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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A virus (from the Latin virus meaning "toxin" or "poison"), is a sub-microscopic infectious agent that is unable to grow or reproduce outside a host cell. Each viral particle, or virion, consists of genetic material, DNA or RNA, within a protective protein coat called a capsid. The capsid shape varies from simple helical and icosahedral (polyhedral or near-spherical) forms, to more complex structures with tails or an envelope. Viruses infect cellular life forms and are grouped into animal, plant and bacterial types, according to the type of host infected.
Biologists debate whether or not viruses are living organisms. Some consider them non-living as they do not meet the criteria of the definition of life. For example, unlike most organisms, viruses do not have cells. However, viruses have genes and evolve by natural selection. Others have described them as organisms at the edge of life. Viral infections in human and animal hosts usually result in an immune response and disease. Often, a virus is completely eliminated by the immune system. Antibiotics have no effect on viruses, but antiviral drugs have been developed to treat life-threatening infections. Vaccines that produce lifelong immunity can prevent viral infections.
The word is from the Latin virus referring to poison and other noxious substances, first used in English in 1392.[1] Virulent, from Latin virulentus, "poisonous", dates to 1400.[2] A meaning of "agent that causes infectious disease" is first recorded in 1728,[1] before the discovery of viruses by the Russian-Ukrainian biologist Dmitry Ivanovsky in 1892. The adjective viral dates to 1948.[3] Today, virus is used to describe the biological viruses discussed above and as a metaphor for other parasitically-reproducing things, such as memes or computer viruses (since 1972).[2] The term virion is also used to refer to a single infective viral particle. The English plural form of virus is viruses.
Discovery of viruses
Viral diseases such as rabies, yellow fever and smallpox have affected humans for centuries. There is hieroglyphical evidence of polio in ancient Egyptian medicine,[4] though the cause of this disease was unknown at the time. In the 10th century, Muhammad ibn Zakarīya Rāzi (Rhazes) wrote the Treatise on Smallpox and Measles, in which he gave the first clear descriptions of smallpox and measles.[5] In the 1020s, Avicenna wrote The Canon of Medicine, in which he discovered the contagious nature of infectious diseases, such as tuberculosis and sexually transmitted diseases, and their distribution through bodily contact or through water and soil;[6] stated that bodily secretion is contaminated by "foul foreign earthly bodies" before being infected;[7] and introduced the method of quarantine as a means of limiting the spread of contagious disease.[8]
When the Black Death bubonic plague reached al-Andalus in the 14th century, Ibn Khatima discovered that infectious diseases are caused by microorganisms which enter the human body. The etiologic cause of the bubonic plague would later be identified as a bacterium. Another 14th century Andalusian physician, Ibn al-Khatib (1313-1374), wrote a treatise called On the Plague, in which he stated how infectious diseases can be transmitted through bodily contact and "through garments, vessels and earrings."[7] In 1717, Mary Montagu, the wife of an English ambassador to the Ottoman Empire, observed local women inoculating their children against smallpox.[9] In the late 18th century, Edward Jenner observed and studied Miss Sarah Nelmes, a milkmaid who had previously caught cowpox and was found to be immune to smallpox, a similar, but devastating virus. Jenner developed the smallpox vaccine based on these findings. After lengthy vaccination campaigns, the World Health Organization (WHO) certified the eradication of smallpox in 1979.
In the late 19th century, Charles Chamberland developed a porcelain filter with pores small enough to remove cultured bacteria from their culture medium.[10] Dimitri Ivanovski used this filter to study an infection of tobacco plants, now known as tobacco mosaic virus. He passed crushed leaf extracts of infected tobacco plants through the filter, then used the filtered extracts to infect other plants, thereby proving that the infectious agent was not a bacterium. Similar experiments were performed by several other researchers, with similar results. These experiments showed that viruses are orders of magnitude smaller than bacteria. The term virus was coined by the Dutch microbiologist Martinus Beijerinck, who showed, using methods based on the work of Ivanovski, that tobacco mosaic disease is caused by something smaller than a bacterium. He coined the Latin phrase "contagium vivum fluidum" (which means "soluble living germ") as the first idea of the virus.[11] The first human virus identified was Yellow Fever virus.
In the early 20th century, Frederick Twort discovered that bacteria could be infected by viruses.[12] Felix d'Herelle, working independently, showed that a preparation of viruses caused areas of cellular death on thin cell cultures spread on agar. Counting the dead areas allowed him to estimate the original number of viruses in the suspension. The invention of electron microscopy provided the first look at viruses. In 1935, Wendell Stanley crystallized the tobacco mosaic virus and found it to be mostly protein.[13] A short time later, the virus was separated into protein and nucleic acid parts.[14][15] In 1939, Max Delbrück and E.L. Ellis demonstrated that, in contrast to cellular organisms, bacteriophage reproduce in "one step", rather than exponentially.[16]
A major problem for early virologists was the inability to propagate viruses on sterile culture media, as is done with cellular microorganisms. This limitation required medical virologists to infect living animals with infectious material, which is dangerous. The first breakthrough came in 1931, when Ernest William Goodpasture demonstrated the growth of influenza and several other viruses in fertile chicken eggs.[17] However, some viruses would not grow in chicken eggs, and a more flexible technique was needed for propagation of viruses. The solution came in 1949 when John Franklin Enders, Thomas H. Weller and Frederick Chapman Robbins together developed a technique to grow the polio virus in cultures of living animal cells.[18] Their methods have since been extended and applied to the growth of viruses and other infectious agents that do not grow on sterile culture media.
The origin of modern viruses is not entirely clear. It may be that no single mechanism can account for their origin.[19] They do not fossilize well, so molecular techniques have been the most useful means of hypothesising how they arose.[20] Research in microfossil identification and molecular biology may yet discern fossil evidence dating to the Archean or Proterozoic eons. Two main hypotheses currently exist.[21]
Small viruses with only a few genes may be runaway stretches of nucleic acid originating from the genome of a living organism. Their genetic material could have been derived from transferable genetic elements such as plasmids or transposons, that are prone to moving within, leaving, and entering genomes. New viruses are emerging de novo and therefore, it is not always the case that viruses have "ancestors".[22]
Viruses with larger genomes, such as poxviruses, may have once been small cells that parasitized larger host cells. Over time, genes not required by their parasitic lifestyle would have been lost in a streamlining process known as "retrograde-evolution" or "reverse-evolution". The bacteria Rickettsia and Chlamydia are living cells that, like viruses, can only reproduce inside host cells. They lend credence to the streamlining hypothesis, as their parasitic lifestyle is likely to have caused the loss of genes that enabled them to survive outside a host cell.
It is possible that viruses represent a primitive form of self replicating DNA and are a precursor to life as it is currently defined.[23] Other infectious particles which are even simpler in structure than viruses include viroids, satellites, and prions.
In taxonomy, the classification of viruses is difficult owing to the lack of a fossil record and the dispute over whether they are living or non-living.[24][25] They do not fit easily into any of the domains of biological classification, and classification begins at the family rank. However, the domain name of Acytota (without cells) has been suggested. This would place viruses on a par with the other domains of Eubacteria, Archaea, and Eukarya. Not all families are currently classified into orders, nor all genera classified into families.
In 1962, André Lwoff, Robert Horne, and Paul Tournier were the first to develop a means of virus classification, based on the Linnaean hierarchical system.[26] This system based classification on phylum, class, order, family, genus, and species. Viruses were grouped according to their shared properties (not of their hosts) and the type of nucleic acid forming their genomes.[27] Following this initial system, a few modifications were made and the International Committee on Taxonomy of Viruses was developed (ICTV).
