mechanisms behind hearing loss and tinnitus allows for developing strategies to prevent or alleviate the symptoms of deafness or tinnitus — for example by using specific drug therapies.”This new study is particularly important because it allows us to understand the pathway from exposure to loud sound leading to the hearing loss. We now have a better idea about the mechanisms behind the auditory signals failing to get transmitted accurately from the cochlea to the brain. Consequently, targeting myelin and promoting its repair after exposure to loud sound could be proven effective in noise induced hearing loss.”Dr Hamann added that getting to dissect the cellular mechanisms underlying hearing loss is likely to bring a very significant healthcare benefit to a wide population.She said: “Understanding mechanisms responsible for hearing loss represents a significant unmet need that is likely to increase as the incidence of the disorder increases due to an aging population and the increasing impact of recreational and workplace noise.”I am very excited by this research. The work will help prevention as well as progression into finding appropriate cures for hearing loss and possibly tinnitus developing from hearing loss.”Dr Hamann’s team at the University of Leicester included Thomas Tagoe who performed all the electrophysiological experiments, Matt Barker and Natalie Allcock who performed the electron microscopy and the imaging experiments. Andrew Jones, a project student in the lab performed computer modelling.Dr Ralph Holme Action on Hearing Loss’ Head of Biomedical Research says: ”We know that exposure to loud noise can lead to hearing loss. Protecting your ears should always be the first line of defence, but medical treatments to combat unavoidable or accidental exposure to noise are also urgently needed. The research we have been funding at University of Leicester makes an important contribution to increasing our understanding of how noise damages the hearing system — knowledge we hope will ultimately lead to medical treatments for this common type of hearing loss.”Story Source:The above story is based on materials provided by University of Leicester. …

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Nanomotors are controlled, for the first time, inside living cells

For the first time, a team of chemists and engineers at Penn State University have placed tiny synthetic motors inside live human cells, propelled them with ultrasonic waves and steered them magnetically. It’s not exactly “Fantastic Voyage,” but it’s close. The nanomotors, which are rocket-shaped metal particles, move around inside the cells, spinning and battering against the cell membrane.”As these nanomotors move around and bump into structures inside the cells, the live cells show internal mechanical responses that no one has seen before,” said Tom Mallouk, Evan Pugh Professor of Materials Chemistry and Physics at Penn State. “This research is a vivid demonstration that it may be possible to use synthetic nanomotors to study cell biology in new ways. We might be able to use nanomotors to treat cancer and other diseases by mechanically manipulating cells from the inside. Nanomotors could perform intracellular surgery and deliver drugs noninvasively to living tissues.”The researchers’ findings will be published in Angewandte Chemie International Edition on 10 February 2014. In addition to Mallouk, co-authors include Penn State researchers Wei Wang, Sixing Li, Suzanne Ahmed, and Tony Jun Huang, as well as Lamar Mair of Weinberg Medical Physics in Maryland U.S.A.Up until now, Mallouk said, nanomotors have been studied only “in vitro” in a laboratory apparatus, not in living human cells. Chemically powered nanomotors first were developed ten years ago at Penn State by a team that included chemist Ayusman Sen and physicist Vincent Crespi, in addition to Mallouk. “Our first-generation motors required toxic fuels and they would not move in biological fluid, so we couldn’t study them in human cells,” Mallouk said. “That limitation was a serious problem.” When Mallouk and French physicist Mauricio Hoyos discovered that nanomotors could be powered by ultrasonic waves, the door was open to studying the motors in living systems.For their experiments, the team uses HeLa cells, an immortal line of human cervical cancer cells that typically is used in research studies. …

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New combined therapy to treat cancer proposed

