In spite of its dangerous reputation, cholesterol is in fact an essential component of human cells. Manufactured by the cells themselves, it serves to stiffen the cell’s membrane, helping to shape the cell and protect it. By mapping the structure of a key enzyme involved in cholesterol production, Rockefeller University researchers and a colleague in Italy have gained new insight into this complex molecular process.
“This is the first report to pinpoint the location of every atom — in this case nearly 3,000 of them — in one of the membrane-embedded enzymes cells use to make cholesterol. With the structure of this enzyme, we can better understand how the body synthesizes it,” says Günter Blobel, John D. Rockefeller Jr. Professor, head of the Laboratory of Cell Biology and recipient of the 1999 Nobel Prize in Physiology or Medicine. “This accomplishment offers new insight on genetic disorders as well as the possibility of new approaches to lowering blood cholesterol when it becomes dangerously high.” The findings were published today (October 12) in Nature.
The cholesterol-making process in cells requires about 30 chemical reactions and 20 enzymes, seven of which are embedded in the cellular membrane. The mapping project focused on one of these, known as a sterol reductase, which helps two electrons travel from a molecule known as NADPH to another molecule that will eventually become cholesterol. This type of reaction is known as a reduction.
“Our images revealed two pockets within the enzyme’s architecture. One contains the NADPH, and the other provides access to the cholesterol precursor. When in place, these molecules are close enough to spark this important step in the synthesis of cholesterol,” says first author Xiaochun Li, a postdoc.
Ashkenazi Jews (AJ), identified as Jewish individuals of Central- and Eastern European ancestry, form the largest genetic isolate in the United States. AJ demonstrate distinctive genetic characteristics1, 2, including high prevalence of autosomal recessive diseases and relatively high frequency of alleles that confer a strong risk of common diseases, such as Parkinson’s disease3and breast and ovarian cancer4. Several recent studies have employed common polymorphisms5,-13 to characterize AJ as a genetically distinct population, close to other Jewish populations as well as to present-day Middle Eastern and European populations. Previous analyses of recent AJ history highlighted a narrow population bottleneck of only hundreds of individuals in late medieval times, followed by rapid expansion12, 14.
The AJ population is much larger and/or experienced a more severe bottleneck than other founder populations, such as Amish, Hutterites or Icelanders15, whose demographic histories facilitated a steady stream of genetic discoveries. This suggests the potential for cataloguing nearly all founder variants in a large extant population by sequencing a limited number of samples, who represent the diversity in the founding group (for example, ref. 16). Such a catalogue of variants can make a threefold contribution: First, it will enable clinical interpretation of personal genomes in the sizeable AJ population by distinguishing between background variation and recent, potentially more deleterious mutations. Second, it will improve disease mapping in AJ by increasing the accuracy of imputation. Third, the ability to extensively sample a population with ancient roots in the Levant is expected to provide insights regarding the histories of both Middle Eastern and European populations.
Now a team of scientists report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Reconstruction of recent AJ history from such data confirms a recent bottleneck of merely ≈350 individuals. Modeling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. The researchers date the split between the two ancestral populations to ≈12–25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum.
Genetic mutations are commonly studied because of links to diseases such as cancer; however, little is known about mutations occurring in healthy individuals. In a study published online in Genome Research, researchers detected over 400 mutations in healthy blood cells of a 115-year-old woman, suggesting that lesions at these sites are largely harmless over the course of a lifetime.
Our blood is continually replenished by hematopoietic stem cells that reside in the bone marrow and divide to generate different types of blood cells, including white blood cells. Cell division, however, is error-prone, and more frequently dividing cells, including the blood, are more likely to accumulategenetic mutations. Hundreds of mutations have been found in patients with blood cancers such as acute myeloid leukemia (AML), but it is unclear whether healthy white blood cells also harbor mutations.
In this new study, the authors used whole genome sequencing of white blood cells from a supercentenarian woman to determine if, over a long lifetime, mutations accumulate in healthy white blood cells. The scientists identified over 400 mutations in the white blood cells that were not found in her brain, which rarely undergoes cell division after birth. These mutations, known as somatic mutations because they are not passed on to offspring, appear to be tolerated by the body and do not lead to disease. The mutations reside primarily in non-coding regions of the genome not previously associated with disease, and include sites that are especially mutation-prone such as methylated cytosine DNA bases and solvent-accessible stretches of DNA.