ICTV classification
The International Committee on Taxonomy of Viruses (ICTV) developed the current classification system and put in place guidelines that put a greater weighting on certain virus properties to maintain family uniformity. A universal system for classifying viruses, and a unified taxonomy, has been established since 1966. In determining order, taxonomists should consider the type of nucleic acid present, whether the nucleic acid is single- or double-stranded, and the presence or absence of an envelope. After these three main properties, other characteristics can be considered: the type of host, the capsid shape, immunological properties and the type of disease it causes. The system makes use of a series of ranked taxons. The general structure is as follows:
The recognition of orders is very recent; to date, only three have been named, and most families remain unplaced. The committee does not formally distinguish between subspecies, strains, and isolates. In total there are three orders, 56 families, nine subfamilies, and 233 genera. ICTV recognizes about 1,550 virus species, but about 30,000 virus strains and isolates are being tracked by virologists.[28]
The Nobel Prize-winning biologist David Baltimore devised the Baltimore classification system.[29][30] The ICTV classification system is used in conjunction with the Baltimore classification system in modern virus classification.[31][32][33]
Baltimore Classification
The Baltimore classification of viruses is based on the mechanism of mRNA production. Viruses must generate positive strand mRNAs from their genomes to produce proteins and replicate themselves, but different mechanisms are used to achieve this in each virus family. This classification places viruses into seven groups:
As an example of viral classification, the chicken pox virus, Varicella zoster (VZV), belongs to family Herpesviridae, subfamily Alphaherpesvirinae and genus Varicellovirus. It remains unranked in terms of order. VZV is in Group I of the Baltimore Classification because it is a dsDNA virus that does not use reverse transcriptase.
A complete virus particle, known as a virion, consists of nucleic acid surrounded by a protective coat of protein called a capsid. Viruses can have a lipid "envelope" derived from the host cell membrane. A capsid is made from proteins encoded by the viral genome and its shape serves as the basis for morphological and antigenic distinction.[34][35] Virally coded protein subunits will self-assemble to form a capsid, generally requiring the presence of the virus genome. However, complex viruses code for proteins which assist in the construction of their capsid.[21] Proteins associated with nucleic acid are known as nucleoproteins, and the association of viral capsid proteins with viral nucleic acid is called a nucleocapsid.
In general, there are four main morphological virus types:
Helical viruses | |
Helical capsids are composed of a single type of subunit stacked around a central axis to form a helical structure which may have a central cavity, or hollow tube. This arrangement results in rod-shaped or filamentous virions: these can be anything from short and highly rigid, to long and very flexible. The genetic material, generally single-stranded RNA, but ssDNA in some cases, is bound into the protein helix, by interactions between the negatively-charged nucleic acid and positive charges on the protein. Overall, the length of a helical capsid is related to the length of the nucleic acid contained within it and the diameter is dependent on the size and arrangement of protomers. The well-studied Tobacco mosaic virus is an example of a helical virus. | |
Icosahedral viruses | |
Icosahedral capsid symmetry results in a spherical appearance of viruses at low magnification but actually consists of capsomers arranged in a regular geometrical pattern, similar to a soccer ball, hence they are not truly "spherical". Capsomers are ring shaped constructed from five to six copies of protomers. These associate via non-covalent bonding to enclose the viral nucleic acid, though generally less intimately than helical capsids, and may involve one or more protomers.
Icosahedral architecture was employed by R. Buckminster Fuller in his geodesic dome, and is the most efficient way of creating an enclosed robust structure from multiple copies of a single protein. The number of proteins required to form a spherical virus capsid is denoted by the T-number,[36] where 60×t proteins are necessary. In the case of the hepatitis B virus the T-number is 4, and 240 proteins assemble to form the capsid. | |
Enveloped viruses | |
Viruses are able to envelope themselves in a modified form of one of the cell membranes either the outer membrane surrounding an infected host cell, or from internal membranes such as nuclear membrane or endoplasmic reticulum, thus gaining an outer lipid bilayer known as a viral envelope. This membrane is studded with proteins coded for by the viral genome and host genome; however the lipid membrane itself and any carbohydrates present are entirely host-coded. The Influenza virus and HIV use this strategy.
The viral envelope can give a virion a few distinct advantages over other capsid-only virions, such as protection from enzymes and certain chemicals. The proteins in it can include glycoproteins functioning as receptor molecules, allowing host cells to recognize and bind these virions, resulting in the possible uptake of the virion into the cell. Most enveloped viruses are dependent on the envelope for infectivity. | |
Complex viruses | |
These viruses possess a capsid which is neither purely helical, nor purely icosahedral, and which may possess extra structures such as protein tails or a complex outer wall. Some bacteriophages have a complex structure consisting of an icosahedral head bound to a helical tail, the latter of which may have a hexagonal base plate with protruding protein tail fibres. | |
The Poxviruses are large, complex viruses which have an unusual morphology. The viral genome is associated with proteins within a central disk structure known as a nucleoid. The nucleoid is surrounded by a membrane and two lateral bodies of unknown function. The virus has an outer envelope with a thick layer of protein studded over its surface. The whole particle is slightly pleiomorphic, ranging from ovoid to brick shape.[37] |
Electron microscopy
Electron microscopy is the most common method used to study the morphology of viruses. To increase the contrast between viruses and the background, electron-dense "stains" are used. These are solutions of salts of heavy metals such as tungsten, that scatter the electrons from regions covered with the stain. When virus particles are coated with stain (positive staining), fine detail is obscured. Negative staining overcomes this problem by staining the background only.[38]
A medium-sized virion next to a flea is roughly equivalent to a human next to a mountain twice the size of Mount Everest. Some filoviruses have a total length of up to 1400 nm, however their capsid diameters are only about 80 nm. Most viruses which have been studied have a capsid diameter between 10 and 300 nanometres. Most viruses are unable to be seen with a light microscope but some are as large or larger than the smallest bacteria and can be seen under high optical magnification. More commonly, both scanning and transmission electron microscopes are used to visualize virus particles.
Property | Parameters |
Nucleic acid |
Shape |
Strandedness |
Sense |
An enormous variety of genomic structures can be seen among viral species; as a group they contain more structural genomic diversity than the entire kingdoms of either plants, animals, or bacteria.[39]
Nucleic acid
A virus may employ either DNA or RNA as the nucleic acid. Rarely do they contain both, however cytomegalovirus is an exception to this, possessing a DNA core with several mRNA segments.[21] By far most viruses have RNA. Plant viruses tend to have single-stranded RNA and bacteriophages tend to have double-stranded DNA.[21] Some virus species possess abnormal nucleotides, such as hydroxymethylcytosine instead of cytosine, as a normal part of their genome.[21]
Viral genomes may be circular, such as polyomaviruses, or linear, such as adenoviruses. The type of nucleic acid is irrelevant to the shape of the genome. Among RNA viruses, the genome is often divided up into separate parts within the virion and are called segmented. Double-stranded RNA genomes and some single-stranded RNA genomes are segmented.[21] Each segment often codes for one protein and they are usually found together in one capsid. Every segment is not required to be in the same virion for the overall virus to be infectious, as demonstrated by the brome mosaic virus.[21]
A viral genome, irrespective of nucleic acid type, may be either single-stranded or double-stranded. Single-stranded genomes consist of an unpaired nucleic acid, analogous to one-half of a ladder split down the middle. Double-stranded genomes consist of 2 complementary paired nucleic acids, analogous to a ladder. Viruses, such as those belonging to the Hepadnaviridae, contain a genome which is partially double-stranded and partially single-stranded.[39] Viruses that infect humans include double-stranded RNA (e.g. Rotavirus), single-stranded RNA (e.g. Influenza virus), single-stranded DNA (e.g. Parvovirus B19) and double-stranded DNA (Herpes virus).