A large part of the effort dedicated to cancer research is directed towards the search for combinations of existing drugs — many of which have already been introduced into clinical practice — that permit higher overall survival rates and improvements in the quality of life of cancer patients.Marcos Malumbres, a researcher at the Spanish National Cancer Research Centre (CNIO), and his team have discovered how etoposide — a drug widely used in the treatment of lung and testicular cancers, leukemias and brain tumours — could increase its efficiency and specificity in combination with other compounds that interfere with cell division. The results are published today in the journal Cell Reports.The study has been carried out jointly with the Groups of scar Fernndez-Capetillo and Javier Muoz’s at the CNIO, and with Hiroyuki Yamano’s team at the University College London’s Cancer Institute.Etoposide, a compound obtained from a variant of the mandrake plant, blocks a protein needed for DNA repair during cell division: the Topoisomerase II (TOP2) enzyme. This blocking action increases the damage to genetic material and causes cell death.Malumbres explains that: “Etoposide affects tumour cells, which are the ones that divide the most and that need TOP2 to repair their DNA, but it also affects healthy cells,” adding that: “this lack of specificity causes alterations in healthy tissues that translate into secondary illnesses and toxicity for the organism.”The researchers point out that “the challenge now is to improve the drug’s therapeutic window, so that the dose range becomes more effective without increasing toxicity and the secondary effects associated with the treatment.”TREATMENTS TARGETING TUMOUR CELLSUp until now, data on molecular pathways that govern topoisomerase levels in cells were scarce and did not clarify much. Now, Manuel Eguren, a researcher on Malumbres’s team, has, for the first time in animal models and in human cell lines, related TOP2 with the cell division protein regulator Cdh1, so that a decrease in Cdh1 activity increases TOP2 levels in cells.This study allows for the identification of the formula for increasing TOP2 levels in cells. The research team therefore proposes a new form of effective tumour treatment: the combination of Cdh1 inhibitors (amongst which can be found a substance called proTAME) with etoposide.”proTAME — which is undergoing preclinical trials to inhibit tumour cell division — could increase the effectiveness of etoposide in cancer cells, those that divide the most and those that therefore have a greater dependency on TOP2 to maintain DNA integrity,” say the researchers. This combination of drugs could maximise the anti-neoplastic effect of etoposide and would imply a reduction in the dose and lower toxicity.Previous studies further indicate that Cdh1 is inactive in some patients due to various oncogenic mutations. “Our data suggest that patient stratification based on their tumours Cdh1 status could improve the effect of etoposide in these patients’ treatment.”The next step for Malumbres’ team is to study this new drug cocktail in patients and to investigate the tumours in which this new therapeutic strategy would be most effective.Story Source:The above story is based on materials provided by Centro Nacional de Investigaciones Oncologicas (CNIO). Note: Materials may be edited for content and length.

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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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Protocol developed to harvest mouse cell lines for melanoma research

Dartmouth researchers have developed a protocol that permits cells harvested from melanoma tumors in mice to grow readily in cell culture. Their findings were published in an article, Multiple murine BRafV600E melanoma cell lines with sensitivity to PLX4032, in the January 25, 2014 issue of Pigment Cell & Melanoma Research.”We anticipate that these cell lines will be extremely useful to many investigators who use mouse melanoma as a model system,” said Constance E. Brinckerhoff, PhD, professor of Medicine and of Biochemistry at the Geisel School of Medicine at Dartmouth College and a member of the Norris Cotton Cancer Center (NCCC) Mechanism Research Program.There is a lack of mouse cell lines that harbor the BRAF mutation that is so prevalent in human melanomas, and the cell lines that are available grow slowly in culture and are not representative of human melanoma cell lines. Detailed experiments on molecular mechanisms controlling mouse cell line behavior have been difficult because the currently available mouse cell lines do not grow well in culture.The Geisel researchers are the first to have developed a protocol that permits mouse melanoma cells to be harvested from tumors in the mice and to grow readily in cell culture. Importantly, these cell lines are genetically compatible with a strain of mice that are immunologically competent, while human cells need to be placed into immunologically weakened mice in order to grow. Thus, the ability to study these mouse melanoma cell lines both in culture and in mice with an intact immune system is an experimental advantage.Story Source:The above story is based on materials provided by Norris Cotton Cancer CenterDartmouth-Hitchcock Medical Center. Note: Materials may be edited for content and length.

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Impaired cell division leads to neuronal disorder

Prof. Erich Nigg and his research group at the Biozentrum of the University of Basel have discovered an amino acid signal essential for error-free cell division. This signal regulates the number of centrosomes in the cell, and its absence results in the development of pathologically altered cells. Remarkably, such altered cells are found in people with a neurodevelopmental disorder, called autosomal recessive primary microcephaly. The results of these investigations have been published in the current issue of the US journal Current Biology.Normal separation of chromosomes (blue) with two centrosomes (red) in a bipolar spindel apparatus (green). Flawed separation of chromosomes (blue) with several centrosomes (red) in a multipolar spindel apparatus (green).Cell division is the basis of all life. Of central importance is the error-free segregation of genetic material, the chromosomes. A flawless division process is a prerequisite for the development of healthy, new cells, whilst errors in cell division can cause illnesses such as cancer. The centrosome, a tiny cell organelle, plays a decisive role in this process.Prof. Erich Nigg’s research group at the Biozentrum of the University of Basel has investigated an important step in cell division: the duplication of the centrosome and its role in the correct segregation of the chromosomes into two daughter cells. …

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Up close and 3-dimensional: HIV caught in the act inside the gut

