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The influence of physical activity in the progression of experimental lung cancer in mice
- PMID: 22683274
- DOI: 10.1016/j.prp.2012.04.006
GRUPO_AF1 – GROUP AFA1 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO AFAN 1 – GROUP AFAN1 – Anaerobic Physical Activity – Atividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO_AF2 – GROUP AFA2 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO AFAN 2 – GROUP AFAN 2 – Anaerobic Physical Activity – Atividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
Slides – mestrado – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
DMBA CARCINOGEN IN EXPERIMENTAL MODELS
Avaliação da influência da atividade física aeróbia e anaeróbia na progressão do câncer de pulmão experimental – Summary – Resumo – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
Lung cancer is one of the most incident neoplasms in the world, representing the main cause of mortality for cancer. Many epidemiologic studies have suggested that physical activity may reduce the risk of lung cancer, other works evaluate the effectiveness of the use of the physical activity in the suppression, remission and reduction of the recurrence of tumors. The aim of this study was to evaluate the effects of aerobic and anaerobic physical activity in the development and the progression of lung cancer. Lung tumors were induced with a dose of 3mg of urethane/kg, in 67 male Balb – C type mice, divided in three groups: group 1_24 mice treated with urethane and without physical activity; group 2_25 mice with urethane and subjected to aerobic swimming free exercise; group 3_18 mice with urethane, subjected to anaerobic swimming exercise with gradual loading 5-20% of body weight. All the animals were sacrificed after 20 weeks, and lung lesions were analyzed. The median number of lesions (nodules and hyperplasia) was 3.0 for group 1, 2.0 for group 2 and 1.5-3 (p=0.052). When comparing only the presence or absence of lesion, there was a decrease in the number of lesions in group 3 as compared with group 1 (p=0.03) but not in relation to group 2. There were no metastases or other changes in other organs. The anaerobic physical activity, but not aerobic, diminishes the incidence of experimental lung tumors.
Copyright © 2012 Elsevier GmbH. All rights reserved.
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Science. 2003 Nov 14;302(5648):1172-5.
Human population: the next half century.
1Rockefeller University and Columbia University, 1230 New York Avenue, Box 20, New York, NY 10021, USA. firstname.lastname@example.org
By 2050, the human population will probably be larger by 2 to 4 billion people, more slowly growing (declining in the more developed regions), more urban, especially in less developed regions, and older than in the 20th century. Two major demographic uncertainties in the next 50 years concern international migration and the structure of families. Economies, nonhuman environments, and cultures (including values, religions, and politics) strongly influence demographic changes. Hence, human choices, individual and collective, will have demographic effects, intentional or otherwise.PMID: 14615528 DOI: 10.1126/science.1088665[Indexed for MEDLINE]
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Human Population: The Next Half Century
- Joel E. Cohen
See all authors and affiliationsScience 14 Nov 2003:
Vol. 302, Issue 5648, pp. 1172-1175
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By 2050, the human population will probably be larger by 2 to 4 billion people, more slowly growing (declining in the more developed regions), more urban, especially in less developed regions, and older than in the 20th century. Two major demographic uncertainties in the next 50 years concern international migration and the structure of families. Economies, nonhuman environments, and cultures (including values, religions, and politics) strongly influence demographic changes. Hence, human choices, individual and collective, will have demographic effects, intentional or otherwise.View Full Text
Vol 302, Issue 5648
14 November 2003
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From Wikipedia, the free encyclopediaJump to navigationJump to searchFor a non-technical introduction to the topic, see Introduction to genetics. For other uses, see DNA (disambiguation).The structure of the DNA double helix. The atoms in the structure are colour-coded by element and the detailed structures of two base pairs are shown in the bottom right.The structure of part of a DNA double helix
Deoxyribonucleic acid (/diːˈɒksɪˌraɪboʊnjuːˌkliːɪk, -ˌkleɪ-/ (listen); DNA) is a molecule composed of two chains that coil around each other to form a double helix carrying genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids; alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.
The two DNA strands are also known as polynucleotides as they are composed of simpler monomeric units called nucleotides. Each nucleotide is composed of one of four nitrogen-containing nucleobases (cytosine [C], guanine [G], adenine [A] or thymine [T]), a sugar called deoxyribose, and a phosphate group. The nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. The nitrogenous bases of the two separate polynucleotide strands are bound together, according to base pairing rules (A with T and C with G), with hydrogen bonds to make double-stranded DNA. The complementary nitrogenous bases are divided into two groups, pyrimidines and purines. In DNA, the pyrimidines are thymine and cytosine; the purines are adenine and guanine.
Both strands of double-stranded DNA store the same biological information. This information is replicated as and when the two strands separate. A large part of DNA (more than 98% for humans) is non-coding, meaning that these sections do not serve as patterns for protein sequences. The two strands of DNA run in opposite directions to each other and are thus antiparallel. Attached to each sugar is one of four types of nucleobases (informally, bases). It is the sequence of these four nucleobases along the backbone that encodes genetic information. RNA strands are created using DNA strands as a template in a process called transcription, where DNA bases are exchanged for their corresponding bases except in the case of thymine (T), which RNA substitutes for uracil (U). Under the genetic code, these RNA strands specify the sequence of amino acids within proteins in a process called translation.
Within eukaryotic cells, DNA is organized into long structures called chromosomes. Before typical cell division, these chromosomes are duplicated in the process of DNA replication, providing a complete set of chromosomes for each daughter cell. Eukaryotic organisms (animals, plants, fungi and protists) store most of their DNA inside the cell nucleus as nuclear DNA, and some in the mitochondria as mitochondrial DNA or in chloroplasts as chloroplast DNA. In contrast, prokaryotes (bacteria and archaea) store their DNA only in the cytoplasm, in circular chromosomes. Within eukaryotic chromosomes, chromatin proteins, such as histones, compact and organize DNA. These compacting structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed.
DNA was first isolated by Friedrich Miescher in 1869. Its molecular structure was first identified by Francis Crick and James Watson at the Cavendish Laboratory within the University of Cambridge in 1953, whose model-building efforts were guided by X-ray diffraction data acquired by Raymond Gosling, who was a post-graduate student of Rosalind Franklin at King’s College London. DNA is used by researchers as a molecular tool to explore physical laws and theories, such as the ergodic theorem and the theory of elasticity. The unique material properties of DNA have made it an attractive molecule for material scientists and engineers interested in micro- and nano-fabrication. Among notable advances in this field are DNA origami and DNA-based hybrid materials.
- 2Chemical modifications and altered DNA packaging
- 3Biological functions
- 4Interactions with proteins
- 5Genetic recombination
- 7Uses in technology
- 9See also
- 11Further reading
- 12External links
Chemical structure of DNA; hydrogen bonds shown as dotted lines
DNA is a long polymer made from repeating units called nucleotides, each of which is usually symbolized by a single letter: either A, T, C, or G. The structure of DNA is dynamic along its length, being capable of coiling into tight loops and other shapes. In all species it is composed of two helical chains, bound to each other by hydrogen bonds. Both chains are coiled around the same axis, and have the same pitch of 34 angstroms (Å) (3.4 nanometres). The pair of chains has a radius of 10 angstroms (1.0 nanometre). According to another study, when measured in a different solution, the DNA chain measured 22 to 26 angstroms wide (2.2 to 2.6 nanometres), and one nucleotide unit measured 3.3 Å (0.33 nm) long. Although each individual nucleotide is very small, a DNA polymer can be very large and contain hundreds of millions, such as in chromosome 1. Chromosome 1 is the largest human chromosome with approximately 220 million base pairs, and would be 85 mm long if straightened.
DNA does not usually exist as a single strand, but instead as a pair of strands that are held tightly together. These two long strands coil around each other, in the shape of a double helix. The nucleotide contains both a segment of the backbone of the molecule (which holds the chain together) and a nucleobase (which interacts with the other DNA strand in the helix). A nucleobase linked to a sugar is called a nucleoside, and a base linked to a sugar and to one or more phosphate groups is called a nucleotide. A biopolymer comprising multiple linked nucleotides (as in DNA) is called a polynucleotide.
The backbone of the DNA strand is made from alternating phosphate and sugar groups. The sugar in DNA is 2-deoxyribose, which is a pentose (five-carbon) sugar. The sugars are joined together by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These are known as the 3′-end (three prime end), and 5′-end (five prime end) carbons, the prime symbol being used to distinguish these carbon atoms from those of the base to which the deoxyribose forms a glycosidic bond. Therefore, any DNA strand normally has one end at which there is a phosphate group attached to the 5′ carbon of a ribose (the 5′ phosphoryl) and another end at which there is a free hydroxyl group attached to the 3′ carbon of a ribose (the 3′ hydroxyl). The orientation of the 3′ and 5′ carbons along the sugar-phosphate backbone confers directionality (sometimes called polarity) to each DNA strand. In a nucleic acid double helix, the direction of the nucleotides in one strand is opposite to their direction in the other strand: the strands are antiparallel. The asymmetric ends of DNA strands are said to have a directionality of five prime end (5′ ), and three prime end (3′), with the 5′ end having a terminal phosphate group and the 3′ end a terminal hydroxyl group. One major difference between DNA and RNA is the sugar, with the 2-deoxyribose in DNA being replaced by the alternative pentose sugar ribose in RNA.A section of DNA. The bases lie horizontally between the two spiraling strands (animated version).
The DNA double helix is stabilized primarily by two forces: hydrogen bonds between nucleotides and base-stacking interactions among aromatic nucleobases. The four bases found in DNA are adenine (A), cytosine (C), guanine (G) and thymine (T). These four bases are attached to the sugar-phosphate to form the complete nucleotide, as shown for adenosine monophosphate. Adenine pairs with thymine and guanine pairs with cytosine, forming A-T and G-C base pairs.
The nucleobases are classified into two types: the purines, A and G, which are fused five- and six-membered heterocyclic compounds, and the pyrimidines, the six-membered rings C and T. A fifth pyrimidine nucleobase, uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring. In addition to RNA and DNA, many artificial nucleic acid analogues have been created to study the properties of nucleic acids, or for use in biotechnology.
Modified bases occur in DNA. The first of these recognised was 5-methylcytosine, which was found in the genome of Mycobacterium tuberculosis in 1925. The reason for the presence of these noncanonical bases in bacterial viruses (bacteriophages) is to avoid the restriction enzymes present in bacteria. This enzyme system acts at least in part as a molecular immune system protecting bacteria from infection by viruses. Modifications of the bases cytosine and adenine the more common and modified DNA bases plays vital roles in the epigenetic control of gene expression in plants and animals.
Listing of non-canonical bases found in DNA
A number of non canonical bases are known to occur in DNA. Most of these are modifications of the canonical bases plus uracil.
