Bioinformatics is a field of multidisciplinary research, combining : computing, biology, physics, organic chemistry and mathematics.
Bioinformatics demonstrated its effectiveness in speeding standard biology protocols and implementing protocols currently unimaginable in standard biology. Thereby, bioinformatics accelerate research and save money that can be invested to better care of patients or to finance another area of research.
Biologists of the University of Zurich have developed a method to visualize the activity of genes in single cells. The method is so efficient that, for the first time, a thousand genes can be studied in parallel in ten thousand single human cells.
Applications lie in fields of basic research and medical diagnostics. The new method shows that the activity of genes, and the spatial organization of the resulting transcript molecules, strongly vary between single cells. Whenever cells activate a gene, they produce gene specific transcript molecules, which make the function of the gene available to the cell. The measurement of gene activity is a routine activity in medical diagnostics, especially in cancer medicine. Today's technologies determine the activity of genes by measuring the amount of transcript molecules. However, these technologies can neither measure the amount of transcript molecules of one thousand genes in ten thousand single cells, nor the spatial organization of transcript molecules within a single cell. The fully automated procedure, developed by biologists of the University of Zurich under the supervision of Prof. Lucas Pelkmans, allows, for the first time, a parallel measurement of the amount and spatial organization of single transcript molecules in ten thousands single cells. The results, which were recently published in the scientific journal Nature Methods, provide completely novel insights into the variability of gene activity of single cells.
The method developed by Pelkmans' PhD students Nico Battich and Thomas Stoeger is based upon the combination of robots, an automated fluorescence microscope and a supercomputer. "When genes become active, specific transcript molecules are produced. We can stain them with the help of a robot", explains Stoeger. Subsequently, fluorescence microscope images of brightly glowing transcript molecules are generated. Those images were analyzed with the supercomputer Brutus, of the ETH Zurich. With this method, one thousand human genes can be studied in ten thousand single cells. According to Pelkmans, the advantages of this method are the high number of single cells and the possibility to study, for the first time, the spatial organization of the transcript molecules of many genes.
The analysis of the new data shows that individual cells distinguish themselves in the activity of their genes. While the scientists had been suspecting a high variability in the amount of transcript molecules, they were surprised to discover a strong variability in the spatial organization of transcript molecules within single cells and between multiple single cells. The transcript molecules adapted distinctive patterns.
The importance of these new insights was summarized by Pelkmans: "Our method will be of importance to basic research and the understanding of cancer tumors because it allows us to map the activity of genes within single tumor cells.
A mutation in one gene means that a girl is unable to sense pain – a discovery that could hold clues for the development of new drugs.
A girl who does not feel physical pain has helped researchers identify a gene mutation that disrupts pain perception. The discovery may spur the development of new painkillers that will block pain signals in the same way.
People with congenital analgesia cannot feel physical pain and often injure themselves as a result – they might badly scald their skin, for example, through being unaware that they are touching something hot.
By comparing the gene sequence of a girl with the disorder against those of her parents, who do not, Ingo Kurth at Jena University Hospital in Germany and his colleagues identified a mutation in a gene called SCN11A.
This gene controls the development of channels on pain-sensing neurons. Sodium ions travel through these channels, creating electrical nerve impulses that are sent to the brain, which registers pain.
Overactivity in the mutated version of SCN11A prevents the build-up of the charge that the neurons need to transmit an electrical impulse, numbing the body to pain. "The outcome is blocked transmission of pain signals," says Kurth.
To confirm their findings, the team inserted a mutated version of SCN11A into mice and tested their ability to perceive pain. They found that 11 per cent of the mice with the modified gene developed injuries similar to those seen in people with congenital analgesia, such as bone fractures and skin wounds. They also tested a control group of mice with the normal SCN11A gene, none of which developed such injuries.
The altered mice also took 2.5 times longer on average than the control group to react to the "tail flick" pain test, which measures how long it takes for mice to flick their tails when exposed to a hot light beam. "What became clear from our experiments is that although there are similarities between mice and men with the mutation, the degree of pain insensitivity is more prominent in humans," says Kurth.
The team has now begun the search for drugs that block the SCN11Achannel. "It would require drugs that selectively block this but not other sodium channels, which is far from simple," says Kurth.
"This is great science," says Geoffrey Wood of the University of Cambridge, whose team discovered in 2006 that mutations in another, closely related ion channel gene can cause insensitivity to pain. "It's completely unexpected and not what people had been looking for," he says.
Wood says that there are three ion channels, called SCN9A, 10A and 11A, on pain-sensing neurons. People experience no pain when either of the first two don't work, and agonising pain when they're overactive. "With this new gene, it's the opposite: when it's overactive, they feel no pain. So maybe it's some kind of gatekeeper that stops neurons from firing too often, but cancels pain signals completely when it's overactive," he says. "If you could get a drug that made SCN11A overactive, it should be a fantastic analgesic."