For viruses with RNA as their nucleic acid, the strands are said to be either positive-sense (called the plus-strand) or negative-sense (called the minus-strand), depending on whether it is complementary to viral mRNA. Positive-sense viral RNA is identical to viral mRNA and thus can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation. DNA nomenclature is similar to RNA nomenclature, in that the coding strand for the viral mRNA is complementary to it (-), and the non-coding strand is a copy of it (+).
Genome size
Genome size in terms of the weight of nucleotides varies between species. The smallest genomes code for only four proteins and weigh about 106 Daltons, the largest weigh about 108 Daltons and code for over one hundred proteins.[21] RNA viruses generally have smaller genome sizes than DNA viruses due to a higher error-rate when replicating, resulting in a maximum upper size limit. Beyond this limit, errors in the genome when replicating render the virus useless or uncompetitive. To compensate for this, RNA viruses often have segmented genomes where the genome is split into smaller molecules, thus reducing the chance of error.[40] In contrast, DNA viruses generally have larger genomes due to the high fidelity of their replication enzymes.[39]
Gene reassortment
There is an evolutionary advantage in having a segmented genome. Different strains of a virus with a segmented genome, from a pig or a bird or a human for example, such as Influenza virus, can shuffle and combine with other genes producing progeny viruses or (offspring) that have unique characteristics. This is called reassortment or viral sex.[41] This is one reason why Influenza virus constantly changes.[42]
Genetic recombination
Genetic recombination is the process by which a strand of DNA is broken and then joined to the end of a different DNA molecule. This can occur when viruses infect cells simultaneously and studies of viral evolution have shown that recombination has been rampant in the species studied.[43] Recombination is common to both RNA and DNA viruses.[44][45]
Genetic change
Viruses undergo genetic change by several mechanisms. These include a process called genetic drift where individual bases in the DNA or RNA mutate to other bases. Most of these point mutations are silent in that they do not change the protein that the gene encodes, but others can confer evolutionary advantages such as resistance to antiviral drugs.[46] Antigenic shift is where there is a major change in the genome of the virus. This occurs as a result of recombination or reassortment (see above). When this happens with influenza viruses, pandemics may result.[47][48] By genome rearrangement the structure of the gene changes although no mutations have necessarily occurred.[49]
RNA viruses are much more likely to mutate than DNA viruses for the reasons outlined above. Viruses often exist as quasispecies or swarms of viruses of the same species but with slightly different genome nucleoside sequences. Such quasispecies are a prime target for natural selection.[50]
Viral populations do not grow through cell division, because they are acellular; instead, they use the machinery and metabolism of a host cell to produce multiple copies of themselves. A virus can still cause degenerative effects within a cell without causing its death; collectively these are termed cytopathic effects.
Virus life cycle
The life cycle of viruses differs greatly between species (see below) but there are six basic stages in the life cycle of viruses:
- Attachment is a specific binding between viral capsid proteins and specific receptors on the host cellular surface. This specificity determines the host range of a virus. For example, the human immunodeficiency virus (HIV) infects only human T cells, because its surface protein, gp120, can interact with CD4 and receptors on the T cell's surface. This mechanism has evolved to favour those viruses that only infect cells that they are capable of replicating in. Attachment to the receptor can induce the viral-envelope protein to undergo changes that results in the fusion of viral and cellular membranes.
- Penetration: following attachment, viruses enter the host cell through receptor mediated endocytosis or membrane fusion.
- Uncoating is a process in which the viral capsid is degraded by viral enzymes or host enzymes thus releasing the viral genomic nucleic acid.
- Replication involves synthesis of viral messenger RNA (mRNA) for viruses except positive sense RNA viruses (see above), viral protein synthesis and assembly of viral proteins and viral genome replication.
- Following the assembly of the virus particles post-translational modification of the viral proteins often occurs. In viruses such as HIV, this modification, (sometimes called maturation), occurs after the virus has been released from the host cell.[51]
- Viruses are released from the host cell by lysis (see below). Enveloped viruses (e.g., HIV) typically are released from the host cell by budding. During this process, the virus acquires its phospholipid envelope which contains embedded viral glycoproteins.
DNA viruses
Animal DNA viruses, such as herpesviruses, enter the host via endocytosis, the process by which cells take in material from the external environment. Frequently after a chance collision with an appropriate surface receptor on a cell, the virus penetrates the cell, the viral genome is released from the capsid, and host polymerases begin transcribing viral mRNA. New virions are assembled and released either by cell lysis or by budding off the cell membrane.
RNA viruses
Animal RNA viruses can be placed into about four different groups depending on their modes of replication. The polarity of the RNA largely determines the replicative mechanism, as well as whether the genetic material is single-stranded or double-stranded. Some RNA viruses are actually DNA-based but use an RNA-intermediate to replicate. RNA viruses are dependent on virally encoded RNA replicase to create copies of their genomes.
Reverse transcribing viruses
Reverse transcribing viruses replicate using reverse transcription, which is the formation of DNA from an RNA template. Reverse transcribing viruses containing RNA genomes use a DNA intermediate to replicate, whereas those containing DNA genomes use an RNA intermediate during genome replication. Both types use the reverse transcriptase enzyme to carry out the nucleic acid conversion. Both types are susceptible to antiviral drugs that inhibit the reverse transcriptase enzyme, e.g. zidovudine and lamivudine.
An example of the first type is HIV which is a retrovirus. Retroviruses often integrate the DNA produced by reverse transcription into the host genome. This is why HIV infection can at present, only be treated and not cured.
Examples of the second type are the Hepadnaviridae, which includes the Hepatitis B virus and the Caulimoviridae - e.g. Cauliflower mosaic virus.
Bacteriophages infect specific bacteria by binding to surface receptor molecules and then enter the cell. Within a short amount of time, in some cases, just minutes, bacterial polymerase starts translating viral mRNA into protein. These proteins go on to become either new virions within the cell, helper proteins which help assembly of new virions, or proteins involved in cell lysis. Viral enzymes aid in the breakdown of the cell membrane, and in the case of the T4 phage, in just over twenty minutes after injection over three hundred phages could be released.
Lifeform debate
Viruses have been described as "organisms at the edge of life",[52] but argument continues over whether viruses are truly alive. According to the United States Code they are considered microorganisms in the sense of biological weaponry and malicious use. Scientists, however, are divided. Things become more complicated as they look at viroids and prions. Viruses resemble other organisms in that they possess genes and can evolve in infected cells by natural selection.[53][54] They can reproduce by creating multiple copies of themselves through self-assembly.
Viruses do not have a cell structure (regarded as the basic unit of life), although they do have genes. Additionally, although they reproduce, they do not self-metabolize and require a host cell to replicate and synthesize new products. However, bacterial species such as Rickettsia and Chlamydia are considered living organisms but are unable to reproduce outside a host cell.
An argument can be made that accepted forms of life use cell division to reproduce, whereas viruses spontaneously assemble within cells. The comparison is drawn between viral self-assembly and the autonomous growth of non-living crystals. Virus self-assembly within host cells has implications for the study of the origin of life, as it lends credence to the hypothesis that life could have started as self-assembling organic molecules.[55]
If viruses are considered alive, then the criteria specifying life will have to exclude the cell. If viruses are said to be alive, the question could follow of whether even smaller infectious particles, such as viroids and prions, are alive.
Viruses and disease
- For more examples of diseases caused by viruses see List of infectious diseases.