- Modified Adenosine
- Modified Guanine
- Modified Cytosine
- Modified Thymidine
- Uracil and modifications
- Base J
DNA major and minor grooves. The latter is a binding site for the Hoechst stain dye 33258.
Twin helical strands form the DNA backbone. Another double helix may be found tracing the spaces, or grooves, between the strands. These voids are adjacent to the base pairs and may provide a binding site. As the strands are not symmetrically located with respect to each other, the grooves are unequally sized. One groove, the major groove, is 22 angstroms (Å) wide and the other, the minor groove, is 12 Å wide. The width of the major groove means that the edges of the bases are more accessible in the major groove than in the minor groove. As a result, proteins such as transcription factors that can bind to specific sequences in double-stranded DNA usually make contact with the sides of the bases exposed in the major groove. This situation varies in unusual conformations of DNA within the cell (see below), but the major and minor grooves are always named to reflect the differences in size that would be seen if the DNA is twisted back into the ordinary B form.
Further information: Base pair
In a DNA double helix, each type of nucleobase on one strand bonds with just one type of nucleobase on the other strand. This is called complementary base pairing. Purines form hydrogen bonds to pyrimidines, with adenine bonding only to thymine in two hydrogen bonds, and cytosine bonding only to guanine in three hydrogen bonds. This arrangement of two nucleotides binding together across the double helix is called a Watson-Crick base pair. DNA with high GC-content is more stable than DNA with low GC-content. A Hoogsteen base pair is a rare variation of base-pairing. As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helix can thus be pulled apart like a zipper, either by a mechanical force or high temperature. As a result of this base pair complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. This reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in organisms.
Top, a GC base pair with three hydrogen bonds. Bottom, an AT base pair with two hydrogen bonds. Non-covalent hydrogen bonds between the pairs are shown as dashed lines.
As noted above, most DNA molecules are actually two polymer strands, bound together in a helical fashion by noncovalent bonds; this double-stranded (dsDNA) structure is maintained largely by the intrastrand base stacking interactions, which are strongest for G,C stacks. The two strands can come apart—a process known as melting—to form two single-stranded DNA (ssDNA) molecules. Melting occurs at high temperature, low salt and high pH (low pH also melts DNA, but since DNA is unstable due to acid depurination, low pH is rarely used).
The stability of the dsDNA form depends not only on the GC-content (% G,C basepairs) but also on sequence (since stacking is sequence specific) and also length (longer molecules are more stable). The stability can be measured in various ways; a common way is the “melting temperature”, which is the temperature at which 50% of the ds molecules are converted to ss molecules; melting temperature is dependent on ionic strength and the concentration of DNA. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determines the strength of the association between the two strands of DNA. Long DNA helices with a high GC-content have stronger-interacting strands, while short helices with high AT content have weaker-interacting strands. In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in some promoters, tend to have a high AT content, making the strands easier to pull apart.
In the laboratory, the strength of this interaction can be measured by finding the temperature necessary to break half of the hydrogen bonds, their melting temperature (also called Tm value). When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules have no single common shape, but some conformations are more stable than others.
Sense and antisense
Further information: Sense (molecular biology)
A DNA sequence is called a “sense” sequence if it is the same as that of a messenger RNA copy that is translated into protein. The sequence on the opposite strand is called the “antisense” sequence. Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands can contain both sense and antisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these RNAs are not entirely clear. One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.
A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction between sense and antisense strands by having overlapping genes. In these cases, some DNA sequences do double duty, encoding one protein when read along one strand, and a second protein when read in the opposite direction along the other strand. In bacteria, this overlap may be involved in the regulation of gene transcription, while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.
Further information: DNA supercoil
DNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its “relaxed” state, a strand usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound. If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases. These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.From left to right, the structures of A, B and Z DNA
Alternative DNA structures
Further information: Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid, Molecular models of DNA, and DNA structure
DNA exists in many possible conformations that include A-DNA, B-DNA, and Z-DNA forms, although, only B-DNA and Z-DNA have been directly observed in functional organisms. The conformation that DNA adopts depends on the hydration level, DNA sequence, the amount and direction of supercoiling, chemical modifications of the bases, the type and concentration of metal ions, and the presence of polyamines in solution.
The first published reports of A-DNA X-ray diffraction patterns—and also B-DNA—used analyses based on Patterson transforms that provided only a limited amount of structural information for oriented fibers of DNA. An alternative analysis was then proposed by Wilkins et al., in 1953, for the in vivo B-DNA X-ray diffraction-scattering patterns of highly hydrated DNA fibers in terms of squares of Bessel functions. In the same journal, James Watson and Francis Crick presented their molecular modeling analysis of the DNA X-ray diffraction patterns to suggest that the structure was a double-helix.
Although the B-DNA form is most common under the conditions found in cells, it is not a well-defined conformation but a family of related DNA conformations that occur at the high hydration levels present in cells. Their corresponding X-ray diffraction and scattering patterns are characteristic of molecular paracrystals with a significant degree of disorder.
Compared to B-DNA, the A-DNA form is a wider right-handed spiral, with a shallow, wide minor groove and a narrower, deeper major groove. The A form occurs under non-physiological conditions in partly dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, and in enzyme-DNA complexes. Segments of DNA where the bases have been chemically modified by methylation may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form. These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription.
Alternative DNA chemistry
For many years, exobiologists have proposed the existence of a shadow biosphere, a postulated microbial biosphere of Earth that uses radically different biochemical and molecular processes than currently known life. One of the proposals was the existence of lifeforms that use arsenic instead of phosphorus in DNA. A report in 2010 of the possibility in the bacterium GFAJ-1, was announced, though the research was disputed, and evidence suggests the bacterium actively prevents the incorporation of arsenic into the DNA backbone and other biomolecules.
Further information: G-quadruplex
At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes. These specialized chromosome caps also help protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected. In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.DNA quadruplex formed by telomere repeats. The looped conformation of the DNA backbone is very different from the typical DNA helix. The green spheres in the center represent potassium ions.
These guanine-rich sequences may stabilize chromosome ends by forming structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules. Here, four guanine bases form a flat plate and these flat four-base units then stack on top of each other, to form a stable G-quadruplex structure. These structures are stabilized by hydrogen bonding between the edges of the bases and chelation of a metal ion in the centre of each four-base unit. Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure.
In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins. At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop.
Branched DNA can form networks containing multiple branches.
In DNA, fraying occurs when non-complementary regions exist at the end of an otherwise complementary double-strand of DNA. However, branched DNA can occur if a third strand of DNA is introduced and contains adjoining regions able to hybridize with the frayed regions of the pre-existing double-strand. Although the simplest example of branched DNA involves only three strands of DNA, complexes involving additional strands and multiple branches are also possible. Branched DNA can be used in nanotechnology to construct geometric shapes, see the section on uses in technology below.
Main article: Nucleic acid analogue
Several artificial nucleobases have been synthesized, and successfully incorporated in the eight-base DNA analogue named Hachimoji DNA. Dubbed S, B, P, and Z, these artificial bases are capable of bonding with each other in a predictable way (S–B and P–Z), maintain the double helix structure of DNA, and be transcribed to RNA. Their existence implies that there is nothing special about the four natural nucleobases that evolved on Earth.
Chemical modifications and altered DNA packaging
Structure of cytosine with and without the 5-methyl group. Deamination converts 5-methylcytosine into thymine.
Base modifications and DNA packaging
The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin. Base modifications can be involved in packaging, with regions that have low or no gene expression usually containing high levels of methylation of cytosine bases. DNA packaging and its influence on gene expression can also occur by covalent modifications of the histone protein core around which DNA is wrapped in the chromatin structure or else by remodeling carried out by chromatin remodeling complexes (see Chromatin remodeling). There is, further, crosstalk between DNA methylation and histone modification, so they can coordinately affect chromatin and gene expression.
For one example, cytosine methylation produces 5-methylcytosine, which is important for X-inactivation of chromosomes. The average level of methylation varies between organisms—the worm Caenorhabditis elegans lacks cytosine methylation, while vertebrates have higher levels, with up to 1% of their DNA containing 5-methylcytosine. Despite the importance of 5-methylcytosine, it can deaminate to leave a thymine base, so methylated cytosines are particularly prone to mutations. Other base modifications include adenine methylation in bacteria, the presence of 5-hydroxymethylcytosine in the brain, and the glycosylation of uracil to produce the “J-base” in kinetoplastids.
Further information: DNA damage (naturally occurring), Mutation, and DNA damage theory of agingA covalentadduct between a metabolically activated form of benzo[a]pyrene, the major mutagen in tobacco smoke, and DNA
DNA can be damaged by many sorts of mutagens, which change the DNA sequence. Mutagens include oxidizing agents, alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and X-rays. The type of DNA damage produced depends on the type of mutagen. For example, UV light can damage DNA by producing thymine dimers, which are cross-links between pyrimidine bases. On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, and double-strand breaks. A typical human cell contains about 150,000 bases that have suffered oxidative damage. Of these oxidative lesions, the most dangerous are double-strand breaks, as these are difficult to repair and can produce point mutations, insertions, deletions from the DNA sequence, and chromosomal translocations. These mutations can cause cancer. Because of inherent limits in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer. DNA damages that are naturally occurring, due to normal cellular processes that produce reactive oxygen species, the hydrolytic activities of cellular water, etc., also occur frequently. Although most of these damages are repaired, in any cell some DNA damage may remain despite the action of repair processes. These remaining DNA damages accumulate with age in mammalian postmitotic tissues. This accumulation appears to be an important underlying cause of aging.
Many mutagens fit into the space between two adjacent base pairs, this is called intercalation. Most intercalators are aromatic and planar molecules; examples include ethidium bromide, acridines, daunomycin, and doxorubicin. For an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. This inhibits both transcription and DNA replication, causing toxicity and mutations. As a result, DNA intercalators may be carcinogens, and in the case of thalidomide, a teratogen. Others such as benzo[a]pyrene diol epoxide and aflatoxin form DNA adducts that induce errors in replication. Nevertheless, due to their ability to inhibit DNA transcription and replication, other similar toxins are also used in chemotherapy to inhibit rapidly growing cancer cells.
Location of eukaryote nuclear DNA within the chromosomes
DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set of chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes. The information carried by DNA is held in the sequence of pieces of DNA called genes. Transmission of genetic information in genes is achieved via complementary base pairing. For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then used to make a matching protein sequence in a process called translation, which depends on the same interaction between RNA nucleotides. In alternative fashion, a cell may simply copy its genetic information in a process called DNA replication. The details of these functions are covered in other articles; here the focus is on the interactions between DNA and other molecules that mediate the function of the genome.
Genes and genomes
Genomic DNA is tightly and orderly packed in the process called DNA condensation, to fit the small available volumes of the cell. In eukaryotes, DNA is located in the cell nucleus, with small amounts in mitochondria and chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid. The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, and regulatory sequences such as promoters and enhancers, which control transcription of the open reading frame.