"It's fascinating that SCN11A appears to work the other way, and that could really advance our knowledge of the role of sodium channels in pain perception, which is a very hot topic," says Jeffrey Mogil at McGill University in Canada, who was not involved in the new study.
Does water drive protein folding? That's the title of a paper by Yutaka Maruyama and Yuichi Harano at Osaka University (Chem. Phys. Lett. 581, 85; 2013 – paper here), and as you'd expect from a title like that, they conclude ...
When it comes to determining whether lung nodules are malignant or benign, a patient typically faces surgery and a biopsy. It's an invasive and costly response, and, in 80 percent of cases, unnecessary.
While host immune receptors detect pathogen-associated molecular patterns to activate immunity, pathogens attempt to deregulate host immunity through secreted effectors. Fungi employ LysM effectors to prevent recognition of cell wall-derived chitin by host immune receptors, although the mechanism to compete for chitin binding remained unclear. Structural analysis of the LysM effector Ecp6 of the fungal tomato pathogen Cladosporium fulvum reveals a novel mechanism for chitin binding, mediated by intrachain LysM dimerization, leading to a chitin-binding groove that is deeply buried in the effector protein. This composite binding site involves two of the three LysMs of Ecp6 and mediates chitin binding with ultra-high (pM) affinity. Intriguingly, the remaining singular LysM domain of Ecp6 binds chitin with low micromolar affinity but can nevertheless still perturb chitin-triggered immunity. Conceivably, the perturbation by this LysM domain is not established through chitin sequestration but possibly through interference with the host immune receptor complex.
The publicly available Proteome Database System for Microbial Research 2D-PAGE has been established at the Max Planck Institute for Infection Biology and serves as a template for a prototype of a European Proteome Database of Pathogenic Bacteria. The database system is centrally administrated, and investigators without specific bioinformatics competence in database construction can submit their data. The system comprises four heterogeneous but interconnected databases: (i) 2D-PAGE database for 2-D gel electrophoresis and mass spectrometry data, (ii) Isotope Coded Affinity Tag (ICAT)-LC/MS database, (iii) FUNC_CLASS database for functional classification of proteins, (iv) DIFF database for presentation of differentially regulated proteins detected by quantitative gel image analysis. The database system is hyperlinked with public databases such as SWISS-PROT; NCBI; PEDANT and KEGG. The current public release (May, 2004) contains proteomic information on 11 microorganisms such as Mycobacterium tuberculosis, Helicobacter pylori, Chlamydophila pneumoniae, Borrelia garinii, Francisella tularensis, Mycoplasma pneumoniae and information on Jurkat T-cells and mouse mammary gland. Proteomic data are presented in 18 two-dimensional gels with 2572 identified protein spots. For 254 of these spots peptide mass fingerprints are available. More than 1000 identified spots of further miroorganisms such asMycobacterium bovis BCG, Salmonella SL-1344, Vibrio cholerae are stored in the internal release of 2D-PAGE which will be publicly accessible after paper submission. The annotated proteome data such as protein name, molecular weight Mr, isoelectric point pI, gene name, ORF, NCBI accession number, identification method, sequence coverage, protein spot number, class (antigen, gastric carcinoma associated antigen etc.) can be retrieved either by clicking on protein spots or by formulating complex queries. Specific data such as pI, Mr-values or codon usage for proteins can be visualized and analyzed on the fly using the statistical software environment R (http://www.r-project.org/) or can be downloaded as spread sheet files. The Proteome Database System for Microbial Research can be accessed from http://www.mpiib-berlin.mpg.de/2D-PAGE.
TED Talks We have personal computing, why not personal biotech?
That’s the question biologist Ellen Jorgensen and her colleagues asked themselves before opening Genspace, a nonprofit DIYbio lab in Brooklyn devoted to citizen science, where amateurs can go and tinker with biotechnology. Far from being a sinister Frankenstein's lab (as some imagined it), Genspace offers a long list of fun, creative and practical uses for DIYbio.
A database of known drug-gene interactions, with information derived from many public sources, allows the identification of genes that are currently targeted by a drug and the membership of genes in a category, such as kinase genes, that have a...