Examples of common human diseases caused by viruses include the common cold, the flu, chickenpox and cold sores. Serious diseases such as Ebola, AIDS, avian influenza and SARS are caused by viruses. The relative ability of viruses to cause disease is described in terms of virulence. Other diseases are under investigation as to whether they too have a virus as the causative agent, such as the possible connection between Human Herpesvirus Six (HHV6) and neurological diseases such as multiple sclerosis and chronic fatigue syndrome. There is current controversy over whether the borna virus, previously thought of as causing neurological diseases in horses, could be responsible for psychiatric illnesses in humans.[56]
Viruses have different mechanisms by which they produce disease in an organism, which largely depends on the species. Mechanisms at the cellular level primarily include cell lysis, the breaking open and subsequent death of the cell. In multicellular organisms, if enough cells die the whole organism will start to suffer the effects. Although viruses cause disruption of healthy homeostasis, resulting in disease, they may exist relatively harmlessly within an organism. An example would include the ability of the herpes simplex virus, which cause cold sores, to remain in a dormant state within the human body. This is called latency[57] and is a characteristic of the herpes viruses including the Epstein-Barr virus, which causes glandular fever, and the Varicella zoster virus, which causes chicken pox. Latent chickenpox infections return in later life as the disease called shingles.
Some viruses can cause life-long or chronic infections, where the viruses continue to replicate in the body despite the hosts' defense mechanisms.[58] This is common in Hepatitis B virus and Hepatitis C Virus infections. People chronically infected with the Hepatitis B virus are known as carriers who serve as reservoirs of infectious virus. In some populations, with a high proportion of carriers, the disease is said to be endemic.[59] When diagnosing Hepatitis B virus infections, it is important to distinguish between acute and chronic infections.[60]
Viral epidemiology is the branch of medical science dealing with the transmission and control of virus infections in humans. Transmission of viruses can be vertical, that is from mother to child, or horizontal, which means from person to person. Examples of vertical transmission include Hepatitis B virus and HIV where the baby is born already infected with the virus.[61] Another, more rare, example is the Varicella zoster virus, which although causing relatively mild infections in humans, can be fatal to the foetus and newly born baby.[62] Horizontal transmission is the most common mechanism of spread of viruses in populations. Transmission can be exchange of blood by sexual activity, e.g. HIV, Hepatitis B and Hepatitis C; by mouth by exchange of saliva, e.g. Epstein-Barr virus, or from contaminated food or water, e.g. Norovirus; by breathing in viruses in the form of aerosols, e.g. Influenza virus; and by insect vectors such as mosquitoes, e.g. dengue. The rate or speed of transmission of viral infections depends on factors that include population density, the number of susceptible individuals, (i.e. those who are not immune),[63] the quality of health care and the weather.[64]
Epidemics and pandemics
Native American populations were devastated by contagious diseases, particularly smallpox, brought to the Americas by European colonists. It is unclear how many Native Americans were killed by foreign diseases after the arrival of Columbus in the Americas, but the numbers have been estimated to be close to 70% of the indigenous population. The damage done by this disease significantly aided European attempts to displace and conquer the native population.[65][66][67][68][69][70][71]
A pandemic is a world-wide epidemic. The 1918 flu pandemic, commonly referred to as the Spanish flu, was a category 5 influenza pandemic caused by an unusually severe and deadly Influenza A virus. The victims were often healthy young adults, in contrast to most influenza outbreaks which predominantly affect juvenile, elderly, or otherwise weakened patients.
The Spanish flu pandemic lasted from 1918 to 1919. Older estimates say it killed 40–50 million people,[72] while more recent research suggests that it may have killed as many as 100 million people, or 5% of the world's population in 1918.[73]
Most researchers believe that HIV originated in sub-Saharan Africa during the twentieth century;[74] it is now a pandemic, with an estimated 38.6 million people now living with the disease worldwide.[75] As of January 2006, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimate that AIDS has killed more than 25 million people since it was first recognized on June 5, 1981, making it one of the most destructive epidemics in recorded history.[76]
Several highly lethal viral pathogens are members of the Filoviridae. Filoviruses are filament-like viruses that cause viral hemorrhagic fever, and include the Ebola and Marburg viruses. The Marburg virus attracted widespread press attention in April 2005 for an outbreak in Angola. Beginning in October 2004 and continuing into 2005, the outbreak was the world's worst epidemic of any kind of viral hemorrhagic fever.[77]
Viruses and cancer
Viruses are an established cause of malignancy in humans and other species. The main viruses associated with human cancers are human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, and human T-lymphotropic virus. Hepatitis viruses, including hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer.[78][79] Infection by human T-lymphotropic virus can lead to tropical spastic paraparesis and adult T-cell leukemia.[80] Human papillomaviruses are an established cause of cancers of cervix, skin, anus, and penis.[81] Within the Herpesviridae, Kaposi's sarcoma-associated herpesvirus causes Kaposi's sarcoma and body cavity lymphoma, and Epstein–Barr virus causes Burkitt's lymphoma, Hodgkin's lymphoma, B lymphoproliferative disorder and nasopharyngeal carcinoma.[82]
Laboratory diagnosis
In the diagnostic laboratory, virus infections are confirmed by several methods that include:
- Growth of the virus in a cell culture from a specimen taken from the patient.
- Detection of virus-specific IgM antibody (see below) in the blood.
- Detection of virus antigens by ELISA in tissues and fluids.
- Detection of virus encoded DNA and RNA by PCR.
- Observation of virus particles by electron microscopy.
Prevention and treatment
Because viruses use the machinery of a host cell to reproduce and reside within them, they are difficult to eliminate without killing the host cell. The most effective medical approaches to viral diseases so far are vaccinations to provide resistance to infection, and antiviral drugs which treat the symptoms of viral infections.
Host immune response
The body's first line of defense against viruses is the innate immune system. This comprises cells and other mechanisms that defend the host from infection in a non-specific manner. This means that the cells of the innate system recognize, and respond to, pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host.[83]
RNA interference is an important innate defense against viruses.[84] Many viruses have a replication strategy that involves double-stranded RNA dsRNA. When such a virus infects a cell, it releases its RNA molecule or molecules, which immediately bind to a protein complex called Dicer that cuts the RNA into smaller pieces. A biochemical pathway called the RISC complex is activated which degrades the viral mRNA and the cell survives the infection. Rotaviruses avoid this mechanism by not uncoating fully inside the cell and by releasing newly produced mRNA through pores in the particle's inner capsid. The genomic dsRNA remains protected inside the core of the virion.[85][86]
When the adaptive immune system of a vertebrate encounters a virus, it produces specific antibodies which bind to the virus and render it non-infectious. This is called humoral immunity. Two types of antibodies are important. The first called IgM is highly effective at neutralizing viruses but is only produced by the cells of the immune system for a few weeks. The second, called, IgG is produced indefinitely. The presence of IgM in the blood of the host is used to test for acute infection, whereas IgG indicates an infection sometime in the past.[87] Both types of antibodies are measured when tests for immunity are carried out.[88]
A second defense of vertebrates against viruses is called cell-mediated immunity and involves immune cells known as T cells. The body's cells constantly display short fragments of their proteins on the cell's surface, and if a T cell recognizes a suspicious viral fragment there, the host cell is destroyed by T killer cells and the virus-specific T-cells proliferate. Cells such as the macrophage are specialists at this antigen presentation.[89][90]
Not all virus infections produce a protective immune response in this way. HIV evades the immune system by constantly changing the amino acid sequence of the proteins on the surface of the virion. These persistent viruses evade immune control by sequestration, blockade of antigen presentation, cytokine resistance, evasion of natural killer cell activities, escape from apoptosis, and antigenic shift.[91] Other viruses, called "neurotropic viruses", are disseminated by neural spread where the immune system may be unable to reach them.