In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences. The reasons for the presence of so much noncoding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species, represent a long-standing puzzle known as the “C-value enigma“. However, some DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression.T7 RNA polymerase (blue) producing an mRNA (green) from a DNA template (orange)
Some noncoding DNA sequences play structural roles in chromosomes. Telomeres and centromeres typically contain few genes but are important for the function and stability of chromosomes. An abundant form of noncoding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation. These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.
Transcription and translation
A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines one or more protein sequences. The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code. The genetic code consists of three-letter ‘words’ called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT).
In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (43 combinations). These encode the twenty standard amino acids, giving most amino acids more than one possible codon. There are also three ‘stop’ or ‘nonsense’ codons signifying the end of the coding region; these are the TAA, TGA, and TAG codons.DNA replication: The double helix is unwound by a helicase and topoisomerase. Next, one DNA polymerase produces the leading strand copy. Another DNA polymerase binds to the lagging strand. This enzyme makes discontinuous segments (called Okazaki fragments) before DNA ligase joins them together.
Further information: DNA replication
Cell division is essential for an organism to grow, but, when a cell divides, it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication. Here, the two strands are separated and then each strand’s complementary DNA sequence is recreated by an enzyme called DNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix. In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.
Extracellular nucleic acids
Naked extracellular DNA (eDNA), most of it released by cell death, is nearly ubiquitous in the environment. Its concentration in soil may be as high as 2 μg/L, and its concentration in natural aquatic environments may be as high at 88 μg/L. Various possible functions have been proposed for eDNA: it may be involved in horizontal gene transfer; it may provide nutrients; and it may act as a buffer to recruit or titrate ions or antibiotics. Extracellular DNA acts as a functional extracellular matrix component in the biofilms of several bacterial species. It may act as a recognition factor to regulate the attachment and dispersal of specific cell types in the biofilm; it may contribute to biofilm formation; and it may contribute to the biofilm’s physical strength and resistance to biological stress.
Interactions with proteins
All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or the protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.
Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure called chromatin. In eukaryotes, this structure involves DNA binding to a complex of small basic proteins called histones, while in prokaryotes multiple types of proteins are involved. The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones, making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are thus largely independent of the base sequence. Chemical modifications of these basic amino acid residues include methylation, phosphorylation, and acetylation. These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription. Other non-specific DNA-binding proteins in chromatin include the high-mobility group proteins, which bind to bent or distorted DNA. These proteins are important in bending arrays of nucleosomes and arranging them into the larger structures that make up chromosomes.
A distinct group of DNA-binding proteins is the DNA-binding proteins that specifically bind single-stranded DNA. In humans, replication protein A is the best-understood member of this family and is used in processes where the double helix is separated, including DNA replication, recombination, and DNA repair. These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.The lambda repressor helix-turn-helix transcription factor bound to its DNA target
In contrast, other proteins have evolved to bind to particular DNA sequences. The most intensively studied of these are the various transcription factors, which are proteins that regulate transcription. Each transcription factor binds to one particular set of DNA sequences and activates or inhibits the transcription of genes that have these sequences close to their promoters. The transcription factors do this in two ways. Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription. Alternatively, transcription factors can bind enzymes that modify the histones at the promoter. This changes the accessibility of the DNA template to the polymerase.
As these DNA targets can occur throughout an organism’s genome, changes in the activity of one type of transcription factor can affect thousands of genes. Consequently, these proteins are often the targets of the signal transduction processes that control responses to environmental changes or cellular differentiation and development. The specificity of these transcription factors’ interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to “read” the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are most accessible.The restriction enzymeEcoRV (green) in a complex with its substrate DNA
Nucleases and ligases
Nucleases are enzymes that cut DNA strands by catalyzing the hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse nucleotides from the ends of DNA strands are called exonucleases, while endonucleases cut within strands. The most frequently used nucleases in molecular biology are the restriction endonucleases, which cut DNA at specific sequences. For instance, the EcoRV enzyme shown to the left recognizes the 6-base sequence 5′-GATATC-3′ and makes a cut at the horizontal line. In nature, these enzymes protect bacteria against phage infection by digesting the phage DNA when it enters the bacterial cell, acting as part of the restriction modification system. In technology, these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.
Enzymes called DNA ligases can rejoin cut or broken DNA strands. Ligases are particularly important in lagging strand DNA replication, as they join together the short segments of DNA produced at the replication fork into a complete copy of the DNA template. They are also used in DNA repair and genetic recombination.
Topoisomerases and helicases
Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount of supercoiling in DNA. Some of these enzymes work by cutting the DNA helix and allowing one section to rotate, thereby reducing its level of supercoiling; the enzyme then seals the DNA break. Other types of these enzymes are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining the helix. Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.
Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates, predominantly adenosine triphosphate (ATP), to break hydrogen bonds between bases and unwind the DNA double helix into single strands. These enzymes are essential for most processes where enzymes need to access the DNA bases.
Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates. The sequence of their products is created based on existing polynucleotide chains—which are called templates. These enzymes function by repeatedly adding a nucleotide to the 3′ hydroxyl group at the end of the growing polynucleotide chain. As a consequence, all polymerases work in a 5′ to 3′ direction. In the active site of these enzymes, the incoming nucleoside triphosphate base-pairs to the template: this allows polymerases to accurately synthesize the complementary strand of their template. Polymerases are classified according to the type of template that they use.
In DNA replication, DNA-dependent DNA polymerases make copies of DNA polynucleotide chains. To preserve biological information, it is essential that the sequence of bases in each copy are precisely complementary to the sequence of bases in the template strand. Many DNA polymerases have a proofreading activity. Here, the polymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is detected, a 3′ to 5′ exonuclease activity is activated and the incorrect base removed. In most organisms, DNA polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the DNA clamp or helicases.
RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by retroviruses, and telomerase, which is required for the replication of telomeres. For example, HIV reverse transcriptase is an enzyme for AIDS virus replication. Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure. It synthesizes telomeres at the ends of chromosomes. Telomeres prevent fusion of the ends of neighboring chromosomes and protect chromosome ends from damage.
Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and separates the DNA strands. It then copies the gene sequence into a messenger RNA transcript until it reaches a region of DNA called the terminator, where it halts and detaches from the DNA. As with human DNA-dependent DNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome, operates as part of a large protein complex with multiple regulatory and accessory subunits.
Structure of the Holliday junction intermediate in genetic recombination. The four separate DNA strands are coloured red, blue, green and yellow.Further information: Genetic recombinationRecombination involves the breaking and rejoining of two chromosomes (M and F) to produce two rearranged chromosomes (C1 and C2).
A DNA helix usually does not interact with other segments of DNA, and in human cells, the different chromosomes even occupy separate areas in the nucleus called “chromosome territories“. This physical separation of different chromosomes is important for the ability of DNA to function as a stable repository for information, as one of the few times chromosomes interact is in chromosomal crossover which occurs during sexual reproduction, when genetic recombination occurs. Chromosomal crossover is when two DNA helices break, swap a section and then rejoin.
Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency of natural selection and can be important in the rapid evolution of new proteins. Genetic recombination can also be involved in DNA repair, particularly in the cell’s response to double-strand breaks.
The most common form of chromosomal crossover is homologous recombination, where the two chromosomes involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known as recombinases, such as RAD51. The first step in recombination is a double-stranded break caused by either an endonuclease or damage to the DNA. A series of steps catalyzed in part by the recombinase then leads to joining of the two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed to the complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can be moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted by cleavage of the junction and re-ligation of the released DNA. Only strands of like polarity exchange DNA during recombination. There are two types of cleavage: east-west cleavage and north-south cleavage. The north-south cleavage nicks both strands of DNA, while the east-west cleavage has one strand of DNA intact. The formation of a Holliday junction during recombination makes it possible for genetic diversity, genes to exchange on chromosomes, and expression of wild-type viral genomes.
Further information: RNA world hypothesis
DNA contains the genetic information that allows all forms of life to function, grow and reproduce. However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been proposed that the earliest forms of life may have used RNA as their genetic material. RNA may have acted as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part of ribozymes. This ancient RNA world where nucleic acid would have been used for both catalysis and genetics may have influenced the evolution of the current genetic code based on four nucleotide bases. This would occur, since the number of different bases in such an organism is a trade-off between a small number of bases increasing replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes. However, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible because DNA survives in the environment for less than one million years, and slowly degrades into short fragments in solution. Claims for older DNA have been made, most notably a report of the isolation of a viable bacterium from a salt crystal 250 million years old, but these claims are controversial.
Building blocks of DNA (adenine, guanine, and related organic molecules) may have been formed extraterrestrially in outer space. Complex DNA and RNA organic compounds of life, including uracil, cytosine, and thymine, have also been formed in the laboratory under conditions mimicking those found in outer space, using starting chemicals, such as pyrimidine, found in meteorites. Pyrimidine, like polycyclic aromatic hydrocarbons (PAHs), the most carbon-rich chemical found in the universe, may have been formed in red giants or in interstellar cosmic dust and gas clouds.
Uses in technology
Methods have been developed to purify DNA from organisms, such as phenol-chloroform extraction, and to manipulate it in the laboratory, such as restriction digests and the polymerase chain reaction. Modern biology and biochemistry make intensive use of these techniques in recombinant DNA technology. Recombinant DNA is a man-made DNA sequence that has been assembled from other DNA sequences. They can be transformed into organisms in the form of plasmids or in the appropriate format, by using a viral vector. The genetically modified organisms produced can be used to produce products such as recombinant proteins, used in medical research, or be grown in agriculture.
Further information: DNA profiling
Forensic scientists can use DNA in blood, semen, skin, saliva or hair found at a crime scene to identify a matching DNA of an individual, such as a perpetrator. This process is formally termed DNA profiling, also called DNA fingerprinting. In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for identifying a matching DNA. However, identification can be complicated if the scene is contaminated with DNA from several people. DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys, and first used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.
The development of forensic science and the ability to now obtain genetic matching on minute samples of blood, skin, saliva, or hair has led to re-examining many cases. Evidence can now be uncovered that was scientifically impossible at the time of the original examination. Combined with the removal of the double jeopardy law in some places, this can allow cases to be reopened where prior trials have failed to produce sufficient evidence to convince a jury. People charged with serious crimes may be required to provide a sample of DNA for matching purposes. The most obvious defense to DNA matches obtained forensically is to claim that cross-contamination of evidence has occurred. This has resulted in meticulous strict handling procedures with new cases of serious crime.
DNA profiling is also used successfully to positively identify victims of mass casualty incidents, bodies or body parts in serious accidents, and individual victims in mass war graves, via matching to family members.
DNA profiling is also used in DNA paternity testing to determine if someone is the biological parent or grandparent of a child with the probability of parentage is typically 99.99% when the alleged parent is biologically related to the child. Normal DNA sequencing methods happen after birth, but there are new methods to test paternity while a mother is still pregnant.
