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  • richardmitnick 6:44 am on October 26, 2015 Permalink | Reply
    Tags: , Biology,   

    From Weizmann: “Awakenings” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science


    Prof. Atan Gross revealed a mechanism for waking up sleeping stem cells

    An energy supply is important for any undertaking; but in stem cells, energy-producing structures sometimes determine the very fate of the cell. A new Weizmann Institute study, reported in Nature Communications, reveals how cellular power plants called mitochondria can wake up blood-forming stem cells from their sleep, causing them to proliferate and mature into different cell types.

    Blood-forming stem cells, which give rise to the entire immune system, lie sleeping in niches in the bone marrow. They are continuously woken up to replenish the blood with mature cells, which have a finite life span. The wake-up call can come in the form of reactive oxygen molecules called free radicals, which are produced in the mitochondria as a byproduct of the manufacture of cellular fuel. A team of Weizmann Institute scientists headed by Prof. Atan Gross of the Biological Regulation Department has now discovered a mechanism by which the wake-up message is sent to these stem cells via their mitochondria.

    Mitochondria (dark gray), viewed under an electron microscope, are significantly enlarged in blood-forming stem cells lacking MTCH2 (right) compared with regular blood-forming stem cells (left)

    The heart of the message is a protein known as MTCH2 – or “Mitch,” as the scientists call it – which sits on the membranes of mitochondria and acts as a molecular switch. When Gross discovered MTCH2 more than a decade ago, he and his team showed that this protein can regulate cell suicide: Under conditions of severe stress, “Mitch” conveys a self-destruct message that prompts the mitochondria to develop holes and disintegrate, ultimately causing the cell to die. In the new study, postdoctoral fellow Dr. Maria Maryanovich and other members of Gross’s lab – Dr. Yehudit Zaltsman and PhD students Antonella Ruggiero and Andres Goldman – found that in blood-forming stem cells, MTCH2 has an additional role: It suppresses the activity of the mitochondria for as long as the cells need to remain in their dormant state.

    When the scientists created genetically engineered mice that lacked MTCH2 throughout their blood system, the mitochondria in the blood-forming stem cells underwent major changes. These organelles more than doubled in size, and their activity increased almost four-fold. As a result, the stem cells became activated, apparently woken from their sleep by the free radicals generated in the hyper-busy mitochondria. The cells left their niches and began to mature in such large numbers that their supply in the bone marrow was exhausted. These findings suggest that enhancing the activity of the mitochondria – by decreasing MTCH2 – can awaken the stem cells when needed.

    This clever control mechanism of the stem cell cycle – awakening the cells by enhancing their metabolism – ensures that the cells have sufficient energy for growing and maturing. “Like travelers waking up in the morning and stocking up on essential provisions before undertaking a long journey, sleepy stem cells need the energy to survive their new journey after they awaken,” says Gross. “We found that turning on mitochondria metabolism supplies the cells with precisely such energy.” Taking part in the study were Dr. Smadar Levin Zaidman of Chemical Research Support, Dr. Ziv Porat of the Biological Services Unit, and Prof. Tsvee Lapidot and Dr. Karin Golan of the Immunology Department.

    A three-dimensional reconstruction of the mitochondrial volume: The volume is larger (yellow and red) in blood-forming stem cells lacking MTCH2 (right), and relatively smaller (blue and green) in regular blood-forming stem cells

    In addition to shedding new light on the basic biology of the stem cell cycle, the Weizmann Institute study may lead to new ways of controlling the activity of stem cells in research as well as in the clinic. The findings suggest that it may be possible to awaken stem cells by altering their metabolism, rather than by manipulating their genes, as is done today. In addition, the findings open up a new avenue of research into leukemia. They suggest that defects in the control of cellular metabolism in blood-forming stem cells at various stages of their maturation may lead to the abnormal cellular proliferation observed in leukemia. If this is indeed found to be the case, it may be possible to treat leukemia by correcting the cells’ metabolic defects.

    Prof. Atan Gross’s research is supported by the Yeda-Sela Center for Basic Research; the Adelis Foundation; the Lubin-Schupf Fund for Women in Science; the Pearl Welinsky Merlo Foundation Scientific Progress Research Fund; the Louis and Fannie Tolz Collaborative Research Project; the Hymen T. Milgrom Trust donation fund; the Rising Tide Foundation; Lord David Alliance, CBE; the estate of Tony Bieber; and the estate of John Hunter. Prof Gross is the incumbent of the Marketa and Frederick Alexander Professorial Chair.

    See the full article here .

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    Weizmann Institute Campus

    The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

    Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

    The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.

  • richardmitnick 6:46 am on October 15, 2015 Permalink | Reply
    Tags: , Biology, Circadian clocks,   

    From Weizmann: “Natural Metabolite Might Reset Aging Biological Clocks” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    12 Oct 2015
    No Writer Credit


    Weizmann Institute researchers show that our daily rhythms are governed by a substance that declines with age

    As we age, our biological clocks tend to wind down. A Weizmann Institute research team has now revealed an intriguing new link between a group of metabolites whose levels drop as our cells age and the functioning of our circadian clocks – mechanisms encoded in our genes that keep time to cycles of day and night. Their results, which appeared in Cell Metabolism, suggest that the substance, which is found in many foods, could possibly help keep our internal timekeepers up to speed.