The production of interferon is an important host defense mechanism.[92]
Vaccination is a cheap and effective way of preventing infections by viruses. Vaccines were used to prevent viral infections long before the discovery of the actual viruses. Their use has resulted in a dramatic decline in morbidity (illness) and mortality (death) associated with viral infections such as polio, measles, mumps and rubella.[93] Smallpox infections have been eradicated.[94] Currently vaccines are available to prevent over thirteen viral infections of humans,[95] and more are used to prevent viral infections of animals.[96] Vaccines can consist of live-attenuated or killed viruses, or viral proteins (antigens).[97] Live vaccines contain weakened forms of the virus that causes the disease. Such viruses are called attenuated. Live vaccines can be dangerous when given to people with a weak immunity, (who are described as immunocompromised), because in these people, the weakened virus can cause the original disease.[98] Biotechnology and genetic engineering techniques are used to produce subunit vaccines. These vaccines use only the capsid proteins of the virus. Hepatitis B vaccine is an example of this type of vaccine.[99] Subunit vaccines are safe for immunocompromised patients because they cannot cause the disease.[100] The Yellow Fever virus vaccine, a live-attenuated strain called 17D, is arguably the safest and most effective vaccine ever generated.
Antiviral drugs
Over the past twenty years, the development of antiviral drugs has increased rapidly. This has been driven by the AIDS epidemic. Antiviral drugs are often nucleoside analogues, (fake DNA building blocks), which viruses incorporate into their genomes during replication. The life-cycle of the virus is then halted because the newly synthesized DNA is inactive. This is because these analogues lack the hydroxyl groups which along with phosphorus atoms, link together to form the strong "backbone" of the DNA molecule. This is called DNA chain termination.[101] Examples of nucleoside analogues are aciclovir for Herpes virus infections and lamivudine for HIV and Hepatitis B virus infections. Aciclovir is one of the oldest and most frequently prescribed antiviral drugs.[102]
Other antiviral drugs in use target different stages of the viral life cycle. HIV is dependent on a proteolytic enzyme called the HIV-1 protease for it to become fully infectious. There is a class of drugs called protease inhibitors which have been designed to inactivate the enzyme.
Hepatitis C is caused by an RNA virus. In 80% of people infected, the disease is chronic, and without treatment, they are infected and infectious for the remainder of their lives. However, there is now an effective treatment using the nucleoside analogue drug ribavirin combined with interferon.[103] The treatment of chronic carriers of the Hepatitis B virus by using a similar strategy using lamivudine is being developed.[104]
Notable examples
The clinically most notable[105] virus species belong to the following families:
Life sciences and medicine
Viruses are important to the study of molecular and cellular biology as they provide simple systems that can be used to manipulate and investigate the functions of cells. The study and use of viruses have provided valuable information about aspects of cell biology. For example, viruses have been useful in the study of genetics and helped our understanding of the basic mechanisms of molecular genetics, such as DNA replication, transcription, RNA processing, translation, protein transport, and immunology.
Geneticists often use viruses as vectors to introduce genes into cells that they are studying. This is useful for making the cell produce a foreign substance, or to study the effect of introducing a new gene into the genome. In similar fashion, virotherapy uses viruses as vectors to treat various diseases, as they can specifically target cells and DNA. It shows promising use in the treatment of cancer and in gene therapy. Eastern European scientists have used phage therapy as an alternative to antibiotics for some time, and interest in this approach is increasing, due to the high level of antibiotic resistance now found in some pathogenic bacteria.[108]
Granulosis (GV) and nucleo-polyhedrosis viruses (NPV) may also be used as biological insecticides (e.g. Cydia pomonella granulovirus).
Materials science and nanotechnology
Current trends in nanotechnology promise to make much more versatile use of viruses. From the viewpoint of a materials scientist, viruses can be regarded as organic nanoparticles.[109] Their surface carries specific tools designed to cross the barriers of their host cells. The size and shape of viruses, and the number and nature of the functional groups on their surface, is precisely defined. As such, viruses are commonly used in materials science as scaffolds for covalently linked surface modifications. A particular quality of viruses is that they can be tailored by directed evolution. The powerful techniques developed by life sciences are becoming the basis of engineering approaches towards nanomaterials, opening a wide range of applications far beyond biology and medicine.[110]
Because of their size, shape, and well-defined chemical structures, viruses have been used as templates for organizing materials on the nanoscale. Recent examples include work at the Naval Research Laboratory in Washington, DC, using Cowpea Mosaic Virus (CPMV) particles to amplify signals in microarray based sensors. In this application, the virus particles separate the fluorescent dyes used for signaling in order to prevent the formation of non-fluorescent dimers that act as quenchers.[111] Another example is the use of CPMV as a nanoscale breadboard for molecular electronics.[112] In April 2006, scientists at the Massachusetts Institute of Technology (MIT) created nanoscale metallic wires using a genetically-modified virus.[113] The MIT team was able to use the virus to create a working battery with an energy density up to three times more than current materials. The potential exists for this technology to be used in liquid crystals, solar cells, fuel cells, and other electronics in the future.
The ability of viruses to cause devastating epidemics in human societies has led to the concern that viruses could be weaponized for biological warfare. Further concern was raised by the successful recreation of the infamous 1918 influenza virus in a laboratory.[114] The smallpox virus devastated numerous societies throughout history before its eradication. It currently exists in several secure laboratories in the world, and fears that it may be used as a weapon are not totally unfounded. The vaccine for smallpox is not safe, and during the years before the eradication of smallpox disease more people became seriously ill as a result of vaccination than did people from smallpox[115] and smallpox vaccination is no longer universally practiced.[116] Thus, the modern global human population has almost no established resistance to smallpox; if it were to be released, a massive loss of life could be sustained before the virus is brought under control.
Electron micrographs of viruses
Norovirus. This RNA virus causes winter vomiting disease. It is often in the news as a cause of gastro-enteritis on cruise ships and in hospitals.
Caliciviruses are related to Noroviruses.
Torovirus. An enveloped RNA virus.
Coronaviruses are a group of viruses that have a halo, or crown-like (corona) appearance when viewed under a microscope.
Ebola Virus is a filamentous RNA virus.
Measles virus. This is called a thin section where the virus particle has been cut in two.
Respiratory Syncytial Virus (RSV). In this preparation the ribonucleoprotein can be seen as a herring bone pattern.
Parvovirus B19. Parvovirus B19 is a small DNA virus best known for causing a childhood exanthema called fifth disease or erythema infectiosum.
Transmission electron micrograph of Herpes virus an enveloped virus that looks like fried eggs by negative stain electron microscopy.
TEM micrograph of Poliovirus virions.
See also
- Influenza
- Rotavirus
- Herpes simplex virus
- Hepatitis B virus
- Satellite
- Neurotropic virus
- Bacteriophages (bacterial viruses)
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ignored (help); Unknown parameter|coauthors=
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- ↑ An Engineered Virus as a Scaffold for Three-Dimensional Self-Assembly on the Nanoscale. Amy Szuchmacher Blum, Carissa M. Soto, Charmaine D. Wilson, Tina L. Brower, Steven K. Pollack, Terence L. Schull, Anju Chatterji, Tianwei Lin, John E. Johnson, Christian Amsinck, Paul Franzon, Ranganathan Shashidhar and Banahalli Ratna, Small, 7, 702 (2005).
- ↑ "Researchers build tiny batteries with viruses". MIT News Office. Retrieved 2007-04-05.
- ↑ "Researchers Reconstruct 1918 Pandemic Influenza Virus; Effort Designed to Advance Preparedness". Centers for Disease Control. Retrieved 2007-04-05.
