Fund for Scientific Research
Fund for Scientific Research
News Article | April 17, 2017
Drug cocktails such as those for treating cancer, like the alcoholic versions offered at the local bar, are best when the proper ingredients are mixed in the right proportions. And like the cocktails we normally drink, the combination of ingredients can be better than the sum of its parts -- or it can leave us with unwanted side effects. A new model developed in the group of Prof. Uri Alon of the Weizmann Institute of Science's Molecular Cell Biology Department can simplify the process of identifying the optimal blends for drug cocktails - even when a large number of ingredients is called for. Drug cocktails - both antibiotic and anti-cancer - are increasingly used, among other things, because simultaneously attacking pathogenic cells with several different methods can reduce the risk of drug resistance. And doctors and pharmaceutical companies are interested in the advance of drug "mixology" because it can help create novel applications for existing drugs, since new ones are costly to develop and slow to reach the market. But adding drugs together does not generally result just in the sum of their effects. For instance, one drug can alert mechanisms in a cell that pump the other drugs out of the cell, thus changing the dose at which the other drugs will be effective. Conversely, side effects can add up, so researchers often want to identify the lowest possible dose of any given drug. And with typically four or more drugs added together in chemotherapy cocktails, the number of possible combinations and doses is astronomical: It would be impossible to test them all to arrive at the optimal mix. This hurdle is known as the combinatorial explosion problem. Because of the combinatorial explosion problem, say research students Anat Zimmer and Itay Katzir, who led the study, drug cocktails are often concocted without any good way of predicting the end result. Zimmer, Katzir and Alon developed a method that bypasses the need for an astronomical number of measurements. Their method requires only a small number of measurements on drug pairs. The tests are conducted on human cancer cells or bacteria grown in lab dishes. The group tested each drug - separately and in pairs - to understand the effects at several different doses. This enabled the researchers to determine how drug A affects the actions of B, and vice versa, and the new mathematical model the group developed was then extrapolated to predict the interactions among three, four and more drugs in combination. Further testing showed that the model performs better than existing methods of dealing with the combinatorial explosion problem. Thus researchers using the model would not need to test every possible combination to arrive at the optimal doses in drug cocktails. "There is an urgent demand for methods that can predict how drug cocktails will work," says Katzir. "This model may take much of the expensive guesswork out of the process of developing such cocktails." "The model might prove especially useful for personalized medicine - for example, in cancer -because each tumor can react differently to the same drugs," adds Zimmer. "It provides a way to mix that perfect cocktail without having to try out all of the possible combinations." Drug cocktails such as those for treating cancer, like the alcoholic versions offered at the local bar, are best when the proper ingredients are mixed in the right proportions. And like the cocktails we normally drink, the combination of ingredients can be better than the sum of its parts -- or it can leave us with unwanted side effects. A new model developed in the group of Prof. Uri Alon of the Weizmann Institute of Science's Molecular Cell Biology Department can simplify the process of identifying the optimal blends for drug cocktails - even when a large number of ingredients is called for. Drug cocktails - both antibiotic and anti-cancer - are increasingly used, among other things, because simultaneously attacking pathogenic cells with several different methods can reduce the risk of drug resistance. And doctors and pharmaceutical companies are interested in the advance of drug "mixology" because it can help create novel applications for existing drugs, since new ones are costly to develop and slow to reach the market. But adding drugs together does not generally result just in the sum of their effects. For instance, one drug can alert mechanisms in a cell that pump the other drugs out of the cell, thus changing the dose at which the other drugs will be effective. Conversely, side effects can add up, so researchers often want to identify the lowest possible dose of any given drug. And with typically four or more drugs added together in chemotherapy cocktails, the number of possible combinations and doses is astronomical: It would be impossible to test them all to arrive at the optimal mix. This hurdle is known as the combinatorial explosion problem. Because of the combinatorial explosion problem, say research students Anat Zimmer and Itay Katzir, who led the study, drug cocktails are often concocted without any good way of predicting the end result. Zimmer, Katzir and Alon developed a method that bypasses the need for an astronomical number of measurements. Their method requires only a small number of measurements on drug pairs. The tests are conducted on human cancer cells or bacteria grown in lab dishes. The group tested each drug - separately and in pairs - to understand the effects at several different doses. This enabled the researchers to determine how drug A affects the actions of B, and vice versa, and the new mathematical model the group developed was then extrapolated to predict the interactions among three, four and more drugs in combination. Further testing showed that the model performs better than existing methods of dealing with the combinatorial explosion problem. Thus researchers using the model would not need to test every possible combination to arrive at the optimal doses in drug cocktails. "There is an urgent demand for methods that can predict how drug cocktails will work," says Katzir. "This model may take much of the expensive guesswork out of the process of developing such cocktails." "The model might prove especially useful for personalized medicine - for example, in cancer -because each tumor can react differently to the same drugs," adds Zimmer. "It provides a way to mix that perfect cocktail without having to try out all of the possible combinations." Prof. Uri Alon's research is supported by the Benoziyo Endowment Fund for the Advancement of Science; the David and Fela Shapell Family Foundation INCPM Fund for Preclinical Studies; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Gurwin Family Fund for Scientific Research; the Kahn Foundation; the Mauerberger Foundation Fund; Katy and Gary Leff, Calabasas, CA; and Dr. Miriam Netzer, Forest Hills, NY. Prof. Alon is the incumbent of the Abisch-Frenkel Professorial Chair. The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
News Article | April 26, 2017
Innovations in stone knapping technology during the South African Middle Stone Age enabled the creation of early projectile weapons, according to a study published April 26, 2017 in the open-access journal PLOS ONE by Veerle Rots from University of Liège, Belgium, and colleagues. The South African Middle Stone Age (MSA) is considered a period of major technological advancement, with hunter-gatherers introducing new manipulative techniques using heat and pressure to create stone projectile weapons. However, the timing and location of these developments is a topic of much debate. The authors of the present study examined 25 weapon point fragments excavated from the Sibudu Cave site, analyzing their technological and functional differences and comparing them with reference samples produced for the purpose by an experienced knapper. Some of the points had two faces, a likely result of applying pressure to both sides. Some had serrations, or jagged edges, that were likely produced by a technique known as pressure flaking. The researchers found that 14 of the 25 point fragments bore evidence of impact-related damage, animal residues, and wear features that strongly indicated that these points may have been were used for hunting. Examination of the impact-related fractures and the distribution of the points indicated that these points may have been attached to handles to form projectile weapons and that these weapons were projected from a distance, most likely with a flexible spear-thrower or a bow. While further research would help to confirm the timeline and development of stone knapping techniques, the new Sibudu Cave site data may push back the evidence for the use of pressure flaking during the MSA to 77,000 years ago. The authors note that these findings highlight the diversity of technical innovations adopted by southern African MSA humans. In your coverage please use this URL to provide access to the freely available article in PLOS ONE: http://journals. Citation: Rots V, Lentfer C, Schmid VC, Porraz G, Conard NJ (2017) Pressure flaking to serrate bifacial points for the hunt during the MIS5 at Sibudu Cave (South Africa). PLoS ONE 12(4): e0175151. doi:10.1371/journal.pone.0175151 Funding: The functional research at Sibudu Cave is funded by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013), ERC Grant Agreement Nr. 312283, V. Rots (http://www. ). Veerle Rots is also indebted to the Fund for Scientific Research (FNRS-FRS, CQ2011) (www1.frs-fnrs.be/). The excavation and archaeological research at Sibudu Cave is financed by the Heidelberger Akademie der Wissenschaft (The Role of Culture in Early Expansion of Humans) (http://www. ), the Tübingen Senckenberg Center for Human Evolution and Paleoecology (http://www. ), and the German research Foundation (DFG) grant (CO 226/27-1) (http://www. ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
