Unit 4


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Unit 4

  1. 1. Dr.N.sangeetha 1 Radiation Biology Unit 4 Radiation DamageRadiation is everywhere. It’s invisible and penetrating. Radiation emanates from the soil, seepsas radon into the basements of our homes, and can be a product of the atomic bomb. Much isoften assumed about exposing our bodies to radiation, but what does happen when an ionizingparticle or photon passes through our cells?The radiation deposits energy in that aqueous environment and so creates reactive chemicalspecies. In particular, radiation will produce a highly reactive species known as the hydroxyl freeradical (OH.). This radical can easily break chemical bonds. An attack on the sugar to which anucleic-acid base is attached can result in a single-strand break because all or nearly all of thesugar is typically lost. In that case, the break is actually a one-base-wide gap in the DNAbackbone. Ionizing radiation induces four major types of DNA lesions. These are nucleic-acidbase alterations, abasic sites, single-strand breaks, and double-strand breaks Mechanisms of DamageInjury to living tissue results from the transfer of energy to atoms and molecules in the cellularstructure. Ionizing radiation causes atoms and molecules to become ionized or excited. Theseexcitations and ionizations can: • Produce free radicals. • Break chemical bonds. • Produce new chemical bonds and cross-linkage between macromolecules. • Damage molecules that regulate vital cell processes (e.g. DNA, RNA, proteins).The cell can repair certain levels of cell damage. At low doses, such as that received every dayfrom background radiation, cellular damage is rapidly repaired.At higher levels, cell death results. At extremely high doses, cells cannot be replaced quicklyenough, and tissues fail to function.
  2. 2. Dr.N.sangeetha 2 Radiation Biology Unit 4 Radiation induced DNA DamageBase alterations and abasic siteIonizing radiation can also cause simple modifications to individual DNA bases, creatingnumerous types of base alterations. An entire base can also become separated from the sugar,creating what is called an abasic site.Base alterations and abasic sites, on the other hand, can result in single base changes to the DNAstrand known as point mutations. Damaged bases must be repaired, because they might possessaltered or ambiguous Watson-Crick pairing properties. As for an abasic site, the DNA structureis compromised due to the in-ability to form hydrogen bonds between the complementary DNAstrands. In both cases, however, the DNA backbone is intact, and during S phase, DNAreplication past those lesions will be attempted. The lesions can cause the replication to be errorprone, potentially resulting in changes in the nucleotide sequence of the newly synthesizedstrand. Because the change in base sequence can affect the amino-acid structure and, hence, theprotein structure, point mutations might alter the activity or regulation of the gene’s proteinproduct. Like single-strand break damage, however, generation of base alterations and abasicsites within the genome are dominated by processes other than ionizing radiation, and the repairof those lesions is similarly rapid and efficient. Probably as a consequence of that repair, ionizingradiation is a relatively poor inducer of point mutations compared with most chemicalcarcinogens.Single-strand breaksAlthough ionizing radiation can lead to the creation of single-strand breaks, the rate at which itdoes so is negligible compared to a cell’s normal metabolic processes. The latter producescopious amounts of hydroxyl radicals. It is estimated that for every single-strand break inducedby background radiation, there are about ten million breaks induced by radicals generated duringnormal cellular metabolism. However, even though the total rate of single-strand breaks fromsuch processes is high, the consequences of single-strand breaks are usually minimal. A cellpossesses efficient and accurate mechanisms for rapidly repairing single-strand breaks (see
  3. 3. Dr.N.sangeetha 3 Radiation Biology Unit 4“DNA Repair”). The repair makes use of the information redundancy built into the double-stranded DNA molecule and uses the undamaged complementary strand to restore the DNA to itsoriginal state. The vast majority of single-strand breaks are repaired without loss of informationand with only a slight risk of genetic mutation.Although single-strand breaks might be lethal lesions to a cell if they are present during DNAreplication, the result of DNA repair is that those particular circumstances are typically avoided. Figure : DNA DAMAGE I DNA bases consist of either one or two ring-like structures that contain both nitrogen and carbon atoms. A base alteration occurs when additional bonds between atoms are formed or broken or new chemical groups attach to the base. All of those situations result in a modified base structure that must be repaired. An abasic site occurs when a base separates from the sugar, leaving behind an unpaired base. Singlestrand breaks in the phosphodiester backbone arise largely from hydroxyl radical attack at sugar units comprising the backbone. A gap opens in the normally intact DNA. All three of these general types of lesions are repaired with only a slight risk of genetic change.Double strand breaks: 1• Involves breakage of both strands at points less than 3 nucleotides apart (there are still questions about whether further spacings are recognized and repaired as dsbs). 2• Production by single particle crossing both strands? 3• Production by two independent events? 4• Can be measured by various techniques (e.g., sucrose gradient centrifugation) 5• Double strand breaks have shown a direct proportionality to radiation dose.