DNA enzymes or catalytic DNA
Further information: Deoxyribozyme
Deoxyribozymes, also called DNAzymes or catalytic DNA, were first discovered in 1994. They are mostly single stranded DNA sequences isolated from a large pool of random DNA sequences through a combinatorial approach called in vitro selection or systematic evolution of ligands by exponential enrichment (SELEX). DNAzymes catalyze variety of chemical reactions including RNA-DNA cleavage, RNA-DNA ligation, amino acids phosphorylation-dephosphorylation, carbon-carbon bond formation, and etc. DNAzymes can enhance catalytic rate of chemical reactions up to 100,000,000,000-fold over the uncatalyzed reaction. The most extensively studied class of DNAzymes is RNA-cleaving types which have been used to detect different metal ions and designing therapeutic agents. Several metal-specific DNAzymes have been reported including the GR-5 DNAzyme (lead-specific), the CA1-3 DNAzymes (copper-specific), the 39E DNAzyme (uranyl-specific) and the NaA43 DNAzyme (sodium-specific). The NaA43 DNAzyme, which is reported to be more than 10,000-fold selective for sodium over other metal ions, was used to make a real-time sodium sensor in cells.
Further information: Bioinformatics
Bioinformatics involves the development of techniques to store, data mine, search and manipulate biological data, including DNA nucleic acid sequence data. These have led to widely applied advances in computer science, especially string searching algorithms, machine learning, and database theory. String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence of letters, were developed to search for specific sequences of nucleotides. The DNA sequence may be aligned with other DNA sequences to identify homologous sequences and locate the specific mutations that make them distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships and protein function. Data sets representing entire genomes’ worth of DNA sequences, such as those produced by the Human Genome Project, are difficult to use without the annotations that identify the locations of genes and regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict the presence of particular gene products and their possible functions in an organism even before they have been isolated experimentally. Entire genomes may also be compared, which can shed light on the evolutionary history of particular organism and permit the examination of complex evolutionary events.
The DNA structure at left (schematic shown) will self-assemble into the structure visualized by atomic force microscopy at right. DNA nanotechnology is the field that seeks to design nanoscale structures using the molecular recognition properties of DNA molecules. Image from Strong, 2004.Further information: DNA nanotechnology
DNA nanotechnology uses the unique molecular recognition properties of DNA and other nucleic acids to create self-assembling branched DNA complexes with useful properties. DNA is thus used as a structural material rather than as a carrier of biological information. This has led to the creation of two-dimensional periodic lattices (both tile-based and using the DNA origami method) and three-dimensional structures in the shapes of polyhedra. Nanomechanical devices and algorithmic self-assembly have also been demonstrated, and these DNA structures have been used to template the arrangement of other molecules such as gold nanoparticles and streptavidin proteins.
History and anthropology
Because DNA collects mutations over time, which are then inherited, it contains historical information, and, by comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny. This field of phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared, population geneticists can learn the history of particular populations. This can be used in studies ranging from ecological genetics to anthropology.
Main article: DNA digital data storage
DNA as a storage device for information has enormous potential since it has much higher storage density compared to electronic devices. However high costs, extremely slow read and write times (memory latency), and insufficient reliability has prevented its practical use.
Further information: History of molecular biologyJames Watson and Francis Crick (right), co-originators of the double-helix model, with Maclyn McCarty (left)Pencil sketch of the DNA double helix by Francis Crick in 1953
DNA was first isolated by the Swiss physician Friedrich Miescher who, in 1869, discovered a microscopic substance in the pus of discarded surgical bandages. As it resided in the nuclei of cells, he called it “nuclein”. In 1878, Albrecht Kossel isolated the non-protein component of “nuclein”, nucleic acid, and later isolated its five primary nucleobases.
In 1909, Phoebus Levene identified the base, sugar, and phosphate nucleotide unit of the RNA (then named “yeast nucleic acid”). In 1929, Levene identified deoxyribose sugar in “thymus nucleic acid” (DNA). Levene suggested that DNA consisted of a string of four nucleotide units linked together through the phosphate groups (“tetranucleotide hypothesis”). Levene thought the chain was short and the bases repeated in a fixed order. In 1927, Nikolai Koltsov proposed that inherited traits would be inherited via a “giant hereditary molecule” made up of “two mirror strands that would replicate in a semi-conservative fashion using each strand as a template”. In 1928, Frederick Griffith in his experiment discovered that traits of the “smooth” form of Pneumococcus could be transferred to the “rough” form of the same bacteria by mixing killed “smooth” bacteria with the live “rough” form. This system provided the first clear suggestion that DNA carries genetic information.
In 1933, while studying virgin sea urchin eggs, Jean Brachet suggested that DNA is found in the cell nucleus and that RNA is present exclusively in the cytoplasm. At the time, “yeast nucleic acid” (RNA) was thought to occur only in plants, while “thymus nucleic acid” (DNA) only in animals. The latter was thought to be a tetramer, with the function of buffering cellular pH.
In 1943, Oswald Avery, along with co-workers Colin MacLeod and Maclyn McCarty, identified DNA as the transforming principle, supporting Griffith’s suggestion (Avery–MacLeod–McCarty experiment). DNA’s role in heredity was confirmed in 1952 when Alfred Hershey and Martha Chase in the Hershey–Chase experiment showed that DNA is the genetic material of the enterobacteria phage T2.A blue plaque outside The Eaglepub commemorating Crick and Watson
Late in 1951, Francis Crick started working with James Watson at the Cavendish Laboratory within the University of Cambridge. In February 1953, Linus Pauling and Robert Corey proposed a model for nucleic acids containing three intertwined chains, with the phosphates near the axis, and the bases on the outside. In May 1952, Raymond Gosling a graduate student working under the supervision of Rosalind Franklin took an X-ray diffraction image, labeled as “Photo 51“, at high hydration levels of DNA. This photo was given to Watson and Crick by Maurice Wilkins and was critical to their obtaining the correct structure of DNA. Franklin told Crick and Watson that the backbones had to be on the outside. Before then, Linus Pauling, and Watson and Crick, had erroneous models with the chains inside and the bases pointing outwards. Her identification of the space group for DNA crystals revealed to Crick that the two DNA strands were antiparallel.
In February 1953, Watson and Crick completed their model, which is now accepted as the first correct model of the double-helix of DNA. On 28 February 1953 Crick interrupted patrons’ lunchtime at The Eagle pub in Cambridge to announce that he and Watson had “discovered the secret of life”.
In the 25 April 1953 issue of the journal Nature, were published a series of five articles giving the Watson and Crick double-helix structure DNA, and evidence supporting it. The structure was reported in a letter titled “MOLECULAR STRUCTURE OF NUCLEIC ACIDS A Structure for Deoxyribose Nucleic Acid“, in which they said, “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” Followed by a letter from Franklin and Gosling, which was the first publication of their own X-ray diffraction data, and of their original analysis method. Then followed a letter by Wilkins, and two of his colleagues, which contained an analysis of in vivo B-DNA X-ray patterns, and supported the presence in vivo of the Watson and Crick structure.
In 1962, after Franklin’s death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine. Nobel Prizes are awarded only to living recipients. A debate continues about who should receive credit for the discovery.
In an influential presentation in 1957, Crick laid out the central dogma of molecular biology, which foretold the relationship between DNA, RNA, and proteins, and articulated the “adaptor hypothesis”. Final confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 through the Meselson–Stahl experiment. Further work by Crick and co-workers showed that the genetic code was based on non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley, and Marshall Warren Nirenberg to decipher the genetic code. These findings represent the birth of molecular biology.
- Comparison of nucleic acid simulation software
- Crystallography – scientific study of crystal structure
- DNA-encoded chemical library
- DNA microarray
- Genetic disorder – Health problem caused by one or more abnormalities in the genome
- Genetic genealogy – The use of DNA testing in combination with traditional genealogical methods to infer relationships between individuals and find ancestors
- Haplotype – Group of genes from one parent
- Meiosis – Type of cell division used by sexually-reproducing organisms to produce gametes
- Nucleic acid notation
- Nucleic acid sequence – succession of nucleotides in a nucleic acid
- Pangenesis – former theory that inheritance was based on particles from all parts of the body
- Ribosomal DNA
- Southern blot
- X-ray scattering techniques
- Xeno nucleic acid
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Ich habe mich daher später mit meinen Versuchen an die ganzen Kerne gehalten, die Trennung der Körper, die ich einstweilen ohne weiteres Präjudiz als lösliches und unlösliches Nuclein bezeichnen will, einem günstigeren Material überlassend. (Therefore, in my experiments I subsequently limited myself to the whole nucleus, leaving to a more favorable material the separation of the substances, that for the present, without further prejudice, I will designate as soluble and insoluble nuclear material (“Nuclein”)
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On p. 264, Kossel remarked presciently: Der Erforschung der quantitativen Verhältnisse der vier stickstoffreichen Basen, der Abhängigkeit ihrer Menge von den physiologischen Zuständen der Zelle, verspricht wichtige Aufschlüsse über die elementaren physiologisch-chemischen Vorgänge. (The study of the quantitative relations of the four nitrogenous bases—[and] of the dependence of their quantity on the physiological states of the cell—promises important insights into the fundamental physiological-chemical processes.)
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From page 313: “I think that the size of the chromosomes in the salivary glands [of Drosophila] is determined through the multiplication of genonemes. By this term I designate the axial thread of the chromosome, in which the geneticists locate the linear combination of genes; … In the normal chromosome there is usually only one genoneme; before cell-division this genoneme has become divided into two strands.”
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- DNA at Curlie
- DNA binding site prediction on protein
- DNA the Double Helix Game From the official Nobel Prize web site
- DNA under electron microscope
- Dolan DNA Learning Center
- Double Helix: 50 years of DNA, Nature
- Proteopedia DNA
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- ENCODE threads explorer ENCODE home page. Nature
- Double Helix 1953–2003 National Centre for Biotechnology Education
- Genetic Education Modules for Teachers – DNA from the Beginning Study Guide
- PDB Molecule of the Month DNA
- Clue to chemistry of heredity found The New York Times June 1953. First American newspaper coverage of the discovery of the DNA structure
- Olby R (January 2003). “Quiet debut for the double helix”. Nature. 421 (6921): 402–05. Bibcode:2003Natur.421..402O. doi:10.1038/nature01397. PMID 12540907.
- DNA from the Beginning Another DNA Learning Center site on DNA, genes, and heredity from Mendel to the human genome project.
- The Register of Francis Crick Personal Papers 1938 – 2007 at Mandeville Special Collections Library, University of California, San Diego
- Seven-page, handwritten letter that Crick sent to his 12-year-old son Michael in 1953 describing the structure of DNA. See Crick’s medal goes under the hammer, Nature, 5 April 2013.