    Dr. Gad Asher’s lab in the Weizmann Institute’s Biological Chemistry Department investigates circadian clocks, trying to understand how these natural timekeepers help regulate, and are affected by, everything from nutrition to metabolism. In the present study, he and his research student Ziv Zwighaft were following clues that certain metabolites called polyamines could be tied to the functioning of circadian clocks. We get polyamines from food, but our cells manufacture them as well. These substances are known to regulate a number of essential processes in the cell, including growth and proliferation. And the levels of polyamines have been found to naturally drop as we age.

    Working with mice and cultured cells, they found that, indeed, enzymes that are needed to manufacture polyamines undergo cycles that are tied to both feeding and circadian rhythms of day and night. In mice engineered to lack a functional circadian clock, these fluctuations did not occur.

    As the researchers continued to investigate, they discovered a sort of feedback loop, so that polyamine production is not only regulated by circadian clocks, these substances also regulate the ticking of those clocks, in turn. In cell cultures, adding high levels of polyamines more or less obliterated the circadian rhythm while maintaining low levels slowed the clock by around two hours. “The polyamines are actually an embedded part of the circadian clockwork,” says Asher.

    The scientists then asked how this plays out in younger and older mice, with naturally higher or lower polyamine levels. It is known that the circadian clocks of elderly mice and run slower; concomitantly, their polyamine levels decline. The team found they could slow down the clocks in the young mice by administering a drug to inhibit polyamine synthesis. In contrast, adding a polyamine to the older mice’s drinking water made their clocks run faster than others of their age group and actually restored their function, similar to that of the young mice.

    Asher and his team intend to continue investigating the function of polyamines in circadian systems. “This discovery demonstrates the tight intertwining between circadian clocks and metabolism,” says Zwighaft. “Our findings today rely on experiments with mice, but we think they might hold true in humans. If so, they will have broad clinical implications,” Asher says. “The ability to repair the clock simply, through nutritional intervention with polyamine supplementation, is exciting and obviously of great clinical potential.”

    See the full article here .

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    Weizmann Institute Campus

    The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

    Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

    The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.

  • richardmitnick 10:33 am on October 11, 2015 Permalink | Reply
    Tags: , Biology, ,   

    From Weizmann: “Getting to the Center” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    No Writer Credit

    The nucleus (red) in the cell center is surrounded by the disorganized actin network in the cytoplasm, on which the myosin-v motors move the vesicles around in the “active random motion” No image credit.

    Before an egg – whether mouse or human – can be fertilized, it must get its “internal affairs” in order. That includes moving its nucleus into position in the exact center of the cell. Under a microscope, the nucleus appears to do a little dance, jigging its way from the edge of the cell to the middle. What is really going on?

    “This is a question that physics can answer,” says Prof. Nir Gov of the Weizmann Institute’s Chemical Physics Department. “We examine the physics of the biological molecules in the cell to see whether the means of motion that are proposed are mechanically possible.” Gov, a theoretical physicist, worked with physicists and biologists led by Prof. Marie-Helen Verlhac at the College de France in Paris, observing what happens to the nuclei in mouse egg cells.

    The nucleus dance, they found, is the result of bumping: Tiny motorized sacs called vesicles continually collide with the nucleus. These vesicles run on tracks – the long, thin actin filaments that provide the cell with support – and they are transported by molecular motors made of a kind of myosin – a relative of the myosin that makes our muscles contract. (“The vesicles with their myosin motors underneath look like little people running on a track,” says Gov.)

    But the actin fibers form a disorganized network in the cell’s cytoplasm, and the movement of the vesicles is random as well. How does this random motion turn into the directed movement of the nucleus? This is where the physics came in. The mechanism that indeed explains the movement turned out to be subtle but effective.

    Prof. Nir Gov

    The researchers found that the motors carrying the vesicles move more vigorously at the cell’s outer edges and more slowly in its center. Since there is about the same number of vesicles everywhere, this means that the bumping is more intense from one side. As the nucleus moves in toward the center, however, the force of the vesicles striking it gradually drops until it reaches the point at which the pressure is equally low all around. The physical model for this motion also reveals that the myosin motors stir up the cytoplasm, making it more fluid so that the nucleus can slide through it more easily.

    Further investigations showed that, unlike the active motion of the vesicles, “random thermal motion” – the heat-induced movement that makes molecules “jumpy” – cannot give rise to this type of movement, and would not be able to direct the nucleus to the center of the cell.

    How does the differential velocity of the tiny motors arise in the cell? This open question is under further study. “This is the first time that we have seen such ‘active random motion’ perform work in biological systems,” says Gov. “Since almost all cells contain actin transport systems, we think it could play a role in other types of intracellular movements. As well as solving a biological puzzle, we have learned something new about basic physics by researching movement in cells,” he adds.

    See the full article here .

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    Weizmann Institute Campus

    The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

    Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

    The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.

  • richardmitnick 4:00 pm on September 19, 2015 Permalink | Reply
    Tags: , Biology, Optics and Biology,   

    From NSF: “Year of Light: The brilliance of mixing physics with biology” 

    National Science Foundation

    September 18, 2015
    No Writer Credit

    Photo credit: Matthew Comstock

    If you thought fluorescence was just meant for eye-shocking crayons, paints, t-shirts and shoelaces, think again. When physics and biology come together to better understand molecules like DNA, using a mixture of techniques known as fluorescence microscopy and optical traps allows researchers to see and learn so much more.