The molecular recognition ability of proteins is essential in biological systems, and therefore a considerable amount of effort has been devoted to constructing desired target-binding proteins using a variety of naturally occurring proteins as scaffolds. However, since generating a binding site in a native protein can often affect its structural properties, highly stablede novo protein scaffolds may be more amenable than the native proteins. We previously reported the generation of de novo proteins comprising three α-helices and three β-strands (α3β3) from a genetic library coding simplified amino acid sets. Two α3β3 de novo proteins, vTAJ13 and vTAJ36, fold into a native-like stable and molten globule-like structures, respectively, even though the proteins have similar amino acid compositions. Here, we attempted to create binding sites for the vTAJ13 and vTAJ36 proteins to prove the utility of de novo designed artificial proteins as a molecular recognition tool. Randomization of six amino acids at two linker sites of vTAJ13 and vTAJ36 followed by biopanning generated binding proteins that recognize the target molecules, fluorescein and green fluorescent protein, with affinities of 10−7–10−8 M. Of note, the selected proteins from the vTAJ13-based library tended to recognize the target molecules with high specificity, probably due to the native-like stable structure of vTAJ13. Our studies provide an example of the potential of de novo protein scaffolds, which are composed of a simplified amino acid set, to recognize a variety of target compounds.
Scientists in the US have devised a stunningly simple way to direct colloids to self-assemble in an almost infinite variety of configurations, in both two and three dimensions. The technique, which relies on the creation of a pre-determined pattern of magnetic fields to generate a ‘virtual mould’ to dictate the final position of the particles, can be used to separate and distribute, in a controlled way, anything from living cells to ions.
‘The concept is trivial,’ Bartosz Grzybowski, who led the research team at Northwestern University, cheerfully concedes. ‘Why no-one thought of it before now is a good question.’
The system consists of a patterned grid of nickel, generated by photolithography, embedded in a layer of poly(dimethyl siloxane) (PDMS). This is placed on a permanent magnet. This forms a patterned magnetic field on the grid: on the nickel the field is strong, on the adjacent ‘islands’ where there is no nickel, the field is weak.
When a colloidal mixture containing magnetic (paramagnetic) and non-magnetic (diamagnetic) particles is placed on the nickel grid and a magnetic field applied, the paramagnetic particles are drawn to the nickel regions, pushing aside any diamagnetic particles and directing them to the adjacent non-magnetic islands or voids.
The ability to construct three-dimensional architectures from the colloids also arises, given that the magnetic field penetrates the space above the nickel regions. An excess of diamagnetic colloid, for example, will coalesce on a low-field island to build a pillar. A further excess of particles can build bridges between pillars to produce arches. Such complex three-dimensional structures could be useful for electronic circuitry. To illustrate the versatility of the approach, the research team patterned a grid in such a way to fashion a microscopic facsimile of the Blue Mosque in Istanbul, featuring large ‘domes’ connected by arches, and surrounded by four unconnected satellite domes.
‘For me, one of the main aspects of this work is in being able to position particles, and in particular living cells,’ says Grzybowski. ‘We should be able to address things that cannot be addressed by other means.’
Stefano Sacanna, who researches colloid self-assembly at New York University, says: ‘This is the kind of work that makes you think how come nobody has ever thought of this before?’ Sacanna says that while template-assisted self-assembly is a well-known technique the new work has ‘completely redefined this concept, introducing virtual magnetic moulds that can manipulate either paramagnetic or diamagnetic colloids simultaneously’.
‘Their idea of modulating magnetic fields at the micron-scale using a combination of paramagnetic fluids and magnetisable composite films is, in its simplicity, extremely powerful,’ he adds. ‘Not only can these virtual moulds extend in the third dimension, but they can also be switched on and off on demand, allowing for the creation of dynamic and reconfigurable three-dimensional colloidal architectures. As if this was not impressive enough already, they showed how magnetic moulds can manipulate objects other than colloids, including ions and colonies of – live! – bacteria. This work greatly extends our ability to manipulate colloidal matter and holds the promise for new exciting opportunities in nano-fabrication.’
Scientists from Yale and Harvard have recoded the entire genome of an organism and improved a bacterium’s ability to resist viruses, a dramatic demonstration of the potential of rewriting an organism’s genetic code.
“This is the first time the genetic code has been fundamentally changed,” said Farren Isaacs, assistant professor of molecular, cellular, and developmental biology at Yale and co-senior author of the research published Oct. 18 in the journal Science. “Creating an organism with a new genetic code has allowed us to expand the scope of biological function in a number of powerful ways.”
The creation of a genomically recoded organism raises the possibility that researchers might be able to retool nature and create potent new forms of proteins to accomplish a myriad purposes — from combating disease to generating new classes of materials.
The research — headed by Isaacs and co-author George Church of Harvard Medical School — is a product of years of studies in the emerging field of synthetic biology, which seeks to re-design natural biological systems for useful purposes.
In this case, the researchers changed fundamental rules of biology.
Proteins, which are encoded by DNA’s instructional manual and are made up of 20 amino acids, carry out many important functional roles in the cell. Amino acids are encoded by the full set of 64 triplet combinations of the four nucleic acids that comprise the backbone of DNA. These triplets (sets of three nucleotides) are called codons and are the genetic alphabet of life.