- ↑ Aragón TJ, Ulrich S, Fernyak S, Rutherford GW (2003). "Risks of serious complications and death from smallpox vaccination: a systematic review of the United States experience, 1963-1968". BMC public health. 3: 26. doi:10.1186/1471-2458-3-26. PMID 12911836.
- ↑ Weiss MM, Weiss PD, Mathisen G, Guze P (2004). "Rethinking smallpox". Clin. Infect. Dis. 39 (11): 1668–73. doi:10.1086/425745. PMID 15578369.
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» 1. Leave a comment on this blog post «
» 4. Follow/tweet us on Instagram: instagram.com/heymamaelephant «
Nichol Magouirk
Lisa Spangler
Elena Roussakis
Debby Hughes
Joy Taylor
Sandy Allnock
And that would be a wrap! Big, big, big thanks to all our friends from days 1 to 3 for joining us! We could not have pulled off this epic 3-day stampede without you!
And thank YOU all for joining us the last two weeks as you shared in our excitement for our 3rd year and this mega anniversary birthday release! As always, Angela and I are deeply humbled by your support through the years! We, Mama Elephants, will never forget!

subset: commoncrawl


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« Prev | The Present Translation. | Next » |
6. The Present Translation.
1. Text. It was proposed at first to make the translation from the text of Herding. This, and all editions, gave so little basis for scientific certainty in regard to various readings that a cursory examination of mss. was made. At the suggestion of Professor O. von Gebhardt of Berlin the examination was made as thorough and systematic as possible with definite reference to a new edition. The translator hoped to finish and publish the new text before the translation was needed for this series, but classification of the mss. proved unexpectedly intricate and the question of the Greek translation so difficult that publication has been delayed. The material has however been gathered, analyzed, sifted and arranged sufficiently to give reasonable certainty as to the body of the work and a tolerably reliable judgment on most of the important variations.
While anxious not to claim too much for his material and unwilling to give a final expression of judgment on disputed readings, until his table of mss. is perfected, he ventures to think that for substantial purposes of translation, if not for the nicer ones of a new text, the material and method which he has made use of will be substantially conclusive.
The following translation has been made first from the text of Herding and then corrected from the manuscripts in all places where the evidence was clearly against the edition. In places where the evidence is fairly conclusive the change has been made and a brief statement of evidence given in the notes. When the evidence is really doubtful the reading has been allowed to stand with evidence generally given.
The materials of evidence used are 1. eight mss. collated entire by the translator A. Parisinus (Corbeiensis or Sangermanensis 7 cent.) T. Vaticanus Reg., 7 cent.; 25 Veronensis, 8 cent.; 30 Vercellensis 8 cent.; 31 Monspessalanensis 8 or 9 cent.; a Monacensis 8 cent.; e Vindobonensis 8 or 9; H. Parisinus 10 or 9.
2. Occasional support from readings gathered by him from other mss., chiefly 10 Cassenatensis 9 cent.; 21 Florentinus, 11 cent.; 32 Toletanus 13 cent.; 40 Guelferbyrtinus, 10? cent.
3. Readings from mss. mentioned by other editors.
4. The various editions, but mainly confined to Vallarsi and Herding in Jerome, Fabricius and Herding in Gennadius.
The translator has examined nearly 90 mss. and secured more or less readings from nearly all with reference to an exact table. The readings of several are extensive enough to have pretty nearly the value of full collations. Quotations are occasionally made from these (e.g. from 10, 21, 29, 32, 40, etc.) but practically quotations from the eight mentioned mss. cover the evidence and without a table more would rather obscure than otherwise.
There is no opportunity here to discuss the relative value of these used. It may be said however that they are the oldest mss., and include pretty much all the oldest. Though age itself is by no means conclusive, the fact that they certainly represent several independent groups makes it safe to say that a consensus of seven against one or even six against any two (with certain reservations) or in the case of Gennadius of 5 against 2 is conclusive for a reading. As a matter of fact against many readings of Herding and even of Vallarsi, 357are arranged all these mss., and against some nearly all or even every ms. seen, e.g. Her. p. 73 d. 12 reads morti dari with Migne-Fabricius but all these mss. have mutandam and so 91. 22 "seven" for "eight." On p. 161. 7. Her. omits Asyncritus against mss. and all modern eds., so 44. 3. "Ponti," 51. 7 "ut quidem putant;" 77. 25. "firmare" and a score of other places.
Of course this is not enough evidence or discussion for a critical scholastic text but for the practical illustrative purpose in hand will serve. Any evidence which does not give a well digested genealogy of mss. and the evidence for their classification must be reckoned as incomplete,—all that the above evidence can claim to do, is to give the translator's judgment respecting the readings and illustrative evidence, but it is not probable that the completed table will alter many (if any) of these readings which are given in view of a tentative table which will likely prove final.
The Translation itself. The plan of this work includes (a) a translation, in which the translator has tried to give a fair representation of the text in a not too ragged form but has failed to improve on the original. The works were written as science rather than literature and have many facts but no style. The translator has therefore aimed rather at representing these facts than at producing a piece of polite literature. (b) Notes are subjoined including, first the brief biographical data which every one wants first to orient himself by, secondly textual notes, and thirdly, occasional explanatory notes.
« Prev | The Present Translation. | Next » |


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Source: here |
For almost four hundred years, 鄭芝龍 has been portrayed by historians as a pirate and a traitor, a one-sided erroneous description that has persisted to this day. Within the Cheng Clan, Koxinga's falling out with his father over the loyalty to Ming Emperor was also a factor. In fact, in Tainan, the seat of power of the Ming Cheng Kingdom, memorial to 鄭芝龍 is nowhere to be found.
We now know that 鄭芝龍 was forced to yield, not by the military might of the Qing, but by a great famine at that time when it was no longer possible to maintain a sizable force without confiscating foodstuff from the general public. Not wishing to do that and after a life-time of fighting enemies from within and without China, he was truly tired looking forward to a peaceful resolution. Only he himself was detained at a meeting with Qing officials. And three of his sons and daughter-in-laws were later ordered to Beijing. All were put to death in 1661. After learning the demise of his father and brothers, a crestfallen Koxinga passed away soon after.
In this temple in Tainan, the father finally took his rightful place with his son Konxiga and his wife Lady Weng.


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Fit Moms Prenatal Exercise
July 30 @ 7:30 pm - 8:45 pm
|Recurring Event (See all)
An event every week that begins at 7:30 pm on Tuesday, repeating indefinitely
Event Navigation
This prenatal fitness class is a unique blend of cardiovascular, resistive training, yoga, and childbirth education. It focuses on overall well-being throughout your pregnancy while emphasizing the primary muscle groups essential for delivery and postpartum recovery. Its s never too early or too late in your pregnancy to start this class and is appropriate for all fitness levels.
Location – Sadhana Yoga Studio in Wilmington, DE
Cost – $70 for 5 classes


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Rocker Dee - 9 Digi stamp bundle in jpg and png files
Rocker Dee - 9 Digi stamp bundle in jpg and png files
Miss Dee is a Vera Lane Studio exclusive. Original images are hand drawn and scanned for instant downloading. Our quirky and whimsical stamps downloads in high quality resolution files 300 dpi in both jpg and png images.
All image sets from VLS are own by VLS and licensed in limited release for limited PERSONAL USE . Limited use license is for the purchaser only and may not be shared, swapped, duplicated, altered or claimed as one's own.
NO RESALE OF ANY ITEMS USING VLS images is permitted. Unlimited personal use for cards, art journals, gifts is permitted. NO CLASS USE is permitted. The images will download free of watermarks and come to you in high quality png and jpg files. Images can be sized up or down to accommodate cards, ATCs, invites, art journals and more.