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US life expectancy on the rise for 1st time in 4 years
Fresh data from the CDC’s National Center for Health Statistics suggests U.S. life expectancy is climbing for the first time since 2014—but heart disease remains the number-one threat to mortality in the country.
By Anicka SlachtaJanuary 30, 2020
Fresh data from the CDC’s National Center for Health Statistics suggests U.S. life expectancy is climbing for the first time since 2014—but heart disease remains the number-one threat to mortality in the country.
The January report, written by Jiaquan Xu, MD, and colleagues, details the CDC’s finalized mortality statistics through 2018. At that point in time, life expectancy at birth in the United States was 78.7 years—a 0.1-point increase from 2017, when life expectancy was 78.6 years.
Xu et al. said the 0.1-year increase in life expectancy the team noted in 2018 was likely due to significant decreases in mortality from cancer, unintentional injuries, chronic lower respiratory diseases and heart disease. The last time U.S. life expectancy was on the rise was between 2010 and 2014, when it increased by 0.2 years on average. It declined between 2014 and 2017 following the widespread damage of the opioid epidemic, and while a 0.1-point increase in 2018 helped boost those numbers, national life expectancy still lagged 0.2 years below the peak expectancy observed in 2014.
Life expectancy increased similarly between the sexes between 2017 and 2018, with men experiencing a jump from 76.1 years in 2017 to 76.2 years in 2018 and women seeing an increase from 81.1 to 81.2 years, respectively. Females have consistently lived longer than males; the difference in life expectancy between women and men was five years in both 2018 and 2017.
The age-adjusted death rate in the U.S. decreased by 1.1% between 2017 and 2018, from 731.9 deaths per 100,000 standard population in 2017 to 723.6 deaths per 100,000 in 2018. During the two-year period, age-specific death rates fell for people aged 15-24, 25-34, 45-54, 65-74, 75-84 and 85 and up.
The 10 leading causes of death in the U.S. were the same in 2018 as they were in 2017, topped by heart disease and cancer. Unintentional injuries, chronic lower respiratory diseases, stroke, Alzheimer’s, diabetes, influenza and pneumonia, kidney disease and suicide followed suit.
Xu and colleagues said around 73.8% of all deaths in the U.S. in 2018 could be attributed to at least one of the top 10 leading causes of death that year. Between 2017 and 2018, age-adjusted death rates decreased by 0.8% for heart disease, 2.2% for cancer, 2.8% for unintentional injuries, 2.9% for chronic lower respiratory diseases, 1.3% for stroke and 1.6% for Alzheimer’s disease. It’s not all good news, though—death rates increased by 4.2% for flu and pneumonia and by 1.4% for suicide.
Leading causes of death also remained uniform among children between 2017 and 2018, though infant mortality rate decreased 2.3% over the two-year period, from 579.3 infant deaths per 100,000 live births in 2017 to 566.2 deaths per 100,000 live births in 2018.
Find the CDC’s full report online here.
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Innovation in its modern meaning is “a new idea, creative thoughts, new imaginations in form of device or method”. Innovation is often also viewed as the application of better solutions that meet new requirements, unarticulated needs, or existing market needs. Such innovation takes place through the provision of more-effective products, processes, services, technologies, or business models that are made available to markets, governments and society. An innovation is something original and more effective and, as a consequence, new, that “breaks into” the market or society. Innovation is related to, but not the same as, invention, as innovation is more apt to involve the practical implementation of an invention (ie new / improved ability) to make a meaningful impact in the market or society, and not all innovations require an invention. Innovation often[quantify] manifests itself via the engineering process, when the problem being solved is of a technical or scientific nature. The opposite of innovation is exnovation.
While a novel device is often described[by whom?] as an innovation, in economics, management science, and other fields of practice and analysis, innovation is generally considered to be the result of a process that brings together various novel ideas in such a way that they affect society. In industrial economics, innovations are created and found[by whom?] empirically from services to meet growing consumer demand.
Innovation also has an older historical meaning which is quite different. From the 1400s through the 1600s, prior to early American settlement, the concept of “innovation” was pejorative. It was an early modern synonym for rebellion, revolt and heresy.
- 2Inter-disciplinary views
- 5Government policies
- 6See also
A 2014 survey of literature on innovation found over 40 definitions. In an industrial survey of how the software industry defined innovation, the following definition given by Crossan and Apaydin was considered to be the most complete, which builds on the Organisation for Economic Co-operation and Development (OECD) manual’s definition:
Innovation is production or adoption, assimilation, and exploitation of a value-added novelty in economic and social spheres; renewal and enlargement of products, services, and markets; development of new methods of production; and the establishment of new management systems. It is both a process and an outcome.
According to Kanter, innovation includes original invention and creative use and defines innovation as a generation, admission and realization of new ideas, products, services and processes.
Two main dimensions of innovation were degree of novelty (patent) (i.e. whether an innovation is new to the firm, new to the market, new to the industry, or new to the world) and kind of innovation (i.e. whether it is processor product-service system innovation). In recent organizational scholarship, researchers of workplaces have also distinguished innovation to be separate from creativity, by providing an updated definition of these two related but distinct constructs:
Workplace creativity concerns the cognitive and behavioral processes applied when attempting to generate novel ideas. Workplace innovation concerns the processes applied when attempting to implement new ideas. Specifically, innovation involves some combination of problem/opportunity identification, the introduction, adoption or modification of new ideas germane to organizational needs, the promotion of these ideas, and the practical implementation of these ideas.
Business and economics
Main article: Innovation economics
In business and in economics, innovation can become a catalyst for growth. With rapid advancements in transportation and communications over the past few decades, the old-world concepts of factor endowments and comparative advantage which focused on an area’s unique inputs are outmoded for today’s global economy. Economist Joseph Schumpeter (1883–1950), who contributed greatly to the study of innovation economics, argued that industries must incessantly revolutionize the economic structure from within, that is innovate with better or more effective processes and products, as well as market distribution, such as the connection from the craft shop to factory. He famously asserted that “creative destruction is the essential fact about capitalism“. Entrepreneurs continuously look for better ways to satisfy their consumer base with improved quality, durability, service and price which come to fruition in innovation with advanced technologies and organizational strategies.
A prime example of innovation involved the explosive boom of Silicon Valley startups out of the Stanford Industrial Park. In 1957, dissatisfied employees of Shockley Semiconductor, the company of Nobel laureate and co-inventor of the transistor William Shockley, left to form an independent firm, Fairchild Semiconductor. After several years, Fairchild developed into a formidable presence in the sector. Eventually, these founders left to start their own companies based on their own, unique, latest ideas, and then leading employees started their own firms. Over the next 20 years, this snowball process launched the momentous startup-company explosion of information-technology firms. Essentially, Silicon Valley began as 65 new enterprises born out of Shockley’s eight former employees. Since then, hubs of innovation have sprung up globally with similar metonyms, including Silicon Alley encompassing New York City.
Another example involves business incubators – a phenomenon nurtured by governments around the world, close to knowledge clusters (mostly research-based) like universities or other Government Excellence Centres – which aim primarily to channel generated knowledge to applied innovation outcomes in order to stimulate regional or national economic growth.
In the organizational context, innovation may be linked to positive changes in efficiency, productivity, quality, competitiveness, and market share. However, recent research findings highlight the complementary role of organizational culture in enabling organizations to translate innovative activity into tangible performance improvements. Organizations can also improve profits and performance by providing work groups opportunities and resources to innovate, in addition to employee’s core job tasks. Peter Drucker wrote:
Innovation is the specific function of entrepreneurship, whether in an existing business, a public service institution, or a new venture started by a lone individual in the family kitchen. It is the means by which the entrepreneur either creates new wealth-producing resources or endows existing resources with enhanced potential for creating wealth. –Drucker
According to Clayton Christensen, disruptive innovation is the key to future success in business. The organization requires a proper structure in order to retain competitive advantage. It is necessary to create and nurture an environment of innovation. Executives and managers need to break away from traditional ways of thinking and use change to their advantage. It is a time of risk but even greater opportunity. The world of work is changing with the increase in the use of technology and both companies and businesses are becoming increasingly competitive. Companies will have to downsize or reengineer their operations to remain competitive. This will affect employment as businesses will be forced to reduce the number of people employed while accomplishing the same amount of work if not more.
While disruptive innovation will typically “attack a traditional business model with a lower-cost solution and overtake incumbent firms quickly,” foundational innovation is slower, and typically has the potential to create new foundations for global technology systems over the longer term. Foundational innovation tends to transform business operating models as entirely new business models emerge over many years, with gradual and steady adoption of the innovation leading to waves of technological and institutional change that gain momentum more slowly. The advent of the packet-switched communication protocol TCP/IP—originally introduced in 1972 to support a single use case for United States Department of Defense electronic communication (email), and which gained widespread adoption only in the mid-1990s with the advent of the World Wide Web—is a foundational technology.
All organizations can innovate, including for example hospitals, universities, and local governments. For instance, former Mayor Martin O’Malley pushed the City of Baltimore to use CitiStat, a performance-measurement data and management system that allows city officials to maintain statistics on several areas from crime trends to the conditions of potholes. This system aids in better evaluation of policies and procedures with accountability and efficiency in terms of time and money. In its first year, CitiStat saved the city $13.2 million. Even mass transit systems have innovated with hybrid bus fleets to real-time tracking at bus stands. In addition, the growing use of mobile data terminals in vehicles, that serve as communication hubs between vehicles and a control center, automatically send data on location, passenger counts, engine performance, mileage and other information. This tool helps to deliver and manage transportation systems.
Still other innovative strategies include hospitals digitizing medical information in electronic medical records. For example, the U.S. Department of Housing and Urban Development‘s HOPE VI initiatives turned severely distressed public housing in urban areas into revitalized, mixed-income environments; the Harlem Children’s Zone used a community-based approach to educate local area children; and the Environmental Protection Agency‘s brownfield grants facilitates turning over brownfields for environmental protection, green spaces, community and commercial development.
There are several sources of innovation. It can occur as a result of a focus effort by a range of different agents, by chance, or as a result of a major system failure.
According to Peter F. Drucker, the general sources of innovations are different changes in industry structure, in market structure, in local and global demographics, in human perception, mood and meaning, in the amount of already available scientific knowledge, etc.Original model of three phases of the process of Technological Change
In the simplest linear model of innovation the traditionally recognized source is manufacturer innovation. This is where an agent (person or business) innovates in order to sell the innovation. Specifically, R&D measurement is the commonly used input for innovation, in particular in the business sector, named Business Expenditure on R&D (BERD) that grew over the years on the expenses of the declining R&D invested by the public sector.
Another source of innovation, only now becoming widely recognized, is end-user innovation. This is where an agent (person or company) develops an innovation for their own (personal or in-house) use because existing products do not meet their needs. MIT economist Eric von Hippel has identified end-user innovation as, by far, the most important and critical in his classic book on the subject, “The Sources of Innovation”.