Isaacs, Jesse Rinehart of Yale, and the Harvard researchers explored whether they could expand upon nature’s handywork by substituting different codons or letters throughout the genome and then reintroducing entirely new letters to create amino acids not found in nature. This work marks the first time that the genetic code has been completely changed across an organism’s genome.
In the new study, the researchers working with E. coli swapped a codon and eliminated its natural stop sign that terminates protein production. The new genome enabled the bacteria to resist viral infection by limiting production of natural proteins used by viruses to infect cells. Isaacs — working with Marc Lajoie of Harvard, Alexis Rovner of Yale, and colleagues — then converted the “stop” codon into one that encodes new amino acids and inserted it into the genome in a plug-and-play fashion.
The work now sets the stage to convert the recoded bacterium into a living foundry, capable of biomanufacturing new classes of “exotic” proteins and polymers. These new molecules could lay the foundation for a new generation of materials, nanostructures, therapeutics, and drug delivery vehicles, Isaacs said.
“Since the genetic code is universal, it raises the prospect of recoding genomes of other organisms,” Isaacs said. “This has tremendous implications in the biotechnology industry and could open entirely new avenues of research and applications.”
Dr. Michio Kaku is a theoretical physicist and the Henry Semat Professor at the City College of New York and the Graduate Center of the City University of New York, where he has taught for more than 30 years. He is a graduate of Harvard University in Cambridge, Massachusetts, and earned his doctorate from the University of California at Berkeley.
Dr. Kaku is one of the founders of string field theory, a field of research within string theory. String theory seeks to provide a unified description for all matter and the fundamental forces of the universe.
His book The Physics of the Impossible addresses how science fiction technology may become possible in the future. His other books include Hyperspace: A Scientific Odyssey Through Parallel Universes, Time Warps, and the Tenth Dimension , selected as one of the best science books of 1994 by both the New York Times and The Washington Post, and Parallel Worlds: A Journey Through Creation, Higher Dimensions, and the Future of the Cosmos , a finalist for the Samuel Johnson Prize.
MicroRNAs (miRNAs) are small (approximately 22 nt) noncoding RNAs that play an important role in the regulation of various biological processes through their interaction with cellular messenger RNAs. They are frequently dysregulated in cancer and have shown promise as tissue-based markers for cancer classification and prognostication. Extracellular miRNAs in serum, plasma, saliva, urine and other body fluids have recently been shown to be associated with various pathological conditions including cancer. miRNAs circulate in the bloodstream in a highly stable, extracellular form, thus they may be used as blood-based biomarkers for cancer and other diseases.
Circulating miRNAs are protected by encapsulation in membrane-bound vesicles such as exosomes, but the majority of circulating miRNAs in human plasma and serum cofractionate with Argonaute2 (Ago2) protein, rather than with vesicles. In the present work, we performed a comprehensive classification of different extracellular circulating miRNA types. A direct link to the knowledge base miRò together with the inclusion of datamining facilities allow users to infer possible biological functions of the circulating miRNAs and their connection with the phenotype. To our knowledge miRandola is the first database that provides information about all kind of extracellular miRNAs and we believe that it will constitute a very important resource for researchers.
Nano technologists at the University of Twente research institute MESA+ have, for the first time, demonstrated quantum effects in tiny nanowires of iridium atoms. These effects, which occur at room temperature, are responsible for ensuring that the wires are almost always 4.8 nanometers—or multiples thereof—long. They only found the effects when they failed to create long nanowires of iridium.
There is an increasing interest in metallic nanowires within the scientific community. This is partly because they are extremely useful as part of (nano-) electronics and partly because nanowires lend themselves to achieving more insight into the exotic and unique physical properties of one-dimensional systems. In 2003, UT researcher, Prof. Harold Zandvliet and his research group, had already succeeded—using self-assembly—in creating nanowires of platinum atoms on a surface. Because gold and iridium are both closely related to platinum, nanowires of these materials were the following logical steps. The researchers managed to create long threads with gold, but when they recently wanted to repeat the trick with iridium, it appeared that the wire lengths occurred only in units of 4.8 nanometers.
Experiment failed, you might think, but that is not the case. Further examination of the nanowires formed produced namely a surprising discovery: nearly all the wires that were formed had a length of 4.8 nanometers, or multiples thereof, and they nearly all contained twelve iridium atoms, or a multiple thereof. The researchers found the explanation for this in quantum effects. The wires of 4.8 nanometers (or multiples thereof) appear to be electronically stabilized by conduction electrons whose (half) wavelength (or a multiple thereof) fits precisely in the nanowire. The existence of these standing electron waves in the nanowires could be demonstrated experimentally. As this stabilizing effect will not occur in nanowires of iridium of a different length, they are formed more slowly.
What makes quantum effects in the nanowires even more interesting is that they occur at room temperature, while many quantum effects normally appear only at extremely low temperatures.
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