News Article | April 30, 2017
Humans mastered complex weapons-creating techniques much earlier than previously suspected, some 77,000 years ago, Belgium researchers say. The researchers from the University of Liège examined 25 weapons fragments found at the Sibudu Cave site in South Africa, dating back to the Middle Stone Age, which began 300,000 years ago and heralded technological advancements for hunter-gatherer groups. “The South African [Middle Stone Age] has become an ideal canvas for the development and elaboration of models helping us to understand the first societies of anatomically modern humans, before their dispersal on the Eurasian continent,” the researchers said. Professor Veerle Rots at the university’s Fund for Scientific Research said humans developed the “pressure flaking” technique, giving them more control over fashioning sharp-edged weapons. The pressure flaking technique involves using a pointed bone tool to remove small flakes of rock from a sharpened stone, producing not only sharp edges but serrated edges as well. In a study published in Plos One, the researchers said the technique was developed earlier than previously suspected, highlighting “the diversity of the technical innovations adopted by southern African [Middle Stone Age] populations.” “The combination of technological, wear and residue evidence allowed us to confirm that the serration was manufactured with bone compressors and that the serrated points were mounted with a composite adhesive as the tips of projectiles used in hunting activities,” an abstract of the study said. The researchers found the Sibudu weapons in 2013 and 2014 in a cave about 9 miles from South Africa’s Indian Ocean coast, in an area protected by a rock shelter along the uThongathi River. The pressure flaking technique also has been found elsewhere, but the artifacts were more recent, as little as 20,000 years old in Europe. The researchers said the serration was not uniform, with some of the specimens showing deep notches and others showing very shallow indentations, possibly indicating the specimens were put to different uses. The weapons showed signs of having been attached to wooden shafts, apparently to make spears or arrows, the researchers said. Some had two sharpened edges. Fourteen of the 25 stone weapons recovered showed evidence they had been used in hunting, indicating "specialized hunting technology was used in South Africa before 77,000 years ago," Rots told Live Science in an email. The publication Archaeology notes stone toolmaking is considered a defining characteristic of humans but a discovery earlier this year indicated such tools predated the first known humans. A 2015 Stony Brook University study found such tools at a site in Kenya that date to 3.3 million years ago, predating Homo habilis by some 700,000 years. Recent research indicates other primates also use stone tools. Wild bearded capuchin monkeys in Brazil break off sharp-edged stones, indicating hominids didn’t need opposable thumbs to get started as toolmakers, research published in Nature last November surmised. "We discovered that some of the stone flakes produced accidentally by these capuchin monkeys were very similar to Oldowan stone tools," said Tiago Falótico, a researcher at the University of São Paulo's Psychology Institute and one of the study’s authors. "When sharp-edged flakes are found at an archeological site, it's usually easier to attribute them to hominins because the same digs generally also turn up many stone cores and signs of human occupation, such as fires. However, when they're found in isolation with few or no other archeological artifacts, we should bear in mind that they might not necessarily have been produced by human ancestors." Hunter-Gatherers Experimented With Farming In Turkey Before Migrating To Europe
News Article | December 5, 2016