The robotics engineer Joseph F. Engelberger asserts that innovations require only three things:
- a recognized need
- competent people with relevant technology
- financial support
However, innovation processes usually involve: identifying customer needs, macro and meso trends, developing competences, and finding financial support.
The Kline chain-linked model of innovation places emphasis on potential market needs as drivers of the innovation process, and describes the complex and often iterative feedback loops between marketing, design, manufacturing, and R&D.
Innovation by businesses is achieved in many ways, with much attention now given to formal research and development (R&D) for “breakthrough innovations”. R&D help spur on patents and other scientific innovations that leads to productive growth in such areas as industry, medicine, engineering, and government. Yet, innovations can be developed by less formal on-the-job modifications of practice, through exchange and combination of professional experience and by many other routes. Investigation of relationship between the concepts of innovation and technology transfer revealed overlap. The more radical and revolutionary innovations tend to emerge from R&D, while more incremental innovations may emerge from practice – but there are many exceptions to each of these trends.
Information technology and changing business processes and management style can produce a work climate favorable to innovation. For example, the software tool company Atlassian conducts quarterly “ShipIt Days” in which employees may work on anything related to the company’s products. Google employees work on self-directed projects for 20% of their time (known as Innovation Time Off). Both companies cite these bottom-up processes as major sources for new products and features.
An important innovation factor includes customers buying products or using services. As a result, organizations may incorporate users in focus groups (user centred approach), work closely with so called lead users (lead user approach) or users might adapt their products themselves. The lead user method focuses on idea generation based on leading users to develop breakthrough innovations. U-STIR, a project to innovate Europe’s surface transportation system, employs such workshops. Regarding this user innovation, a great deal of innovation is done by those actually implementing and using technologies and products as part of their normal activities. Sometimes user-innovators may become entrepreneurs, selling their product, they may choose to trade their innovation in exchange for other innovations, or they may be adopted by their suppliers. Nowadays, they may also choose to freely reveal their innovations, using methods like open source. In such networks of innovation the users or communities of users can further develop technologies and reinvent their social meaning.
One technique for innovating a solution to an identified problem is to actually attempt an experiment with many possible solutions. This technique was famously used by Thomas Edison’s laboratory to find a version of the incandescent light bulb economically viable for home use, which involved searching through thousands of possible filament designs before settling on carbonized bamboo.
This technique is sometimes used in pharmaceutical drug discovery. Thousands of chemical compounds are subjected to high-throughput screening to see if they have any activity against a target molecule which has been identified as biologically significant to a disease. Promising compounds can then be studied; modified to improve efficacy, reduce side effects, and reduce cost of manufacture; and if successful turned into treatments.
The related technique of A/B testing is often used to help optimize the design of web sites and mobile apps. This is used by major sites such as amazon.com, Facebook, Google, and Netflix. Procter & Gamble uses computer-simulated products and online user panels to conduct larger numbers of experiments to guide the design, packaging, and shelf placement of consumer products. Capital One uses this technique to drive credit card marketing offers.
Goals and failures
Programs of organizational innovation are typically tightly linked to organizational goals and objectives, to the business plan, and to market competitive positioning. One driver for innovation programs in corporations is to achieve growth objectives. As Davila et al. (2006) notes, “Companies cannot grow through cost reduction and reengineering alone… Innovation is the key element in providing aggressive top-line growth, and for increasing bottom-line results”.
One survey across a large number of manufacturing and services organizations found, ranked in decreasing order of popularity, that systematic programs of organizational innovation are most frequently driven by: improved quality, creation of new markets, extension of the product range, reduced labor costs, improved production processes, reduced materials, reduced environmental damage, replacement of products/services, reduced energy consumption, conformance to regulations.
These goals vary between improvements to products, processes and services and dispel a popular myth that innovation deals mainly with new product development. Most of the goals could apply to any organization be it a manufacturing facility, marketing company, hospital or government. Whether innovation goals are successfully achieved or otherwise depends greatly on the environment prevailing in the organization.
Conversely, failure can develop in programs of innovations. The causes of failure have been widely researched and can vary considerably. Some causes will be external to the organization and outside its influence of control. Others will be internal and ultimately within the control of the organization. Internal causes of failure can be divided into causes associated with the cultural infrastructure and causes associated with the innovation process itself. Common causes of failure within the innovation process in most organizations can be distilled into five types: poor goal definition, poor alignment of actions to goals, poor participation in teams, poor monitoring of results, poor communication and access to information.
Main article: Diffusion of innovations
Diffusion of innovation research was first started in 1903 by seminal researcher Gabriel Tarde, who first plotted the S-shaped diffusion curve. Tarde defined the innovation-decision process as a series of steps that include:
- forming an attitude
- a decision to adopt or reject
- implementation and use
- confirmation of the decision
Once innovation occurs, innovations may be spread from the innovator to other individuals and groups. This process has been proposed that the lifecycle of innovations can be described using the ‘s-curve‘ or diffusion curve. The s-curve maps growth of revenue or productivity against time. In the early stage of a particular innovation, growth is relatively slow as the new product establishes itself. At some point, customers begin to demand and the product growth increases more rapidly. New incremental innovations or changes to the product allow growth to continue. Towards the end of its lifecycle, growth slows and may even begin to decline. In the later stages, no amount of new investment in that product will yield a normal rate of return
The s-curve derives from an assumption that new products are likely to have “product life” – ie, a start-up phase, a rapid increase in revenue and eventual decline. In fact, the great majority of innovations never get off the bottom of the curve, and never produce normal returns.
Innovative companies will typically be working on new innovations that will eventually replace older ones. Successive s-curves will come along to replace older ones and continue to drive growth upwards. In the figure above the first curve shows a current technology. The second shows an emerging technology that currently yields lower growth but will eventually overtake current technology and lead to even greater levels of growth. The length of life will depend on many factors.
Measuring innovation is inherently difficult as it implies commensurability so that comparisons can be made in quantitative terms. Innovation, however, is by definition novelty. Comparisons are thus often meaningless across products or service. Nevertheless, Edison et al. in their review of literature on innovation management found 232 innovation metrics. They categorized these measures along five dimensions; ie inputs to the innovation process, output from the innovation process, effect of the innovation output, measures to access the activities in an innovation process and availability of factors that facilitate such a process.
There are two different types of measures for innovation: the organizational level and the political level.
The measure of innovation at the organizational level relates to individuals, team-level assessments, and private companies from the smallest to the largest company. Measure of innovation for organizations can be conducted by surveys, workshops, consultants, or internal benchmarking. There is today no established general way to measure organizational innovation. Corporate measurements are generally structured around balanced scorecards which cover several aspects of innovation such as business measures related to finances, innovation process efficiency, employees’ contribution and motivation, as well benefits for customers. Measured values will vary widely between businesses, covering for example new product revenue, spending in R&D, time to market, customer and employee perception & satisfaction, number of patents, additional sales resulting from past innovations.
For the political level, measures of innovation are more focused on a country or region competitive advantage through innovation. In this context, organizational capabilities can be evaluated through various evaluation frameworks, such as those of the European Foundation for Quality Management. The OECD Oslo Manual (1992) suggests standard guidelines on measuring technological product and process innovation. Some people consider the Oslo Manual complementary to the Frascati Manual from 1963. The new Oslo Manual from 2018 takes a wider perspective to innovation, and includes marketing and organizational innovation. These standards are used for example in the European Community Innovation Surveys.
Other ways of measuring innovation have traditionally been expenditure, for example, investment in R&D (Research and Development) as percentage of GNP (Gross National Product). Whether this is a good measurement of innovation has been widely discussed and the Oslo Manual has incorporated some of the critique against earlier methods of measuring. The traditional methods of measuring still inform many policy decisions. The EU Lisbon Strategy has set as a goal that their average expenditure on R&D should be 3% of GDP.
Many scholars claim that there is a great bias towards the “science and technology mode” (S&T-mode or STI-mode), while the “learning by doing, using and interacting mode” (DUI-mode) is ignored and measurements and research about it rarely done. For example, an institution may be high tech with the latest equipment, but lacks crucial doing, using and interacting tasks important for innovation.
A common industry view (unsupported by empirical evidence) is that comparative cost-effectiveness research is a form of price control which reduces returns to industry, and thus limits R&D expenditure, stifles future innovation and compromises new products access to markets. Some academics claim cost-effectiveness research is a valuable value-based measure of innovation which accords “truly significant” therapeutic advances (ie providing “health gain”) higher prices than free market mechanisms. Such value-based pricing has been viewed as a means of indicating to industry the type of innovation that should be rewarded from the public purse.
An Australian academic developed the case that national comparative cost-effectiveness analysis systems should be viewed as measuring “health innovation” as an evidence-based policy concept for valuing innovation distinct from valuing through competitive markets, a method which requires strong anti-trust laws to be effective, on the basis that both methods of assessing pharmaceutical innovations are mentioned in annex 2C.1 of the Australia-United States Free Trade Agreement.
Several indices attempt to measure innovation and rank entities based on these measures, such as:
- Bloomberg Innovation Index
- “Bogota Manual” similar to the Oslo Manual, is focused on Latin America and the Caribbean countries.
- “Creative Class” developed by Richard Florida
- EIU Innovation Ranking
- Global Competitiveness Report
- Global Innovation Index (GII), by INSEAD
- Information Technology and Innovation Foundation (ITIF) Index
- Innovation 360 – From the World Bank. Aggregates innovation indicators (and more) from a number of different public sources
- Innovation Capacity Index (ICI) published by a large number of international professors working in a collaborative fashion. The top scorers of ICI 2009–2010 were: 1. Sweden 82.2; 2. Finland 77.8; and 3. United States 77.5
- Innovation Index, developed by the Indiana Business Research Center, to measure innovation capacity at the county or regional level in the United States
- Innovation Union Scoreboard
- innovationsindikator for Germany, developed by the Federation of German Industries (Bundesverband der Deutschen Industrie) in 2005
- INSEAD Innovation Efficacy Index
- International Innovation Index, produced jointly by The Boston Consulting Group, the National Association of Manufacturers (NAM) and its nonpartisan research affiliate The Manufacturing Institute, is a worldwide index measuring the level of innovation in a country; NAM describes it as the “largest and most comprehensive global index of its kind”
- Management Innovation Index – Model for Managing Intangibility of Organizational Creativity: Management Innovation Index
- NYCEDC Innovation Index, by the New York City Economic Development Corporation, tracks New York City’s “transformation into a center for high-tech innovation. It measures innovation in the City’s growing science and technology industries and is designed to capture the effect of innovation on the City’s economy”
- OECD Oslo Manual is focused on North America, Europe, and other rich economies
- State Technology and Science Index, developed by the Milken Institute, is a U.S.-wide benchmark to measure the science and technology capabilities that furnish high paying jobs based around key components
- World Competitiveness Scoreboard
Many research studies try to rank countries based on measures of innovation. Common areas of focus include: high-tech companies, manufacturing, patents, post secondary education, research and development, and research personnel. The left ranking of the top 10 countries below is based on the 2016 Bloomberg Innovation Index. However, studies may vary widely; for example the Global Innovation Index 2016 ranks Switzerland as number one wherein countries like South Korea and Japan do not even make the top ten.