    A good deal of biological research today now intertwines physics to better comprehend molecules and their dynamic processes. In modern medicine, for example, this approach enables us to better recognize molecular interactions in living systems, such as the actual mechanisms of cellular components and how they move and interact within a cell or on an even smaller level, parsing how parts – of DNA or other molecules so small they refer to them in piconewtons – ambulate in sickness and health, thereby strengthening our ability to combat critical diseases in the long-term, and simultaneously improving our economy, especially in the field of commercial pharmaceuticals.

    To advance research in this field, two physics professors, Taekjip Ha and Yann Chemla at the University of Illinois at Urbana-Champaign and the NSF-funded Center for Physics of Living Cells, have coupled two unique biophysical techniques – optical traps and fluorescence microscopy – to examine the binding processes that underlie DNA strands. Optical traps, which are also referred to as optical tweezers, use a highly focused laser beam to provide an attractive or repulsive force to physically hold and move microscopic objects that are susceptible to this kind of control. The fluorescence microscope is based on the phenomenon that certain materials emit energy detectable as visible light when irradiated with the light of a specific wavelength. The material can be naturally fluorescent or be treated to make it so. The light then in this kind of microscope “excites” the material, allowing researchers to view molecules, for example, in an active state and observe mechanisms they wouldn’t in a static environment.

    Together, this combined technique paves the foundation for others to clearly visualize protein motion and conformational changes, thereby greatly enhancing our ability to measure how molecules interact with one another. The image displayed above offers a small visual sample of the advanced capabilities their new technique offers the field. DNA (blue double helix) is stretched out between two beads (gray spheres) held by optical traps (red cones) with a bound protein glowing with fluorescence excited by a “confocal” laser (green cones).

    See the full article here .

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    The National Science Foundation (NSF) is an independent federal agency created by Congress in 1950 “to promote the progress of science; to advance the national health, prosperity, and welfare; to secure the national defense…we are the funding source for approximately 24 percent of all federally supported basic research conducted by America’s colleges and universities. In many fields such as mathematics, computer science and the social sciences, NSF is the major source of federal backing.


  • richardmitnick 12:13 pm on August 23, 2015 Permalink | Reply
    Tags: , Biology, ,   

    From Scripps: “Hands-On Research 101: Internships Introduce Undergrads to Biomedical Science in Action” 


    Scripps Research Institute

    August 24, 2015
    Madeline McCurry-Schmidt

    SURF Intern Joshua David says the internship at TSRI gave him new opportunities to learn about biomedicine. (Photo by Cindy Bruaer.)

    When Joshua David saw scientists from The Scripps Research Institute (TSRI) discussing Ebola virus research on the news last year, he wanted to help.

    “I discovered that Scripps is one of the top places looking at Ebola virus at the molecular level,” said David, an undergraduate chemistry major at Virginia Commonwealth University. “The scientists at Scripps are trying to help people who are suffering and dying right now.”

    David quickly got in touch with Ebola researchers at TSRI and learned about the institute’s Summer Undergraduate Research Fellows (SURF) Program, organized by the TSRI Office of Graduate Studies. The SURF Program is a 10-week internship program at TSRI that has brought 38 undergraduates to TSRI’s California and Florida campuses this year. It’s one of several outreach programs, including a summer high school internship program where another 30 students work side-by-side with researchers.

    As a SURF intern, David flew into San Diego in June and spent his summer in Associate Professor Andrew Ward’s lab.

    Learning New Techniques

    David said the internship gave him new opportunities to learn about biomedicine.

    “I’m very interested in structural biology and virology; however, these courses are not offered at my university,” David explained. “Coming here is a great opportunity because it allows me learn techniques used in these fields and gain general knowledge of each field in the process.”

    Under the guidance of C. Daniel Murin, a graduate student in the Ward lab, David learned how to build 3-D structures of proteins involved in Ebola virus attacks. The SURF program emphasizes hands-on research, so David learned to use a technique called electron microscopy (EM) to study exactly how Ebola virus interacts with antibodies.

    “I wanted to take him through that process, so he can go through it almost independently by the end of the summer,” said Murin.

    David worked with Murin on several projects, including studies involving the experimental Ebola virus treatment ZMapp, which has also been the topic of previous studies at TSRI.

    David said one challenge this summer was tackling how to use a molecular imaging program necessary for research with EM.

    “Then I just had to sit down and figure it out,” he said. “It took me about eight hours, but now I understand how to do it.”

    Helping Patients

    David hopes to bring together research and patient care in a future career as a physician-scientist. As a high school student, David interned in a hospital’s intensive care unit. He watched as patients succumbed to diseases like acute respiratory distress syndrome (ARDS)—where doctors have few treatments to offer.

    A technique like EM could give David and other scientists a better look at the proteins involved in disease—from Ebola to ARDS—and lead to new treatments.

    “You can understand how things work in cells at the atomic level, and that really interests me,” said David.

    Before David headed back to Virginia at the end of the summer, he presented a poster outlining his work to peers and supervisors at TSRI. It was chance to show what he’s learned—and why he wants to be part of the next generation of scientists.