Combination drug treatments have become successful at long-term control of HIV infection, but the goal of totally wiping out the virus and curing patients has so far been stymied by HIV's ability to hide out in cells and become dormant for long periods of time. Now a new study on HIV's close cousin, simian immunodeficiency virus (SIV), in macaques finds that a proposed curative strategy could backfire and make things worse if the virus is in fact lurking in the brain. One of the proposed curative strategies for HIV, known as "shock and kill," first uses so-called latency-reversing agents to wake up dormant viruses in the body, making them vulnerable to the patient's immune system. The idea is that this, in combination with antiretroviral medicines, would wipe out the majority of infected cells. But based on a study of macaques with SIV, a group of researchers warns in a report published in the January 2 issue of the journal AIDS that such a strategy could cause potentially harmful brain inflammation. "The potential for the brain to harbor significant HIV reservoirs that could pose a danger if activated hasn't received much attention in the HIV eradication field," says Janice Clements, Ph.D., professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine. "Our study sounds a major cautionary note about the potential for unintended consequences of the shock-and-kill treatment strategy." HIV research efforts have long focused on prevention and developing antiretroviral therapies that keep the virus in check without eradicating it, essentially transforming HIV into a manageable chronic condition, says Lucio Gama, Ph.D., assistant professor of molecular and comparative pathobiology at Johns Hopkins and the lead author of the new study. Then, in 2009, a group in Berlin reported it had cured a man of HIV by giving him a bone marrow transplant from a donor whose genetics conferred natural resistance to the virus. This galvanized federal funding of new research projects aimed at finding a more broadly applicable "AIDS cure," Gama says. He and Clements are part of that pursuit as members of the Collaboratory of AIDS Researchers for Eradication. One cure strategy being pursued is to find a medication that would "wake up" virus in the reservoirs, forcing it to reveal itself. But Gama says that could be problematic if HIV reservoirs exist in the brain, and investigators already had some evidence that they do: the many cases of AIDS dementia that developed before the current antiretroviral cocktail treatment was developed. "Research had also shown that HIV can infect monocytes in the blood, which we know cross into the brain," he says. But no studies had definitively answered whether significant reservoirs of latent HIV in patients under long-term therapy could be sustained in the brain -- in part because, in autopsies, it is unclear whether virus detected in the brain comes from brain cells themselves or surrounding blood. For the new study, Clements, Gama and their collaborators treated three pig-tailed macaque monkeys infected with SIV with antiretrovirals for more than a year. Then the researchers gave two of the macaques ingenol-B, a latency-reversing agents thought to "wake up" the virus. "We didn't really see any significant effect," Gama says, "So we coupled ingenol-B with another latency-reversing agent, vorinostat, which is used in some cancer treatments to make cancer cells more vulnerable to the immune system." The macaques also continued their course of antiretrovirals throughout the experiment. After a 10-day course of the combined treatment, one of the macaques remained healthy, while the other developed symptoms of encephalitis, or brain inflammation, Gama says, and blood tests revealed an active SIV infection. When the animal's illness worsened, the researchers humanely killed it and carefully removed the blood from its body so that blood sources of the virus would not muddle their examination of the brain. Testing revealed SIV was still present in the brain, but only in one of the regions analyzed: the occipital cortex, which processes visual information. The affected area was so small that "we almost missed it," he says. Gama cautions that the results of their study on macaques with SIV may not apply to humans with HIV. It's also possible, he says, that the encephalitis was transient and could have resolved by itself. Still, he says, the results signal a need for extra caution in exploring ways to flush out HIV reservoirs and eradicate the virus from the body. Other authors on the paper are Celina M. Abreu, Erin N. Shirk, Sarah L. Price, Ming Li, Greg M. Laird, Kelly A. Metcalf Pate and Robert F. Siliciano of The Johns Hopkins University; Stephen W. Wietgrefe and Ashley T. Haase of the University of Minnesota; Shelby L. O'Connor of the University of Wisconsin; Luiz Pianowski of Kyolab in Brazil; Carine van Lint of the Université Libre de Bruxelles in Belgium; and the LRA-SIV Study Group. Research reported in this publication was supported by the National Institute of Mental Health (grant number P01MH070306-01), the National Institute of Allergy and Infectious Disease (grant number U19A1076113), the National Institutes of Health's Office of the Director (grant numbers P40OD013117 and P51OD011106), the Research Facilities Improvement Program (grant numbers RR15459-01 and RR020141-01), the France Recherche Nord & Sud Sida-HIV Hépatites, the Belgian Fund for Scientific Research (FRS-FNRS Belgium), the Fondation Roi Baudouin, the NEAT program and the Wallo on Region (the Excellence Program Cibles).