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The charts below allow for comparisons to be made between district scores and the scores for the nation and large cities nationally.
See district results for grade 8 for a more detailed report with average scores, achievement levels, and percentile results for the nation, large cities, and districts.
Average scale scores for all students in eighth-grade NAEP reading, by jurisdiction: 2011
The order of jurisdictions is based on numeric precision (up to eight decimal places) rather than the displayed precision and does not take statistical significance into consideration. To see whether there is a significant difference between jurisdictions, consult the column "Cross-jurisdiction significant difference."
A negative number in the average score gap column indicates that the latter group in the comparison is higher than the group that it is compared to.
When scores for a single student group (e.g., all students) are compared, the significant differences are displayed using adjustments for multiple comparisons. When gaps are compared, the significant differences displayed are based on single pairwise tests of statistical significance.
For complete data, visit the NAEP Data Explorer. See scale score results for all students, by race/ethnicity, and family income.
When comparing the results for urban districts to results for the nation and large cities, it is important to consider how the demographics of the jurisdictions are different. For example, large cities and participating urban districts differ from the nation in the proportion of students eligible for the National School Lunch Program (an indicator of lower family income). While the percentages of students from lower-income families eligible for free/reduced-price school lunch in the nation in 2011 were 52 percent at grade 4 and 48 percent at grade 8, the percentages of lower-income students in the districts ranged from 51 to 100 percent.


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Evolutionary Materialism: Towards a Theory of Anticipatory Adaptive Assemblages
Time: Thu 2020-11-26 10.00
Subject area: Civil and Architectural Engineering, Building Materials
Doctoral student: Magnus Larsson , Byggnadsmaterial, EnWoBio
Opponent: Professor Olga Popovic Larsen, KADK The Royal Danish Academy of Fine Arts, Copenhagen, Denmark
Supervisor: Professor Magnus Wålinder, Byggnadsmaterial; PhD Andreas Falk,
This thesis is an investigation into how meta-heuristic multi-objective optimisation processes (genetic algorithms driven by evolutionary solvers) can bring about materials-related advantages in architectural performance. It redefines the architect's and engineer's role from being designers of a singular space or structure to being designers of entire species of spaces, and discusses a particular method – anticipatory adaptive assemblages (AAA) – that allows such processes to produce many generations of design iterations that eventually yield individuals optimised for a set of predefined objectives. This includes in particular the optimisation of building materials, with a certain focus on timber structures.
The thesis provides a theoretical foundation (assemblage theory) that connects an ontology, a methodology, an epistemology, and an axiology to the computational operations used, elevating the domain beyond simplistic notions of parametricism. It leverages contemporary generative design methods to introduce a range of novel concepts and tools such as auxiliary loads, material phase transition (MPT) diagrams, generative life cycle assessments (GLCA), parametric epistemic things (PET), presilience, and postponism. Finally, it provides a case study that shows how this assortment of contrivances, and AAA theory at large, can be used not just for theoretical musings, but to produce actual architectural schemes based on more precise data analyses than is typically the case in today's built environment.
A concluding discussion establishes that the use of more advanced and complex optimisation strategies is not just a possibility but a necessary obligation for an architecture, engineering, and construction (AEC) industry that – if the manufacturing of building materials are added to the construction and operation of buildings – is responsible for between 35% and 40% of both global final energy use and worldwide energy-related CO2 emissions. Claiming that our knowledge of materials, including the auxiliary loads that they carry (such as their global warming potential) can be used to design and engineer architectural assemblages capable of replacing energy-consuming with energy-producing buildings, it suggests that Le Corbusier's famous dictum that buildings are 'machines for living in' should be replaced with the notion that all buildings are potential power plants for living in. Risks associated with the development of AAAs are discussed, and future studies proposed.


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Cabrera and Perry Tied
After holding off Tiger Woods and Jim Furyk to win the 2007 U.S. Open, Cabrera is a battle tested veteran.
AUGUSTA, Ga. (AP) -- Angel Cabrera and Kenny Perry have proven they can handle the pressure on golf's biggest stage. Next up is Sunday at Augusta National, a test unlike any other they have faced.
Cabrera, who won the U.S. Open two years ago at Oakmont, made three birdies on the back nine and scratched out an important par on the final hole Saturday at the Masters for a 3-under 69.
Perry, who thrived under the spotlight of a Ryder Cup in his native Kentucky last September, overcame two mistakes with his putter around Amen Corner and finished with five straight pars for a 70 to join the Argentine in the lead.
It will be the first time they've played in the final group at a major.
And not just any major.
They were at 11-under 205, the lowest 54-hole score at the Masters since the course was supersized seven years ago. The back nine at Augusta National is among the most intense in golf, and officials are expected to set up the course to allow for birdies and eagles.
"I'm lucky enough to be in a very good position," Cabrera said. "I haven't been in this position before so I'll try to make the most of it."
Perry lost in a playoff at the PGA Championship at Valhalla in 1996, when he was criticized for being in the broadcast booth instead of keeping loose on the practice range. He never would have imagined that all these years later, he would have a chance to become golf's oldest major champion at 48.
"The first two days felt like I was on vacation," Perry said. "Today felt like a job."
They had a two-shot lead over Chad Campbell, who led briefly on the back nine until a blunder on the 16th hole when he took two shots to get out of the bunker, made double bogey and wound up with a 72.
Jim Furyk, another former U.S. Open champion, shot 68 and was three shots behind at 8-under 208.
The Masters began with the anticipation of Tiger Woods and Phil Mickelson going head-to-head in the final round, and that's what happened. Trouble is, both were seven shots behind and still trying to convince themselves that they still had a chance.
Woods began his Saturday charge by hooking his tee shot into the trees and making double bogey. His tee shot on the par-3 sixth hit the base of the pin and tumbled off the green. He rallied with three birdies over the last six holes for a 70.
Mickelson's rally was slowed by three poor chips, and he escaped with a 71 only after hitting a big slice from the trees on the 18th hole that started down the 10th fairway and wound up on the green.
They were at 4-under 212.
"A lot of things happen on Sunday at Augusta, and I would never put it past happening again," Mickelson said. "I think that at this golf course, funny things can happen, and if you get momentum on your side and you're making some birdies, you can make a lot of them."
And then he offered another scenario that he and Woods desperately need.
"When it starts coming apart, it's hard to get it back," Mickelson said. "And it's easy to tumble."
There was little sign of that happening with Perry and Cabrera on a breezy afternoon, on a course where the greens remained relatively soft from an overnight downpour.
Perry became the first player to reach 12-under par at any point in the tournament since 2002 when he rolled in an 8-foot birdie on the 10th hole, and it allowed him to wonder if this might really be his week.
But he three-putted from just off the front of the 11th green of his first bogey, then fell out of the lead on the par-3 12th. After hitting over the green, Perry tried putting up the slope and hit it too hard, the ball bouncing over the cup 15 feet away for another bogey.
He recovered with a 4-iron to about 25 feet for a two-putt birdie on the 13th.
Woods left the course knowing that even having a remote chance would depend on how the leaders played the back nine. They helped slightly but not running away, with Campbell shooting a 38 on the back and Perry getting around in 36.
The world's No. 1 player has never won a major when trailing after 54 holes, and only once has he won when trailing by more than seven shots going into the final round of any tournament.
"That was a hell of a fight," Woods said. "I'm pretty proud of the fact I got myself back in the tournament, considering that I didn't hit it as well as I wanted to and had two three-putts."
The forecast was for sunshine and fireworks, perhaps a back-nine charge not seen this decade at Augusta National.
Steve Stricker played bogey-free for a 68 that put him four shots behind at 7-under 209, with former British Open champion Todd Hamilton (72), Shingo Katayama (70) and Rory Sabbatini (70) another shot behind.