    About the Summer Undergraduate Research Fellows (SURF) Program

    TSRI’s 10-week SURF program provides participants the opportunity to perform cutting-edge research in one of 250 laboratories side-by-side with TSRI’s world-renowned faculty. The goals of the program are to:

    Make program participants feel comfortable in a lab setting and increase their research skills
    Teach participants to think critically about the theory and application of biomedical research
    Increase the participants’ proficiency in communicating scientific concepts
    Increase the number of underrepresented and first-generation to college students who consider careers in biomedical research.

    Students can choose to apply to either the La Jolla campus in California or the Jupiter campus in Florida. Learn more at TSRI’s Education website.

    See the full article here.

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

  • richardmitnick 10:49 pm on August 12, 2015 Permalink | Reply
    Tags: , Biology, , Flippases, Lipids   

    From ETH: “How lipids are flipped” 

    ETH Zurich bloc

    ETH Zurich

    Peter Rüegg

    Comparison of cavities (green) in inward-facing (left) and outward-occluded (right) states of PglK, with native LLO (middle) shown as space-filling model for size reference. (Illustration: from Perez et al, 2015)

    A team of researchers at ETH Zurich and the University of Bern has succeeded in determining the structure of a lipid flippase at high resolution, which has provided insight into how this membrane protein transports lipids by flipping.

    Biological membranes have a fundamental role in separating the interior of cells from the extracellular space and in helping determine cellular shape and size. They consist of a double layer (“bilayer”) of lipids that contain a hydrophilic head group and generally two long, hydrophobic tails. Whereas the head groups face outwards, the hydrophobic tail face each other. Numerous other components are embedded in membranes, including pore-forming proteins and transport proteins.

    Countless vital processes occur at membranes, including the transport of various substances. The transport of phospholipids and lipid-linked oligosaccharides (LLO) is particularly difficult to achieve due to the bipolar nature of the lipid bilayer – hydrophobic interior, hydrophilic surface. This is why flippases are required to transport lipids from one side of the membrane to the other, essentially flipping their orientation. Flippases have important roles in maintaining the asymmetry of cellular membranes, i.e. in the different lipid composition of the outer and inner sides. In mammals, this affects various processes such as blood coagulation, immune recognition and programmed cell death, or apoptosis. Flippases are also essential for transporting lipid-linked oligosaccharides (“LLOs”), which are transferred onto acceptor proteins during N-linked protein glycosylation.

    Flippase structure revealed for the first time

    Until now biologists knew neither the high-resolution structures of flippases nor the exact mechanism used to flip LLOs. Three research teams from ETH Zurich and the University of Bern, led by ETH professor Kaspar Locher, have now determined the structure of one such flippase, the PglK protein from the bacterium Campylobacter jejuni. The study has been published in the journal Nature.

    This required the researchers to purify the flippase from bacterial membranes and generate three-dimensional crystals, which were then analysed using X-ray crystallography to determine the positions of all atoms. The scientists determined three distinct structures that corresponded to different states of the flippase during the reaction. Their data allowed the researchers to deduce a molecular mechanism of how PglK flips LLOs.

    The researchers show that PglK consists of two identical subunits that move like a pair of scissors when energy (ATP) is consumed. Similar to a credit card reader, the oligosaccharide moiety of the lipid-linked oligosaccharide is then pulled into a hydrophilic channel within the flippase. The hydrophobic, lipidic tail of the LLO molecule remains exposed to the lipidic membrane, causing the LLO to change its orientation so that the sugar part ends up on the outside of the membrane. The flippase itself does not change its orientation during translocation reaction and therefore acts as a catalyst.

    Fundamentally different mechanism

    The newly-discovered mechanism fundamentally differs from previously known transport processes that catalyze import or export of soluble substrates. “The flipping of lipids in membranes has always fascinated biochemists and cell biologists; the biological solution to this problem thrills us!” says co-author Markus Aebi, Professor of Microbiology at ETH Zurich.

    The research groups from ETH Zurich and the University of Bern are the first to have solved the fundamental biological puzzle of how LLOs are flipped. They developed a novel method for studying the reaction in vitro. ETH Professor Aebi insists that only through the cooperation of structural biologists, chemists and microbiologists was it possible to decipher this basic mechanism. “Every group brought their own expertise from their respective fields. This was the only way we could succeed.”

    Therapeutic applications?

    Although the present work constitutes basic research, there are diseases associated with mutations in a human flippase, explains Aebi. These diseases are termed ‘congenital disorders of glycosylation’. More than 10,000 glycosylation sites in various proteins have been identified in humans, “which is why changes in glycosylation in which flippase plays a crucial role affect so many processes in the body,” says the ETH professor. Examples of this include the development and maturation of the central nervous system.

    Whether the newly acquired knowledge of the bacterial flippase PglK leads to novel therapeutic approaches is unclear at present. However, flippases already form an essential part of biotechnological systems that are used to generate glycoproteins desigend for various uses in diagnostics and potential therapeutic agents.

    LLO synthesis and N-glycosylation in Campylobacter jejuni at a glance: The LLO’s lipidic tail is shown in purple. A polypeptide chain is shown in blue. PglH (red) is the glycosyltransferace that couples the oligosaccharide to the polypeptide chain.


    Perez C, Gerber S, Boilevin J, Bucher M, Darbre T, Aebi M, Reymond J-L, Locher KP. Molecular view of lipid-linked oligosaccharide translocation across biological membranes. Nature, Advanced online publication, 12th August 2015. DOI: 10.1038/nature14953

    See the full article here.