News Article | December 1, 2016
Even gut microbes have a routine. Like clockwork, they start their day in one part of the intestinal lining, move a few micrometers to the left, maybe the right, and then return to their original position. New research in mice now reveals that the regular timing of these small movements can influence a host animal's circadian rhythms by exposing gut tissue to different microbes and their metabolites as the day goes by. Disruption of this dance can affect the host. The study appears December 1 in Cell. "This research highlights how interconnected the behavior is between prokaryotes and eukaryotes, between mammalian organisms and the microbes that live inside them," says Eran Elinav, an immunologist at the Weizmann Institute of Science, who led the work with co-senior author Eran Segal, a computational biologist also at the Weizmann. "These groups interact with and are affected by each other in a way that can't be separated." The new study had three major findings: Previous work by Elinav and Segal revealed that our biological clocks work in tandem with the biological clocks in our microbiota and that disrupting sleep-wake patterns and feeding times in mice induced changes in the microbiome in the gut. "Circadian rhythms are a way of adapting to changes in light and dark, metabolic changes, and the timing of when we eat," says Segal. "Other studies have shown the importance of the microbiome in metabolism and its effect on health and disease. Now, we've shown for the first time how circadian rhythms in the microbiota have an effect on circadian rhythms in the host." The investigators say their work has potential implications for human health in two important ways. First of all, because drugs ranging from acetaminophen to chemotherapy are metabolized in the liver, understanding -- and potentially being able to manipulate -- the circadian rhythms of our microbiota could affect how and when medications are administered. Second, understanding more about this relationship could help to eventually intervene in health problems like obesity and metabolic syndrome, which are more common in people whose circadian rhythms are frequently disrupted due to shift work or jet lag. "What we learned from this study is that there's a very tight interconnectivity between the microbiome and the host. We should think of it now as one supraorganism that can't be separated," Segal says. "We have to fully integrate our thinking with regard to any substance that we consume." This research was primarily funded by Yael and Rami Ungar, Israel; Leona M. and Harry B. Helmsley Charitable Trust; the Gurwin Family Fund for Scientific Research; Crown Endowment Fund for Immunological Research; estate of Jack Gitlitz; estate of Lydia Hershkovich; the Benoziyo Endowment Fund for the Advancement of Science; Adelis Foundation; John L. and Vera Schwartz, Pacific Palisades; Alan Markovitz, Canada; Cynthia Adelson, Canada; CNRS (Centre National de la Recherche Scientifique); estate of Samuel and Alwyn J. Weber; Mr. and Mrs. Donald L. Schwarz, Sherman Oaks; grants funded by the European Research Council; the German-Israel Binational foundation; the Israel Science Foundation; the Minerva Foundation; the Rising Tide foundation; the Alon Foundation scholar award; the Rina Gudinski Career Development Chair; and the Canadian Institute For Advanced Research (CIFAR). Cell (@CellCellPress), the flagship journal of Cell Press, is a bimonthly journal that publishes findings of unusual significance in any area of experimental biology, including but not limited to cell biology, molecular biology, neuroscience, immunology, virology and microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. Visit: http://www. . To receive Cell Press media alerts, contact firstname.lastname@example.org.
Guns M.,Catholic University of Louvain |
Guns M.,Fund for Scientific Research |
Vanacker V.,Catholic University of Louvain
Environmental Earth Sciences | Year: 2013
Tropical mountain regions are prone to landslide hazards. Given the current land pressure with increasing occupation of steep uplands, landslide hazards are expected to increase in the near future. Understanding the factors that control landslide hazards is therefore essential. Rare event logistic regression allows us to perform a robust detection of landslide controlling factors. This technique is here applied to the tropical Andes to evaluate the impact of dynamic land cover changes on landslide occurrences. Land cover change trajectories (i.e. dynamic evolution of land cover through time) were specifically included in the probabilistic landslide analysis. While natural physical processes such as slope undercutting by rivers and failure of oversteepened slopes are important in this tropical mountainous site, landslides are increasingly associated with human activities. The data show that land cover trajectories are associated with landslide patterns. In this humid mountainous site, forest degradation does not lead to a measurable increase in landslide occurrence. However, few years after forests are converted to pastures, a rapid decline of slope stability is observed. Land cover conversion from forest to pasture permanently reduces slope stability. It is assumed that major changes in soil properties and hydrology induced by the vegetation conversion play a role in accelerating landslide hazards. © 2013 Springer-Verlag Berlin Heidelberg.