By examining the fraction of the white blood cells containing the mutations, the authors made a major discovery that may hint at the limits of human longevity. "To our great surprise we found that, at the time of her death, the peripheral blood was derived from only two active hematopoietic stem cells (in contrast to an estimated 1,300 simultaneously active stem cells), which were related to each other," said lead author of the study, Dr. Henne Holstege.
The authors also examined the length of the telomeres, or repetitive sequences at the ends of chromosomes that protects them from degradation. After birth, telomeres progressively shorten with each cell division. The supercentenarian's white blood cell telomeres were extremely short.
After years of failed attempts, researchers have successfully generated stem cells from adults. The process could provide a new way for scientists to generate healthy replacements for diseased or damaged cells in patients
After years of failed attempts, researchers have finally generated stem cells from adults using the same cloning technique that produced Dolly the sheep in 1996.
A previous claim that Korean investigators had succeeded in the feat turned out to be fraudulent. Then last year, a group at Oregon Health & Science University generated stem cells using the Dolly technique, but with cells from fetuses and infants.In this case, cells from a 35-year-old man and a 75-year-old man were used to generate two separate lines of stem cells. The process, known as nuclear transfer, involves taking the DNA from a donor and inserting it into an egg that has been stripped of its DNA. The resulting hybrid is stimulated to fuse and start dividing; after a few days the “embryo” creates a lining of stem cells that are destined to develop into all of the cells and tissues in the human body. Researchers extract these cells and grow them in the lab, where they are treated with the appropriate growth factors and other agents to develop into specific types of cells, like neurons, muscle, or insulin-producing cells. Reporting in the journal Cell Stem Cell, Dr. Robert Lanza, chief scientific officer at biotechnology company Advanced Cell Technology, and his colleagues found that tweaking the Oregon team’s process was the key to success with reprogramming the older cells. Like the earlier team, Lanza’s group used caffeine to prevent the fused egg from dividing prematurely. Rather than leaving the egg with its newly introduced DNA for 30 minutes before activating the dividing stage, they let the eggs rest for about two hours. This gave the DNA enough time to acclimate to its new environment and interact with the egg’s development factors, which erased each of the donor cell’s existing history and reprogrammed it to act like a brand new cell in an embryo.
The team, which included an international group of stem cell scientists, used 77 eggs from four different donors. They tested their new method by waiting for 30 minutes before activating 38 of the resulting embryos, and waiting two hours before triggering 39 of them. None of the 38 developed into the next stage, while two of the embryos getting extended time did. “There is a massive molecular change occurring. You are taking a fully differentiated cell, and you need to have the egg do its magic,” says Lanza. “You need to extend the reprogramming time before you can force the cell to divide.”
While a 5% efficiency may not seem laudable, Lanza says that it’s not so bad given that the stem cells appear to have had their genetic history completely erased and returned to that of a blank slate. “This procedure works well, and works with adult cells,” says Lanza.
The results also teach stem cell scientists some important lessons. First, that the nuclear transfer method that the Oregon team used is valid, and that with some changes it can be replicated using older adult cells. “It looks like the protocols we described are real, they are universal, they work in different hands, in different labs and with different cells,” says Shoukhrat Mitalopov, director of the center for embryonic cell and gene therapy at Oregon Health & Science University, and lead investigator of that study.
VIDEO: Breakthrough in Cloning Human Stem Cells: Explainer
"Google is using a new technology to automatically generate 3D buildings from 45-degree angle aerial photography made by overlapping passes of aircraft. The aerial photos are combined to create 3D models."
The first photographs have emerged of a newly formed volcanic island in the Pacific Ocean after three men climbed to the peak of the land mass off the coast of Tonga. Experts believe a volcano exploded underwater and then expanded until an island formed. The island is expected to erode back into the ocean in a matter of months.
Cells regulate the uptake of nutrients and messenger cargos and their transport within the cell. This process is known as endocytosis and membrane traffic. Different cargos dock onto substrate specific receptors on the cell membrane. Special proteins such as kinases, GTPases and coats, activate specific entry routes and trigger the uptake of the receptors into the cell. For their uptake, the receptors and docked cargos become enclosed by the cell membrane. In the next steps, the membrane invaginates and becomes constricted. The resulting vesicle is guided via several distinct stations, cellular organelles, to its final destination in the cell.
For her study, Dr. Prisca Liberali, senior scientist in the team of Professor Lucas Pelkmans, sequentially switched off 1200 human genes. Using automated high-throughput light microscopy and computer vision, she could monitor and compare 13 distinct transport paths involving distinct receptors and cellular organelles. Precise quantifications of thousands of single cells identified the genes required for the different transport routes. Surprisingly, sets of transport routes are co-regulated and coordinated in specific ways by different programs of regulatory control.