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    ETH Zurich campus
    ETH Zurich is one of the leading international universities for technology and the natural sciences. It is well known for its excellent education, ground-breaking fundamental research and for implementing its results directly into practice.

    Founded in 1855, ETH Zurich today has more than 18,500 students from over 110 countries, including 4,000 doctoral students. To researchers, it offers an inspiring working environment, to students, a comprehensive education.

    Twenty-one Nobel Laureates have studied, taught or conducted research at ETH Zurich, underlining the excellent reputation of the university.

  • richardmitnick 11:49 am on August 4, 2015 Permalink | Reply
    Tags: , Biology,   

    From LBL: “Atomic View of Microtubules” 

    Berkeley Logo

    Berkeley Lab

    August 4, 2015
    Lynn Yarris (510) 486-5375

    Microtubules are hollow cylinders with walls made up of tubulin proteins – alpha (green) and beta (blue) – plus EB proteins (orange) that can either stabilize or destabilize the structure of the tubulin proteins.

    Microtubules, hollow fibers of tubulin protein only a few nanometers in diameter, form the cytoskeletons of living cells and play a crucial role in cell division (mitosis) through their ability to undergo rapid growth and shrinkage, a property called “dynamic instability.” Through a combination of high-resolution cryo-electron microscopy (cryo-EM) and a unique methodology for image analysis, a team of researchers with Berkeley Lab and the University of California (UC) Berkeley has produced an atomic view of microtubules that enabled them to identify the crucial role played by a family of end-binding (EB) proteins in regulating microtubule dynamic instability.

    During mitosis, microtubules disassemble and reform into spindles that are used by the dividing cell to move chromosomes. For chromosome migration to occur, the microtubules attached to them must disassemble, carrying the chromosomes in the process. The dynamic instability that makes it possible for microtubules to transition from a rigid polymerized or “assembled” nucleotide state to a flexible depolymerized or “disassembled” nucleotide state is driven by guanosine triphosphate (GTP) hydrolysis in the microtubule lattice.

    “Our study shows how EB proteins can either facilitate microtubule assembly by binding to sub-units of the microtubule, essentially holding them together, or else cause a microtubule to disassemble by promoting GTP hydrolysis that destabilizes the microtubule lattice,” says Eva Nogales, a biophysicist with Berkeley Lab’s Life Sciences Division who led this research.

    Gregory Alushin and Eva Nogales studying images of microtubule structures. (Photo by Roy Kaltschmidt)

    Nogales, who is also a professor of biophysics and structural biology at UC Berkeley and investigator with the Howard Hughes Medical Institute, is a leading authority on the structure and dynamics of microtubules. In this latest study, she and her group used cryo-EM, in which protein samples are flash-frozen at liquid nitrogen temperatures to preserve their natural structure, to determine microtubule structures in different nucleotide states with and without EB3. With cryo-EM and their image analysis methodology, they achieved a resolution of 3.5 Angstroms, a record for microtubules. For perspective, the diameter of a hydrogen atom is about 1.0 Angstroms.

    “We can now study the atomic details of microtubule polymerization and depolymerization to develop a complete description of microtubule dynamics,” Nogales says.

    Beyond their importance to our understanding of basic cell biology, microtubules are a major target for anticancer drugs, such as Taxol, which can prevent the transition from growing to shrinking nucleotide states or vice versa.

    Rui Zhang is the lead author of a Cell paper describing the record 3.5 Angstroms resolution imaging of microtubules

    “A better understanding of how microtubule dynamic instability is regulated could open new opportunities for improving the potency and selectivity of existing anti-cancer drugs, as well as facilitate the development of novel agents,” Nogales says.

    Nogales is the corresponding author of a paper describing this research in the journal Cell. The paper is entitled Mechanistic Origin of Microtubule Dynamic Instability and Its Modulation by EB Proteins. Co-authors are Rui Zhang, Gregory Alushin and Alan Brown.

    This work was funded by a grant from NIH’s National Institute of General Medical Sciences.

    See the full article here.

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  • richardmitnick 9:31 am on July 30, 2015 Permalink | Reply
    Tags: , Biology, , , ,   

    From livescience: “Origin-of-Life Story May Have Found Its Missing Link” 


    June 06, 2015
    Jesse Emspak

    A field of geysers called El Tatio located in northern Chile’s Andes Mountains. Credit: Gerald Prins

    How did life on Earth begin? It’s been one of modern biology’s greatest mysteries: How did the chemical soup that existed on the early Earth lead to the complex molecules needed to create living, breathing organisms? Now, researchers say they’ve found the missing link.

    Between 4.6 billion and 4.0 billion years ago, there was probably no life on Earth. The planet’s surface was at first molten and even as it cooled, it was getting pulverized by asteroids and comets. All that existed were simple chemicals. But about 3.8 billion years ago, the bombardment stopped, and life arose. Most scientists think the “last universal common ancestor” — the creature from which everything on the planet descends — appeared about 3.6 billion years ago.

    But exactly how that creature arose has long puzzled scientists. For instance, how did the chemistry of simple carbon-based molecules lead to the information storage of ribonucleic acid, or RNA?

    A hairpin loop from a pre-mRNA. Highlighted are the nucleobases (green) and the ribose-phosphate backbone (blue). Note that this is a single strand of RNA that folds back upon itself.

    The RNA molecule must store information to code for proteins. (Proteins in biology do more than build muscle — they also regulate a host of processes in the body.)