One player too far out of contention is Padraig Harrington, who saw his hopes of a third straight major end on the second hole when he twice hit a tree and took a quadruple-bogey 9. He shot a 73 and was 10 shots back.
Only once in the last 18 years at the Masters has the winner not come out of the final group, which bodes well for Perry and Cabrera. Even so, Perry glanced at the white leaderboard behind the 18th green and realized Sunday would be no picnic.
"There are actually quite a few guys who have a shot at this thing tomorrow," he said. "You will definitely see something happen on the back nine, where somebody is going to win it."


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Pure Tranquility
Class Details
Vibrant violets radiate from this tranquil sunset landscape.
ALL SALES ARE FINAL - No Refund and Class Credit Policy: (Based on class start time) 21+ ID Required.
GROUPS: Let us know about any celebrations and who is in your group via email or seating request.
LATE ARRIVAL POLICY: Arrivals more than 15 minutes after painting session has started are welcome to paint, but will need to catch up on their own. Painters arriving 30+ minutes after start of a class will not be allowed to paint or receive credit.
Due to the custom nature of ALL our classes, NO REFUNDS will be issued for reservations. However, if you cancel with at least 48 hours' notice your payment will be turned into a store credit that can ONLY be used for a future class within 30 days. Please email us (email@example.com) to cancel.
If you no-show, or don't give at least 48 hours' notice, you forfeit your reservation payment and will not receive a credit. Seats are transferable, but you need to notify us at least 3 hours prior to a class with the name change.
BE RESPECTFUL: We reserve the right to request loud guests to leave without refund or credit if you do not respond to our polite requests.
By purchasing your seats, you confirm agreement with this policy.
The Perfect Night Out
Enjoy drinks, upbeat music and hanging out with your favorite people while you paint! It's as fun for first-time painters as it is for experienced artists.
Fun Atmosphere
From the moment you walk in, the mood is light, the music is fun and the conversation comes easy!
Easy to Do
You don't need to be a seasoned painter — we make it easy for everyone to find their inner artist!
Sit Together
You'll get seats with all your friends, even if you book separately. Just tell us your friends' names when you register.
Paint Your Way
There's no rule that says you have to follow the artist's steps. It's your art, so paint it however you like!
Frequently Asked Questions
Check out our FAQs to learn more about what to expect from your Pinot's Palette experience or feel free to call the studio to speak to a member of our staff.
Do you host private In-Studio events?
We'd love to host your event! Details here: https://pinotspalette.com/san-bruno/blog/team-building/private-parties
Is there parking nearby?
Yes, there is street and lot parking. Please make sure to pay for parking at designated times. https://www.sanbruno.ca.gov/958/Paid-Parking
What is paint and sip?
Paint and sip events combine social drinking with painting. Our paint and sip studio offers beer, wine, and other non-alcoholic beverages. Everyone gets a canvas and follows an artist's instructions to recreate the featured painting on their own canvas. Paint and sip is not a serious art course – it's about socializing and having fun.
Do I need to know anything about art?
Not at all. Our artists provide easy, step-by-step instructions to help everyone produce a great finished product.
This is my first time. What should I expect?
Expect a relaxed, fun atmosphere – there's no pressure to be Van Gogh! We provide everything, including aprons to protect your clothes and a paint-free space for your purse or coat.


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U.S. Department of Transportation
Federal Highway Administration
1200 New Jersey Avenue, SE
Washington, DC 20590
Federal Highway Administration Research and Technology
Coordinating, Developing, and Delivering Highway Transportation Innovations
This report is an archived publication and may contain dated technical, contact, and link information |
Publication Number: FHWA-RD-99-128
Date: October 1999 |
Crash Models for Rural Intersections: Four-Lane by Two-Lane Stop-Controlled and Two-lane by Two-lane Signalized FOREWORDThis report provides direct input into the Accident Analysis Module (AAM) of the Interactive Highway Safety Design Model. The AAM is a tool that highway engineers can use to evaluate the impacts of highway design elements in project planning and preliminary design. Three crash models were developed relating crashes to three types of rural intersections. These types are: (1) three-legged intersections with major four-lane roads and minor two-lane roads that are stop-controlled, (2) four-legged intersections with major four-lane roads and minor two-lane roads that are stop-controlled, and (3) signalized intersections with both major and minor two-lane roads. Elaborate sets of data were acquired from State data sources (Michigan and California) and collected in the field. The final data sets consist of 84 sites of three-legged intersections, 72 sites of the four-legged intersections, and 49 sites of the signalized intersections. Negative binomial models -- variants of Poisson models that allow for overdispersion -- were developed for each of the three data sets. Significant variables included major and minor road traffic; peak major and minor left-turn percentage; peak truck percentage; number of driveways; and channelization, intersection median widths, vertical alignment, and, in the case of signalized intersections, the presence or absence of protected left-turn phases. Separate models were developed for crashes resulting in injuries and total crashes.
PDF Version (7.16 MB) PDF files can be viewed with the Acrobat® Reader® TECHNICAL REPORT DOCUMENTATION PAGE
Form DOT F 1700.7 (8-72) Reproduction of completed page authorized FHWA-RD-99-128 |


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For the past 15 years, Beata Kowalczyk served up hearty Polish fare at her Roncesvalles mainstay, Lala Bistro. Earlier this spring she decided to throw her apron away, and reopen the place as Marcy. And while the old regulars are grieving over the loss of her cabbage rolls, a new generation of patrons has quickly filled their seats—due in part, no doubt, to the presence of manager and resident mixologist Vanessa Handford, formerly of Goodnight.
Kowalczyk asked her neighbourhood pal Catherine Huizenga (of Mrs. Huizenga's, a vintage furniture and tchotchke shop located a block south) to help with the revamp and the rebrand. Huizenga rechristened her friend's bar Marcy, after the label on her well-loved fur coat (the official back-story: the Edvard Munch-esque painting at the bar's entrance is of "Marcy" and her husband). Apart from inventing a fictitious owner, Huizenga reupholstered the chairs and booths with paisley, polka dots and even a comic strip print. She also decked out the exposed brick walls with an eccentric collection of paintings and knickknacks like a porcelain Pierrot head and rocking horse cutouts. In homage to Lala Bistro, the old backlit Lala Bistro sign, in the colours of the Polish flag, now hangs opposite the bar.
Although Kowalczyk may have turned her oven off for good, she doesn't want her customers to go hungry. On offer are four cold plates: smoked mackerel ($14), smoked salmon ($12), kielbasa ($12) and avocado ($10), all served with Ubashi baguette, assorted pickles, feta cheese, sun-dried tomatoes, pesto and tapenade. Handford has also named one of her six signature cocktails (all $8.50) in memory of the bar's Polish past; the Lala's Mule is made with gin, limoncello, stirred mint and cucumbers, fresh squeezed citrus and soda. In keeping with the Polish-Canadian mash-up, the beers on offer include the big Polish beers (Tyskie, Żywiec and Tatra, all $6) and local craft beers on draft (Stonehammer Dark Ale, Beau's Lug Tread Lagered Ale and Beau's IPA, all $6.50).
Marcy, 145 Roncesvalles Ave., 416-516-2577, Facebook page
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Free Beer & Hot Wings: Single Mom Pleads With Thief To Return Stolen Minivan (Video)
Megan Bratten, of Independence, Mo., had just gone into the local Kmart to pick up some last-minute school supplies. She was in the store for about 15 minutes and when she came out discovered that her minivan had been stolen.
Thinking quickly, she sent a text to her estranged husband's phone which was still in the minivan, pleading with the thief to return the vehicle.


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