Subsequently, Dr. Liberali calculated the hierarchical order within the genetic network and thereby identified the regulatory topology of cellular transport. "The transport into the cell and within the cells proceeds analogously to the cargo transport within a city" describes the scientist. "Like in a city, the traffic on the routes within a cell and their intersections is tightly regulated by traffic lights and signs to guide the cargo flow."
Thanks to this unique quantitative map, the fine regulatory details of transport paths and processes within a cells could be mapped for the first time. Particularly the genes that encode for these traffic lights and switches are often de-regulated in disease. With this map, it is now possible to predict how this leads to traffic jams in the cells, causing the disease phenotype. Alternatively, since many drugs have been developed to target these traffic lights and switches, the map can be used to come up with possible drug combinations to target unwanted traffic, such as viruses, to the waste disposal system of the cell.
The higher you look in the cerebral cortex, the less myelin you'll find. Myelin, the electrical insulating material in the body long known to be essential for the fast transmission of impulses along the axons of nerve cells, is not as ubiquitous as thought, according to new work led by Professor Paola Arlotta of the Harvard Stem Cell Institute (HSCI) and the University’s Department of Stem Cell and Regenerative Biology, in collaboration with Professor Jeff Lichtman of Harvard’s Department of Molecular and Cellular Biology.
“Myelin is a relatively recent invention during evolution,” says Arlotta. “It’s thought that myelin allowed the brain to communicate really fast to the far reaches of the body, and that it has endowed the brain with the capacity to compute higher-level functions.”
In fact, loss of myelin is a feature in a number of devastating diseases, including multiple sclerosis and schizophrenia. But the new research shows that despite myelin’s essential roles in the brain, “some of the most evolved, most complex neurons of the nervous system have less myelin than older, more ancestral ones,” said Arlotta, co-director of the HSCI neuroscience program.
She said the higher one looks in the cerebral cortex — closer to the top of the brain, which is its most evolved part — the less myelin one finds. Not only that, but “neurons in this part of the brain display a brand-new way of positioning myelin along their axons that has not been previously seen. They have ‘intermittent myelin’ with long axon tracts that lack myelin interspersed among myelin-rich segments.”
“Contrary to the common assumptions that neurons use a universal profile of myelin distribution on their axons, the work indicates that different neurons choose to myelinate their axons differently,” Arlotta said.
“In classic neurobiology textbooks, myelin is represented on axons as a sequence of myelinated segments separated by very short nodes that lack myelin. This distribution of myelin was tacitly assumed to be always the same, on every neuron, from the beginning to the end of the axon. This new work finds this not to be the case.”
The results of the research by Arlotta and postdoctoral fellow Giulio Srubek Tomassy, the first author on the report, are published in the latest edition of the journal Science.
An enveloped virus (left) coats itself with lipid as part of its life cycle. New lipid-coated DNA nanodevices (right) closely resemble those viruses and evade.
Scientists at Harvard’s Wyss Institute for Biologically Inspired Engineering have built the first DNA nanodevices that survive the body’s immune defenses.
The results pave the way for smart DNA nanorobots that could use logic to diagnose cancer earlier and more accurately than doctors can today, target drugs to tumors, or even manufacture drugs on the spot to cripple cancer, the researchers report in the April 22 online issue of ACS Nano.
“We’re mimicking virus functionality to eventually build therapeutics that specifically target cells,” said Wyss Institute Core Faculty member William Shih, Ph.D., the paper’s senior author. Shih is also an Associate Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and Associate Professor of Cancer Biology at the Dana-Farber Cancer Institute.
The same cloaking strategy could also be used to make artificial microscopic containers called protocells that could act as biosensors to detect pathogens in food or toxic chemicals in drinking water.
DNA is well known for carrying genetic information, but Shih and other bioengineers are using it instead as a building material. To do this, they use DNA origami — a method Shih helped extend from 2D to 3D. In this method, scientists take a long strand of DNA and program it to fold into specific shapes, much as a single sheet of paper is folded to create various shapes in the traditional Japanese art.
Shih’s team assembles these shapes to build DNA nanoscale devices that might one day be as complex as the molecular machinery found in cells. For example, they are developing methods to build DNA into tiny robots that sense their environment, calculate how to respond, then carry out a useful task, such as performing a chemical reaction or generating mechanical force or movement.
In 2012 Wyss Institute researchers reported in Science that they had built a nanorobot that uses logic to detect a target cell, then reveals an antibody that activates a “suicide switch” in leukemia or lymphoma cells.
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