    The new research — which involves two studies, one led by Charles Carter and one led by Richard Wolfenden, both of the University of North Carolina — suggests a way for RNA to control the production of proteins by working with simple amino acids that does not require the more complex enzymes that exist today. [7 Theories on the Origin of Life on Earth]

    Missing RNA link

    This link would bridge this gap in knowledge between the primordial chemical soup and the complex molecules needed to build life. Current theories say life on Earth started in an “RNA world,” in which the RNA molecule guided the formation of life, only later taking a backseat to DNA, which could more efficiently achieve the same end result.

    The structure of the DNA double helix. The atoms in the structure are colour-coded by element and the detailed structure of two base pairs are shown in the bottom right.

    Like DNA, RNA is a helix-shaped molecule that can store or pass on information. (DNA is a double-stranded helix, whereas RNA is single-stranded.) Many scientists think the first RNA molecules existed in a primordial chemical soup — probably pools of water on the surface of Earth billions of years ago. [Photo Timeline: How the Earth Formed]

    The idea was that the very first RNA molecules formed from collections of three chemicals: a sugar (called a ribose); a phosphate group, which is a phosphorus atom connected to oxygen atoms; and a base, which is a ring-shaped molecule of carbon, nitrogen, oxygen and hydrogen atoms. RNA also needed nucleotides, made of phosphates and sugars.

    The question: How did the nucleotides come together within the soupy chemicals to make RNA? John Sutherland, a chemist at the University of Cambridge in England, published a study in May in the journal Nature Chemistry that showed that a cyanide-based chemistry could make two of the four nucleotides in RNA and many amino acids.

    That still left questions, though. There wasn’t a good mechanism for putting nucleotides together to make RNA. Nor did there seem to be a natural way for amino acids to string together and form proteins. Today, adenosine triphosphate (ATP) does the job of linking amino acids into proteins, activated by an enzyme called aminoacyl tRNA synthetase. But there’s no reason to assume there were any such chemicals around billions of years ago.

    Also, proteins have to be shaped a certain way in order to function properly. That means RNA has to be able to guide their formation — it has to “code” for them, like a computer running a program to do a task.

    Carter noted that it wasn’t until the past decade or two that scientists were able to duplicate the chemistry that makes RNA build proteins in the lab. “Basically, the only way to get RNA was to evolve humans first,” he said. “It doesn’t do it on its own.”

    Perfect sizes

    In one of the new studies, Carter looked at the way a molecule called “transfer RNA,” or tRNA, reacts with different amino acids.

    They found that one end of the tRNA could help sort amino acids according to their shape and size, while the other end could link up with amino acids of a certain polarity. In that way, this tRNA molecule could dictate how amino acids come together to make proteins, as well as determine the final protein shape. That’s similar to what the ATP enzyme does today, activating the process that strings together amino acids to form proteins.

    Carter told Live Science that the ability to discriminate according to size and shape makes a kind of “code” for proteins called peptides, which help to preserve the helix shape of RNA.

    “It’s an intermediate step in the development of genetic coding,” he said.

    In the other study, Wolfenden and colleagues tested the way proteins fold in response to temperature, since life somehow arose from a proverbial boiling pot of chemicals on early Earth. They looked at life’s building blocks, amino acids, and how they distribute in water and oil — a quality called hydrophobicity. They found that the amino acids’ relationships were consistent even at high temperatures — the shape, size and polarity of the amino acids are what mattered when they strung together to form proteins, which have particular structures.

    “What we’re asking here is, ‘Would the rules of folding have been different?'” Wolfenden said. At higher temperatures, some chemical relationships change because there is more thermal energy. But that wasn’t the case here.

    By showing that it’s possible for tRNA to discriminate between molecules, and that the links can work without “help,” Carter thinks he’s found a way for the information storage of chemical structures like tRNA to have arisen — a crucial piece of passing on genetic traits. Combined with the work on amino acids and temperature, it offers insight into how early life might have evolved.

    This work still doesn’t answer the ultimate question of how life began, but it does show a mechanism for the appearance of the genetic codes that pass on inherited traits, which got evolution rolling.

    The two studies are published in the June 1 issue of the journal Proceedings of the National Academy of Sciences.

    See the full article here.

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  • richardmitnick 4:04 pm on July 28, 2015 Permalink | Reply
    Tags: , Biology, , , ,   

    From BNL: “New Computer Model Could Explain how Simple Molecules Took First Step Toward Life” 

    Brookhaven Lab

    July 28, 2015
    Alasdair Wilkins

    Two Brookhaven researchers developed theoretical model to explain the origins of self-replicating molecules

    Brookhaven researchers Sergei Maslov (left) and Alexi Tkachenko developed a theoretical model to explain molecular self-replication.

    Nearly four billion years ago, the earliest precursors of life on Earth emerged. First small, simple molecules, or monomers, banded together to form larger, more complex molecules, or polymers. Then those polymers developed a mechanism that allowed them to self-replicate and pass their structure on to future generations.

    We wouldn’t be here today if molecules had not made that fateful transition to self-replication. Yet despite the fact that biochemists have spent decades searching for the specific chemical process that can explain how simple molecules could make this leap, we still don’t really understand how it happened.