Bastin C.,University of Liège |
Bastin C.,Fund for Scientific Research |
Salmon E.,University of Liège
European Journal of Clinical Nutrition | Year: 2014
Lifestyle modification offers a promising way of preventing or delaying Alzheimer's disease (AD). In particular, nutritional interventions can contribute to decrease the risk of dementia. The efficacy of such interventions should be assessed in individuals thought to be prone to AD. It is therefore necessary to identify markers that may help detecting AD as early as possible. This review will focus on subtle neuropsychological changes that may already exist in the predementia phase, and that could point to individuals at risk of dementia. Episodic memory decline appears consistently as the earliest sign of incipient typical AD. An episodic memory test that ensures deep encoding of information and assesses retrieval with free as well as cued recall appears as a useful tool to detect patients at an early stage of AD. Beyond the memory domain, category verbal fluency has been shown to decline early and to predict progression to AD. Moreover, in line with current diagnosis criteria for prodromal AD, combining neuropsychological scores and neuroimaging data allows a better discrimination of future AD patients than neuroimaging or neuropsychological data alone. Altogether, the detection of cognitive changes that are predictive of the typical form of probable AD already in the predementia stage points to at risk people who are the best target for therapeutic interventions, such as nutrition or physical exercise counseling or dietary interventions. © 2014 Macmillan Publishers Limited.
Demoulin A.,University of Liège |
Demoulin A.,Fund for Scientific Research
Geophysical Research Letters | Year: 2012
Despite constant progress in numerical and field studies of landscape evolution, time evolution is still poorly constrained in many uplifted areas where low denudation rates prevent the use of low temperature thermochronology, especially outside high relief mountainous areas. Here, I show that regional statistics of the landscape metric R involving hypsometric integrals at three nested levels of a catchment are able to isolate the time effect on landscape geometry during the latter's transient response to a tectonic perturbation. Analysis of 210 catchments from 9 regions of known uplift age worldwide shows that the regionally characteristic, R-derived S R index is in inverse power law relation with the time elapsed since a base level lowering. Suggesting a response time of ∼5 My, this finding has important implications for quantifying the rate of landform evolution and determining whether a landscape has reached steady-state form. © 2012. American Geophysical Union. All Rights Reserved.
Guns M.,Catholic University of Louvain |
Guns M.,Fund for Scientific Research |
Vanacker V.,Catholic University of Louvain
Natural Hazards and Earth System Science | Year: 2012
Statistical analysis of natural hazards needs particular attention, as most of these phenomena are rare events. This study shows that the ordinary rare event logistic regression, as it is now commonly used in geomorphologic studies, does not always lead to a robust detection of controlling factors, as the results can be strongly sample-dependent. In this paper, we introduce some concepts of Monte Carlo simulations in rare event logistic regression. This technique, so-called rare event logistic regression with replications, combines the strength of probabilistic and statistical methods, and allows overcoming some of the limitations of previous developments through robust variable selection. This technique was here developed for the analyses of landslide controlling factors, but the concept is widely applicable for statistical analyses of natural hazards. © 2012 Author(s). CC Attribution 3.0 License.
News Article | April 20, 2016
The Acknowledgements of this Letter should have included the following sentence: “This work was also supported in part by the University of Antwerp (TOP BOF 29069 to A.J.); the Fund for Scientific Research-Flanders (grant number G078414N to A.J.); the Association Belge contre les Maladies Neuromusculaire (to A.J.); the Association Française contre les Myopaties (grant number 16197 to A.J.).