In 2005 Jonathan Huebner, a physicist working at the Pentagon‘s Naval Air Warfare Center, argued on the basis of both U.S. patents and world technological breakthroughs, per capita, that the rate of human technological innovation peaked in 1873 and has been slowing ever since. In his article, he asked “Will the level of technology reach a maximum and then decline as in the Dark Ages?” In later comments to New Scientist magazine, Huebner clarified that while he believed that we will reach a rate of innovation in 2024 equivalent to that of the Dark Ages, he was not predicting the reoccurrence of the Dark Ages themselves.
John Smart criticized the claim and asserted that technological singularity researcher Ray Kurzweil and others showed a “clear trend of acceleration, not deceleration” when it came to innovations. The foundation replied to Huebner the journal his article was published in, citing Second Life and eHarmony as proof of accelerating innovation; to which Huebner replied. However, Huebner’s findings were confirmed in 2010 with U.S. Patent Office data. and in a 2012 paper.
Innovation and development
The theme of innovation as a tool to disrupting patterns of poverty has gained momentum since the mid-2000s among major international development actors such as DFID, Gates Foundation‘s use of the Grand Challenge funding model, and USAID‘s Global Development Lab. Networks have been established to support innovation in development, such as D-Lab at MIT. Investment funds have been established to identify and catalyze innovations in developing countries, such as DFID’s Global Innovation Fund, Human Development Innovation Fund, and (in partnership with USAID) the Global Development Innovation Ventures.
Given the noticeable effects on efficiency, quality of life, and productive growth, innovation is a key factor in society and economy. Consequently, policymakers have long worked to develop environments that will foster innovation and its resulting positive benefits, from funding Research and Development to supporting regulatory change, funding the development of innovation clusters, and using public purchasing and standardisation to ‘pull’ innovation through.
For instance, experts are advocating that the U.S. federal government launch a National Infrastructure Foundation, a nimble, collaborative strategic intervention organization that will house innovations programs from fragmented silos under one entity, inform federal officials on innovation performance metrics, strengthen industry-university partnerships, and support innovation economic development initiatives, especially to strengthen regional clusters. Because clusters are the geographic incubators of innovative products and processes, a cluster development grant program would also be targeted for implementation. By focusing on innovating in such areas as precision manufacturing, information technology, and clean energy, other areas of national concern would be tackled including government debt, carbon footprint, and oil dependence. The U.S. Economic Development Administration understand this reality in their continued Regional Innovation Clusters initiative. In addition, federal grants in R&D, a crucial driver of innovation and productive growth, should be expanded to levels similar to Japan, Finland, South Korea, and Switzerland in order to stay globally competitive. Also, such grants should be better procured to metropolitan areas, the essential engines of the American economy.
Many countries recognize the importance of research and development as well as innovation including Japan’s Ministry of Education, Culture, Sports, Science and Technology (MEXT); Germany’s Federal Ministry of Education and Research; and the Ministry of Science and Technology in the People’s Republic of China. Furthermore, Russia’s innovation programme is the Medvedev modernisation programme which aims at creating a diversified economy based on high technology and innovation. Also, the Government of Western Australia has established a number of innovation incentives for government departments. Landgate was the first Western Australian government agency to establish its Innovation Program.
Regions have taken a more proactive role in supporting innovation. Many regional governments are setting up regional innovation agency to strengthen regional innovation capabilities. In Medellin, Colombia, the municipality of Medellin created in 2009 Ruta N to transform the city into a knowledge city.
- Bold hypothesis
- Communities of innovation
- Creative competitive intelligence
- Creative problem solving
- Diffusion of innovations
- Disruptive innovation
- Diffusion (anthropology)
- Global Innovation Index (Boston Consulting Group)
- Global Innovation Index (INSEAD)
- Hype cycle
- Individual capital
- Induced innovation
- Information revolution
- Innovation leadership
- Innovation management
- Innovation system
- Knowledge economy
- List of countries by research and development spending
- List of emerging technologies
- List of Russian inventors
- Multiple discovery
- Open Innovation
- Open Innovations (Forum and Technology Show)
- Outcome-Driven Innovation
- Paradigm shift
- Participatory design
- Pro-innovation bias
- Public domain
- State of art
- Sustainable Development Goals (Agenda 9)
- Technology Life Cycle
- Technological innovation system
- Theories of technology
- Timeline of historic inventions
- Toolkits for User Innovation
- UNDP Innovation Facility
- Value network
- Virtual product development
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Bill Gates warned in 2018 that new disease could kill 30M people in 6 months
Bill Gates, Co-Chair of Bill & Melinda Gates Foundation, attends a conversation at the 2019 New Economy Forum in Beijing, China Nov. 21, 2019. (Reuters File Photo)Related Articles
Microsoft founder Bill Gates predicted in 2018 that a new disease could kill 30 million people in six months, while his foundation posted a simulation showing an epidemic spreading from China, which is currently facing a “grave situation” to handle the accelerating speed of the deadly coronavirus.
In a December 2018 report, the Business Insider cited Gates as saying that the world is not prepared for pandemics amid an increase in the population and environmental degradation.
He claimed that a small non-state actor even had the ability to build a deadlier form of smallpox in a lab environment.
Touching upon the fact that people have the ability to travel across the globe in a matter of hours in our day, Gates said that a new outbreak like SARS could kill some 30 million people in six months.
“In the case of biological threats, that sense of urgency is lacking,” Gates said, adding that countries need to prepare for pandemics in the same serious way they prepare for war.
Chinese President Xi Jinping held a politburo meeting on Saturday to discuss means to fight the coronavirus outbreak, which he said is accelerating its spread and the country is facing a “grave situation.”
The central Chinese city of Wuhan, where 41 people were reported dead, remains under lockdown to prevent the spread of the disease.Share on FacebookShare on Twitter
- Feeling sleepy all the time? Maybe it’s time to see a doctor
- Coronavirus may affect two-thirds of world population, specialist says
- Coronavirus ‘world’s number one public enemy’: WHO’s Tedros
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Here’s what coronavirus does to the body
From blood storms to honeycomb lungs, here’s an organ-by-organ look at how COVID-19 harms humans.
PUBLISHED FEBRUARY 15, 2020
MUCH REMAINS UNKNOWN about the novel coronavirus ripping through China, but one thing is certain. The disease can cast a storm over the whole human body.
Such has been the nature of past zoonotic coronaviruses, ones that hopped from animals to humans like SARS and MERS. Unlike their common-cold-causing cousins, these emergent coronaviruses can spark a viral-induced fire throughout many of a person’s organs, and the new disease—dubbed “COVID-19” by the World Health Organization on Tuesday—is no exception when it is severe.
That helps explain why the COVID-19 epidemic has killed more than 1,500 people, surpassing the SARS death toll in a matter of weeks. While the death rate for COVID-19 appears to be a tenth of SARS, the novel coronavirus has spread faster.
Confirmed cases rose to more than 60,000 on Thursday, nearly a 50 percent jump relative to the prior day, and the tally has risen by another 7,200 since then. This leap reflects a change in the way Chinese authorities are diagnosing infections instead of a massive shift in the scope of the outbreak. Rather than wait for patients to test positive for the virus, diagnoses now include anyone whose chest scan reveals COVID-19’s distinctive pattern of pneumonia. This method will hopefully allow authorities to isolate and treat patients more quickly.
If this outbreak continues to spread, there’s no telling how harmful it could become. A leading epidemiologist at the University of Hong Kong warned this week that COVID-19 could infect 60 percent of the globe if left unchecked. On Thursday, China’s National Health Commission said more than 1,700 health care workers are ill with the new virus, and the announcement came just a day after the WHO wrapped a summit on the best protocols for hospital care and the development of therapeutics, like vaccines.
But what actually happens to your body when it is infected by the coronavirus? The new strain is so genetically similar to SARS that it has inherited the title SARS-CoV-2. So combining early research on the new outbreak with past lessons from SARS and MERS can provide an answer.
The Lungs: Ground zero
For most patients, COVID-19 begins and ends in their lungs, because like the flu, coronaviruses are respiratory diseases.
They spread typically when an infected person coughs or sneezes, spraying droplets that can transmit the virus to anyone in close contact. Coronaviruses also cause flu-like symptoms: Patients might start out with a fever and cough that progresses to pneumonia or worse. (Find out how coronavirus spreads on a plane—and the safest place to sit).
After the SARS outbreak, the World Health Organization reported that the disease typically attacked the lungs in three phases: viral replication, immune hyper-reactivity, and pulmonary destruction.
Not all patients went through all three phases—in fact only 25 percent of SARS patients suffered respiratory failure, the defining signature of severe cases. Likewise, COVID-19, according to early data, causes milder symptoms in about 82 percent of cases, while the remainder are severe or critical.
Look deeper, and the novel coronavirus appears to follow other patterns of SARS, says University of Maryland School of Medicine associate professor Matthew B. Frieman, who studies highly pathogenic coronaviruses.
Medical staff members hugging each other in an isolation ward at a hospital in Zouping in China’s easter Shandong Province.PHOTOGRAPH BY STR/AFP VIA GETTY IMAGES
In the early days of an infection, the novel coronavirus rapidly invades human lung cells. Those lung cells come in two classes: ones that make mucus and ones with hair-like batons called cilia.
Mucus, though gross when outside the body, helps protect lung tissue from pathogens and make sure your breathing organ doesn’t dry out. The cilia cells beat around the mucus, clearing out debris like pollen or viruses.
Frieman explains that SARS loved to infect and kill cilia cells, which then sloughed off and filled patients’ airways with debris and fluids, and he hypothesizes that the same is happening with the novel coronavirus. That’s because the earliest studies on COVID-19 have shown that many patients develop pneumonia in both lungs, accompanied by symptoms like shortness of breath.
That’s when phase two and the immune system kicks in. Aroused by the presence of a viral invader, our bodies step up to fight the disease by flooding the lungs with immune cells to clear away the damage and repair the lung tissue.
When working properly, this inflammatory process is tightly regulated and confined only to infected areas. But sometimes your immune system goes haywire and those cells kill anything in their way, including your healthy tissue.
“So you get more damage instead of less from the immune response,” Frieman says. Even more debris clogs up the lungs, and pneumonia worsens. (Find out how the novel coronavirus compares to flu, Ebola, and other major outbreaks).LUNGS 101The lungs replenish the body with life-giving oxygen. Learn about the anatomy of the lungs, how the organs make respiration possible, and how they are vulnerable to illnesses.