    Now Sergei Maslov, a computational biologist at the U.S. Department of Energy’s Brookhaven National Laboratory and adjunct professor at Stony Brook University, and Alexei Tkachenko, a scientist at Brookhaven’s Center for Functional Nanomaterials (CFN), have taken a different, more conceptual approach. They’ve developed a model that explains how monomers could very rapidly make the jump to more complex polymers. And what their model points to could have intriguing implications for CFN’s work in engineering artificial self-assembly at the nanoscale. Their work is published in the July 28, 2015 issue of The Journal of Chemical Physics.

    To understand their work, let’s consider the most famous organic polymer, and the carrier of life’s genetic code: DNA. This polymer is composed of long chains of specific monomers called nucleotides, of which the four kinds are adenine, thymine, guanine, and cytosine (A, T, G, C). In a DNA double helix, each specific nucleotide pairs with another: A with T, and G with C. Because of this complementary pairing, it would be possible to put a complete piece of DNA back together even if just one of the two strands was intact.

    While DNA has become the molecule of choice for encoding biological information, its close cousin RNA likely played this role at the dawn of life. This is known as the RNA world hypothesis, and it’s the scenario that Maslov and Tkachenko considered in their work.

    The single complete RNA strand is called a template strand, and the use of a template to piece together monomer fragments is what is known as template-assisted ligation. This concept is at the crux of their work. They asked whether that piecing together of complementary monomer chains into more complex polymers could occur not as the healing of a broken polymer, but rather as the formation of something new.

    “Suppose we don’t have any polymers at all, and we start with just monomers in a test tube,” explained Tkachenko. “Will that mixture ever find its way to make those polymers? The answer is rather remarkable: Yes, it will! You would think there is some chicken-and-egg problem—that, in order to make polymers, you already need polymers there to provide the template for their formation. Turns out that you don’t really.”

    Instilling memory

    A schematic drawing of template-assisted ligation, shown in this model to give rise to autocatalytic systems. No image credit.

    Maslov and Tkachenko’s model imagines some kind of regular cycle in which conditions change in a predictable fashion—say, the transition between night and day. Imagine a world in which complex polymers break apart during the day, then repair themselves at night. The presence of a template strand means that the polymer reassembles itself precisely as it was the night before. That self-replication process means the polymer can transmit information about itself from one generation to the next. That ability to pass information along is a fundamental property of life.

    “The way our system replicates from one day cycle to the next is that it preserves a memory of what was there,” said Maslov. “It’s relatively easy to make lots of long polymers, but they will have no memory. The template provides the memory. Right now, we are solving the problem of how to get long polymer chains capable of memory transmission from one unit to another to select a small subset of polymers out of an astronomically large number of solutions.”

    According to Maslov and Tkachenko’s model, a molecular system only needs a very tiny percentage of more complex molecules—even just dimers, or pairs of identical molecules joined together—to start merging into the longer chains that will eventually become self-replicating polymers. This neatly sidesteps one of the most vexing puzzles of the origins of life: Self-replicating chains likely need to be very specific sequences of at least 100 paired monomers, yet the odds of 100 such pairs randomly assembling themselves in just the right order is practically zero.

    “If conditions are right, there is what we call a first-order transition, where you go from this soup of completely dispersed monomers to this new solution where you have these long chains appearing,” said Tkachenko. “And we now have this mechanism for the emergence of these polymers that can potentially carry information and transmit it downstream. Once this threshold is passed, we expect monomers to be able to form polymers, taking us from the primordial soup to a primordial soufflé.”

    While the model’s concept of template-assisted ligation does describe how DNA—as well as RNA—repairs itself, Maslov and Tkachenko’s work doesn’t require that either of those was the specific polymer for the origin of life.

    “Our model could also describe a proto-RNA molecule. It could be something completely different,” Maslov said.

    Order from disorder

    The fact that Maslov and Tkachenko’s model doesn’t require the presence of a specific molecule speaks to their more theoretical approach.

    “It’s a different mentality from what a biochemist would do,” said Tkachenko. “A biochemist would be fixated on specific molecules. We, being ignorant physicists, tried to work our way from a general conceptual point of view, as there’s a fundamental problem.”

    That fundamental problem is the second law of thermodynamics, which states that systems tend toward increasing disorder and lack of organization. The formation of long polymer chains from monomers is the precise opposite of that.

    “How do you start with the regular laws of physics and get to these laws of biology which makes things run backward, which make things more complex, rather than less complex?” Tkachenko queried. “That’s exactly the jump that we want to understand.”

    Applications in nanoscience

    The work is an outgrowth of efforts at the Center for Functional Nanomaterials, a DOE Office of Science User Facility, to use DNA and other biomolecules to direct the self-assembly of nanoparticles into large, ordered arrays. While CFN doesn’t typically focus on these kinds of primordial biological questions, Maslov and Tkachenko’s modeling work could help CFN scientists engaged in cutting-edge nanoscience research to engineer even larger and more complex assemblies using nanostructured building blocks.

    “There is a huge interest in making engineered self-assembled structures, so we were essentially thinking about two problems at once,” said Tkachenko. “One is relevant to biologists, and second asks whether we can engineer a nanosystem that will do what our model does.”

    The next step will be to determine whether template-aided ligation can allow polymers to begin undergoing the evolutionary changes that characterize life as we know it. While this first round of research involved relatively modest computational resources, that next phase will require far more involved models and simulations.