HIV infection has many unhealthy consequences on the body, but in particular it messes up the gut. The human intestine has the highest concentration of HIV target cells, the majority of which are destroyed within days of infection, and before CD4 T cell counts drop measurably in the blood. A study published on January 30th in PLOS Pathogens reports the first three-dimensional ultra-structural study of HIV infection in vivo. Not only does it reveal details on how the virus quickly infects immune cells in the gut, using them as virus-producing factories, but it also highlights where the virus “hides out” deep within the intestinal tissue.Pamela Bjorkman, from the Howard Hughes Medical Institute and the California Institute of Technology, USA, and colleagues used electron tomography for a high-resolution study of HIV virus in the guts of “humanized” mice, whose immune system is made up to a large degree of human cells. They infected these “BLT mice” (so-called because they have human bone marrow, thymus, and liver cells) with HIV virus and developed methods that allowed them to safely examine and visualize the three-dimensional architecture of infected parts of the gut.They saw HIV-infected human immune cells, caught virus particles in the act of budding from such cells, and also found groups of free immature and mature viruses. For one infected host cell (turned HIV factory) the researchers counted 63 virus particles it had likely released. The actual number is almost certainly much higher, because the method can only visualize virus particles surrounding the host cell within a relatively small part of the tissue. Nevertheless, they discovered that groups of viruses that were farther from the host cell were more mature than those closer to it, which suggested that the host cell releases new virus in a series of “semi-synchronized” waves.Among the samples, the researchers found some where viruses released from one infected cell seemed directly to attach to a neighboring host cell, presumably infecting it. In addition to such “virological synapses,” they also observed free virus particles that appear to have covered some distance between their “mother” cell and the cell that would become their target to infect.These images provide the first 3D ultrastructural details on HIV infection and virus production in a setting that closely resembles the gut of human patients. Some results confirm earlier findings from in vitro experiments — cells grown and infected in a petri dish — but others are seen for the first time and advance the understanding of how HIV infection spreads in real life.”To me, an important finding is that the majority of the viral transmission events within tissue involved free virus rather than virological synapses,” says Bjorkman. …

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Physical cues help mature cells revert into embryonic-like stem cells

Oct. 21, 2013 — Bioengineers at the University of California, Berkeley, have shown that physical cues can replace certain chemicals when nudging mature cells back to a pluripotent stage, capable of becoming any cell type in the body.The researchers grew fibroblasts cells taken from human skin and mouse ears on surfaces with parallel grooves measuring 10 micrometers wide and 3 micrometers high. After two weeks of culture in a special cocktail used to reprogram mature cells, the researchers found a four-fold increase in the number of cells that reverted back to an embryonic-like state compared with cells grown on a flat surface. Growing cells in scaffolds of nanofibers aligned in parallel had similar effects.The study, published online Sunday, Oct. 20, in the journal Nature Materials, could significantly enhance the process of reprogramming adult cells into embryonic-like stem cells that can differentiate, or develop, into any type of tissue that makes up our bodies.The 2012 Nobel Prize in Physiology or Medicine was awarded to scientists who discovered that it was possible to reprogram cells using biochemical compounds and proteins that regulate gene expression. These induced pluripotent stem cells have since become a research mainstay in regenerative medicine, disease modeling and drug screening.”Our study demonstrates for the first time that the physical features of biomaterials can replace some of these biochemical factors and regulate the memory of a cell’s identity,” said study principal investigator Song Li, UC Berkeley professor of bioengineering. “We show that biophysical signals can be converted into intracellular chemical signals that coax cells to change.”The current process for reprogramming cells relies on a formula that uses a virus to introduce gene-altering proteins into mature cells. Certain chemical compounds, including valproic acid, that can dramatically affect global DNA structure and expression are also used to boost the efficiency of the reprogramming process.”The concern with current methods is the low efficiency at which cells actually reprogram and the unpredictable long-term effects of certain imposed genetic or chemical manipulations,” said study lead author Timothy Downing, who did this research as a graduate student in the UC Berkeley-UC San Francisco Joint Graduate Program in Bioengineering. “For instance, valproic acid is a potent chemical that drastically alters the cell’s epigenetic state and can cause unintended changes inside the cell. Given this, many people have been looking at different ways to improve various aspects of the reprogramming process.”Previous studies have shown that physical and mechanical forces can influence cell fate, but the effect on epigenetic state and cell reprogramming had not been clear.The new study found that culturing cells on micro-grooved biomaterials improved the quality and consistency of the reprogramming process, and was just as effective as valproic acid.”Cells elongate, for example, as they migrate throughout the body,” said Downing, who is now a research scientist in Li’s lab. …

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Watching the heartbeat of molecules

Oct. 17, 2013 — A team of scientists around Prof. Theodor W. Hänsch and Dr. Nathalie Picqué at the Laser Spectroscopy Division of the Max Planck Institute of Quantum Optics (Garching), in a collaboration with the Ludwig-Maximilians-Universität Munich and the Institut des Sciences Moléculaires d’Orsay (France) now report on a new method of rapidly identifying different molecular species under a microscope. Their technique of coherent Raman spectro-imaging with two laser frequency combs takes a big step towards the holy grail of real-time label-free biomolecular imaging, as published recently in Nature.How does a drug influence a living cell? In which way can signal molecules change the cell metabolism? Such questions are difficult to answer, since cells are highly complex “chemical factories” which constantly manufacture and break down a large number of different molecular species. Biologists have learnt to attach fluorescent dye labels to certain proteins so that they can distinguish them under a microscope. However, such labels can alter the cell functions. …

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