During the third phase, lung damage continues to build—which can result in respiratory failure. Even if death doesn’t occur, some patients survive with permanent lung damage. According to the WHO, SARS punched holes in the lungs, giving them “a honeycomb-like appearance”—and these lesions are present in those afflicted by novel coronavirus, too.
These holes are likely created by the immune system’s hyperactive response, which creates scars that both protect and stiffen the lungs.
When that occurs, patients often have to be put on ventilators to assist their breathing. Meanwhile, inflammation also makes the membranes between the air sacs and blood vessels more permeable, which can fill the lungs with fluid and affect their ability to oxygenate blood.
“In severe cases, you basically flood your lungs and you can’t breathe,” Frieman says. “That’s how people are dying.”
The Stomach: A shared gateway
During the SARS and MERS outbreaks, nearly a quarter of patients had diarrhea—a much more significant feature of those zoonotic coronaviruses. But Frieman says it’s still not clear whether gastrointestinal symptoms play a major part in the latest outbreak, given cases diarrhea and abdominal pain have been rare. But why does a respiratory virus bother the gut at all?
When any virus enters your body, it looks for human cells with its favorite doorways—proteins on the outside of the cells called receptors. If the virus finds a compatible receptor on a cell, it can invade.WHAT IS A VIRUS?Scientists at USAMRID, the U.S. Army Medical Research Institute of Infectious diseases, work with some of the most deadly forms of life on earth, killer viruses. Learn more.
Some viruses are picky about which door they choose, but others are a little more promiscuous. “They can very easily penetrate into all types of cells,” says Anna Suk-Fong Lok, assistant dean for clinical research at the University of Michigan Medical School and former president of the American Association for the Study of Liver Diseases.
Both SARS and MERS viruses can access the cells that line your intestines and large and small colon, and those infections appear to flourish in the gut, potentially causing the damage or the leakage of fluid that becomes diarrhea.
But Frieman says we don’t know yet if the novel coronavirus does the same. Researchers believe COVID-19 uses the same receptor as SARS, and this doorway can be found in your lungs and small intestines.
Two studies—one in the New England Journal of Medicine and one preprint in medRxiv involving 1,099 cases—have also detected the virus in stool samples, which might indicate the virus could spread via feces. But this is far from conclusive.
“Whether that kind of fecal transmission is occuring for this Wuhan virus, we don’t know at all,” Frieman says. “But it definitely looks like it’s there in the stool and it looks like people do have GI symptoms associated with this.”
Coronaviruses can also cause problems in other systems of the body, due to the hyperactive immune response we mentioned earlier.
A 2014 study showed that 92 percent of patients with MERS had at least one manifestation of the coronavirus outside of the lungs. In fact, signs of a full body blitz have been witnessed with all three of the zoonotic coronaviruses: elevated liver enzymes, lower white blood cell and platelet count, and low blood pressure. In rare cases, patients have suffered from acute kidney injury and cardiac arrest.
But this isn’t necessarily a sign that the virus itself is spreading throughout the body, says Angela Rasmussen, a virologist and associate research scientist at Columbia University Mailman School of Public Health. It might be a cytokine storm.
Basically you’re bleeding out of your blood vessels.
ANGELA RASMUSSEN, VIROLOGIST
Cytokines are proteins used by the immune system as alarm beacons—they recruit immune cells to the site of infection. The immune cells then kill off the infected tissue in a bid to save the rest of the body.
Humans rely on our immune systems to keep their cool when facing a threat. But during a runaway coronavirus infection, when the immune system dumps cytokines into the lungs without any regulation, this culling becomes a free-for-all, Rasmussen says “Instead of shooting at a target with a gun, you’re using a missile launcher,” she says. That’s where the problem arises: Your body is not just targeting the infected cells. It is attacking healthy tissue too.
The implications extend outside the lungs. Cytokine storms create inflammation that weakens blood vessels in the lungs and causes fluid to seep through to the air sacs. “Basically you’re bleeding out of your blood vessels,” Rasmussen says. The storm spills into your circulatory system and creates systemic issues across multiple organs.
From there, things can take a sharp turn for the worse. In some of the most severe COVID-19 cases, the cytokine response—combined with a diminished capacity to pump oxygen to the rest of the body—can result in multi-organ failure. Scientists don’t know exactly why some patients experience complications outside of the lung, but it might be linked to underlying conditions like heart disease or diabetes.
“Even if the virus doesn’t get to kidneys and liver and spleen and other things, it can have clear downstream effects on all of those processes,” Frieman says. And that’s when things can get serious.TODAY’SPOPULAR STORIESSCIENCESTARSTRUCKThe first person to see the ‘Pale Blue Dot’ image still has it stashed in her closetANIMALSWorld’s largest cave fish discovered in IndiaSCIENCEA huge iceberg just broke off West Antarctica’s most endangered glacier
Liver: Collateral damage
When a zoonotic coronavirus spreads from the respiratory system, your liver is often one downstream organ that suffers. Doctors have seen indications of liver injury with SARS, MERS, and COVID-19—often mild, though more severe cases have led to severe liver damage and even liver failure. So what’s happening?
“Once a virus gets into your bloodstream, they can swim to any part of your body,” Lok says. “The liver is a very vascular organ so [a coronavirus] can very easily get into your liver.”
Your liver works pretty hard to make sure your body can function properly. Its main job is to process your blood after it leaves the stomach, filtering out the toxins and creating nutrients your body can use. It also makes the bile that helps your small intestine break down fats. Your liver also contains enzymes, which speed up chemical reactions in the body.
In a normal body, Lok explains, liver cells are constantly dying off and releasing enzymes into your bloodstream. This resourceful organ then quickly regenerates new cells and carries on with its day. Because of that regeneration process, the liver can withstand a lot of injury.
When you have abnormally high levels of enzymes in your blood, though—as has been a common characteristic of patients suffering from SARS and MERS—it’s a warning sign. It might be a mild injury that the liver will quickly bounce back from or it could be something more severe—even liver failure.
Lok says scientists don’t completely understand how these respiratory viruses behave in the liver. The virus might be directly infecting the liver, replicating and killing off the cells itself. Or those cells might be collateral damage as your body’s immune response to the virus sets off a severe inflammatory reaction in the liver.
Either way, she notes that liver failure was never the sole cause of death for SARS patients. “By the time the liver fails,” she says, “oftentimes you’ll find that the patient not only has lung problems and liver problems but they may also have kidney problems. By then it becomes a systemic infection.”
Kidney: It’s all connected
Yes, your kidneys are caught up in this mess, too. Six percent of SARS patients—and a full quarter of MERS patients—suffered acute renal injury. Studies have shown the novel coronavirus can do the same. It may be a relatively uncommon feature of the disease, but it is a fatal one. Ultimately 91.7 percent of SARS patients with acute renal impairment died, according to a 2005 study in Kidney International.
Like the liver, your kidneys act as a filter your blood. Each kidney is filled with about 800,000 of microscopic distilling units called nephrons. These nephrons have two main components: a filter to clean the blood and a little tubes that return the good stuff back to your body or send the waste down to your bladder as urine.
It’s the kidney tubules that seem to be most affected by these zoonotic coronaviruses. After the SARS outbreak, the WHO reported that the virus was found in kidney tubules, which can become inflamed.
It’s not uncommon to detect a virus in the tubules if it’s in your bloodstream, says Kar Neng Lai, a professor emeritus at the University of Hong Kong and consultant nephrologist at Hong Kong Sanatorium and Hospital. As your kidneys are continuously filtering blood, sometimes the tubular cells can trap the virus and cause a transient, or milder, injury.HOW FLU VIRUSES ATTACKSee how a flu virus attacks, mutates, and becomes contagious—perhaps resulting in an outbreak or even pandemic.
That injury could become lethal if the virus penetrates the cells and begins to replicate. But Lai—who was also a member of the first group of researchers reporting on SARS and contributed to the Kidney International study—says there was no evidence that the SARS virus was replicating in the kidney.
That finding, Lai says, suggests acute kidney injury in SARS patients might be due to a diverse set of causes, including low blood pressure, sepsis, drugs, or a metabolic disturbance. Meanwhile, the more severe cases that led to acute renal failure showed signs of—you guessed it—a cytokine storm.
Acute renal failure can also sometimes be brought on by antibiotics, multi-organ failure, or being connected to a ventilator for too long. Everything is connected.
Pregnancy and coronavirus?
It’s the great irony of the Twitter age that we know too little about the novel coronavirus as we drown in information updates about it. Medical journals have published several studies about this outbreak—some more vetted than others as researchers rush to feed the maw. Meanwhile, news outlets are reporting every development. All this information whirls around the internet where discerning fact from fiction is a notorious challenge.
“This is really unprecedented in terms of the up-to-the-minute reporting on what’s going on in these studies,” Rasmussen says. “It’s really tricky trying to sort through all of the information and figure out what’s really supported, what’s speculative, and what’s plain wrong.”
For example last week, doctors at a hospital in Wuhan reported that two infants tested positive for the novel coronavirus, one just 30 hours after birth. Naturally, this troubling headline spread across news organizations, given it raised questions of whether pregnant women can infect their unborn children in utero or whether the disease can be transmitted during birth or through breast milk.
But let’s pump the breaks. Mother-to-infant transmission wasn’t observed with SARS nor MERS despite numerous cases involving pregnant women. Plus, there are other ways a newborn could catch the coronavirus, Rasmussen says, such as by being born at hospital overrun with infected patients during a hectic emergency.
In fact, a new study published Thursday in The Lancet offers preliminary evidence that the coronavirus cannot be passed from mother to child.
In the report, researchers observed nine women in Wuhan who had COVID-19 pneumonia. Some of the women had pregnancy complications, but all cases resulted in live births without evidence of transmitting the infection. While this study doesn’t completely rule out the possibility of transmission during pregnancy, it underscores the need to exercise caution in speculating about this disease.
“There needs to be a high standard of evidence before you can say that’s happening definitively—and certainly before you start making changes to how cases are managed clinically or in terms of public policy,” Rasmussen says.
Frieman agrees. He hopes this epidemic will prompt more funding for coronavirus research like the recent pledges from the European Union and the Bill & Melinda Gates Foundation. But Frieman wants the support and interest to last even if this outbreak eventually fizzles out, unlike what happened with SARS research.
“Right after the SARS outbreak, there was a big bunch of money and then it went away,” Frieman says. “Why don’t we have these answers? Nobody funded these things.”
Editor’s Note: This article has been updated to reflect the death toll and case count as of February 15. Also, the article originally misstated Anna Suk-Fong Lok’s title. She is the assistant dean for clinical research at the University of Michigan Medical School and former president of the American Association for the Study of Liver Diseases.
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