    Maslov and Tkachenko’s work has solved the problem of how long polymer chains capable of information transmission from one generation to the next could emerge from the world of simple monomers. Now they are turning their attention to how such a system could naturally narrow itself down from exponentially many polymers to only a select few with desirable sequences.

    “What we needed to show here was that this template-based ligation does result in a set of polymer chains, starting just from monomers,” said Tkachenko. “So the next question we will be asking is whether, because of this template-based merger, we will be able to see specific sequences that will be more ‘fit’ than others. So this work sets the stage for the shift to the Darwinian phase.”

    This work was supported by the DOE Office of Science.

    See the full article here.

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    BNL Campus

    One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. The Laboratory’s almost 3,000 scientists, engineers, and support staff are joined each year by more than 5,000 visiting researchers from around the world.Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.

  • richardmitnick 10:40 am on May 8, 2015 Permalink | Reply
    Tags: , , Biology, ,   

    From AAAS: “Electron microscopes close to imaging individual atoms” 



    7 May 2015
    Robert F. Service

    This composite image of the protein β-galactosidase shows the progression of cryo-EM’s ability to resolve a protein’s features from mere blobs (left) a few years ago to the ultrafine 0.22-nanometer resolution today (right). Veronica Falconieri/ Subramaniam Lab/CCR/ NCI/ NIH

    Today’s digital photos are far more vivid than just a few years ago, thanks to a steady stream of advances in optics, detectors, and software. Similar advances have also improved the ability of machines called cryo-electron microscopes (cryo-EMs) to see the Lilliputian world of atoms and molecules. Now, researchers report that they’ve created the highest ever resolution cryo-EM image, revealing a druglike molecule bound to its protein target at near atomic resolution. The resolution is so sharp that it rivals images produced by x-ray crystallography, long the gold standard for mapping the atomic contours of proteins. This newfound success is likely to dramatically help drugmakers design novel medicines for a wide variety of conditions.

    “This represents a new era in imaging of proteins in humans with immense implications for drug design,” says Francis Collins, who heads the U.S. National Institutes of Health in Bethesda, Maryland. Collins may be partial. He’s the boss of the team of researchers from the National Cancer Institute (NCI) and the National Heart, Lung, and Blood Institute that carried out the work. Still, others agree that the new work represents an important milestone. “It’s a major advance in the technology,” says Wah Chiu, a cryo-EM structural biologist at Baylor College of Medicine in Houston, Texas. “It shows [cryo-EM] technology is here.”

    Cryo-EM has long seemed behind the times—an old hand tool compared with the modern power tools of structural biology. The two main power tools, x-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, enable researchers to pin down the position of protein features to less than 0.2 nanometers, good enough to see individual atoms. By contrast, cryo-EM has long been limited to a resolution of 0.5 nm or more.

    Cryo-EM works by firing a beam of electrons at a thin film containing myriad copies of a protein that have been instantly frozen in place by plunging them in liquid nitrogen. Detectors track the manner in which electrons scatter off different atoms in the protein. When an image is taken, the proteins are strewn about in random orientations. So researchers use imaging software to do two things; first, they align their images of individual proteins into a common orientation. Then, they use the electron scattering data to reconstruct the most likely position of all the protein’s amino acids and—if possible—its atoms.

    Cryo-EM has been around for decades. But until recently its resolution hasn’t even been close to crystallography and NMR. “We used to be called the field of blob-ology,” says Sriram Subramaniam, a cryo-EM structural biologist at NCI, who led the current project. But steady improvements to the electron beam generators, detectors, and imaging analysis software have slowly helped cryo-EM inch closer to the powerhouse techniques. Earlier this year, for example, two groups of researchers broke the 0.3-nm-resolution benchmark, enough to get a decent view of the side arms of two proteins’ individual amino acids. Still, plenty of detail in the images remained fuzzy.

    For their current study, Subramaniam and his colleagues sought to refine their images of β-galactosidase, a protein they imaged last year at a resolution of 0.33 nm. The protein serves as a good test case, Subramaniam says, because researchers can compare their images to existing x-ray structures to check their accuracy. Subramaniam adds that the current advance was more a product of painstaking refinements to a variety of techniques—including protein purification procedures that ensure each protein copy is identical and software improvements that allow researchers to better align their images. Subramaniam and his colleagues used some 40,000 separate images to piece together the final shape of their molecule. They report online today in Science that these refinements allowed them to produce a cryo-EM image of β-galactosidase at a resolution of 0.22 nm, not quite sharp enough to see individual atoms, but clear enough to see water molecules that bind to the protein in spots critical to the function of the molecule.

    That level of detail is equal to the resolution of many structures using x-ray crystallography, Chiu says. That’s vital, he adds, because for x-ray crystallography to work, researchers must produce millions of identical copies of a protein and then coax them to align in exactly the same orientation as they solidify into a crystal. But many proteins resist falling in line, making it impossible to determine their x-ray structure. NMR spectroscopy doesn’t require crystals, but it works only on small proteins. Cryo-EM represents the best of both worlds: It can work with massive proteins, but it doesn’t require crystals.

    As a result, the new advances could help structural biologists map vast numbers of new proteins they’ve never mapped before, Chiu says. That, in turn, could help drug developers design novel drugs for a multitude of conditions associated with different proteins. But one thing the technique has already shown is crystal clear, that in imaging, as well as biology, slow, evolutionary advances over time can produce big results.

    See the full article here.

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

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