  4. 4. Dr.N.sangeetha 4 Radiation Biology Unit 4Although single-strand breaks, abasic sites, and base alterations are induced by both ionizingradiation and normal metabolic processes, one particularly dangerous type of DNA lesion, thedouble-strand break, is induced preferentially by ionizing radiation. This is due to the manner inwhich radiation creates radical species within the cell, versus that of metabolic processes.Normal metabolism generates radicals one at a time and at essentially random locationsthroughout the cell volume.DNA lesions resulting from metabolically derived radicals, therefore, tend to occur at relativelyisolated positions along the DNA molecule. Ionizing radiation, in contrast, deposits energyunevenly along the narrow track that is traversed by the ionizing photon or particle. As a result,many radical species are formed in a relatively limited area and tend to form clusters of radicals.If a radical cluster of this type envelops a DNA molecule, then multiple independent lesionsmight be induced within a localized region of the DNA and both DNA strands might becomedamaged, broken, or both. Not surprisingly, ionizing radiation can induce very complex lesionscomprised of abasic sites and base alterations in addition to strand breaks, as illustrated in thefigure.The probability of a double-strand break occurring in any given cell is actually quite low.Thermal diffusion and chemical annihilation will quickly reduce the free-radical density within aradiation track. It has been estimated from Monte Carlo simulations that if the track passes at adistance greater than 2 nanometers from the DNA strand, the probability for DNA damage isslight. It has been estimated from cell-culture studies that approximately twenty to forty double-strand breaks occur per genome at 100 rad of exposure. At that rate, exposures equivalent toordinary background radiation (typically about 0.3 rad per year) should produce only one double-strand break per ten cells per year! A double-strand break is usually a mess, and repairing it can
  5. 5. Dr.N.sangeetha 5 Radiation Biology Unit 4 Figure : DNA DAMAGE II Double-strand breaks result from two single-strand breaks that are induced at closely opposed positions in the complementary strands. Simple doublestrand breaks (upper red box) can often be repaired by a simple end-joining procedure. Ionizing radiation often induces a complex lesion (lower red box) with base alterations and base deletions accompanying the breaks.be problematic. Even a fairly clean double-strand break, wherein the two backbones are brokendirectly opposite from each other, results in at least a one-base-pair deletion and a disruption ofthe linkage between the two DNA segments. The passage of densely ionizing particles, such asalpha particles or neutrons, may break several proximal DNA molecules and cause base damagewithin each strand that can span several nanometers, or fifteen to twenty base pairs. Notsurprisingly, the damaged bases are often excised as the free DNA ends are made ready forrepair. The excision permanently removes bases. Simple rejoining of the exposed DNA ends isprobably the major mechanism for the repair of double-strand breaks, but this mechanism wouldresult in a loss of genetic information. Remarkably, another mechanism, called homologousrecombination, exists within the cell that can restore missing information while repairing double-strand breaks discussed in detail in “DNA Repair”). At present, it is not clear what fraction ofdouble-strand breaks are repaired using this mechanism. It is known, however, that ionizingradiation. induces many deletion mutations and that these mutations probably arise during therepair of the double-strand breaks.
  6. 6. Dr.N.sangeetha 6 Radiation Biology Unit 4Because the repair of a double-strand break is generally nonspecific, free ends that arise frommultiple breaks in chromosomes can get mixed and spliced back together arbitrarily. The resultis a chromosomal rearrangement. These rearrangements include chromosome deletions, in whichan entire section of a chromosome is spliced out, or a translocation, in which a piece of onechromosome is reattached to another chromosome. Chromosomal rearrangements that result inlarge DNA deletions, multiple translocations, or incomplete or distorted chromosomes arefrequently fatal to a cell line. A surprising number of such aberrations, however, are not fatal.Stable translocations that don’t result in cell death are readily found within the cells of healthypeople, as well as in the cells of an irradiated population. Almost fifty years after the exposure,stable translocations can still be observed in the atomic-bomb survivors of Hiroshima andNagasaki. Methods for measuring DNA damageBase damage: various techniques exist for measuring the release of bases, ordamaged base fragments: e.g., HPLC, GC-MS, 3H release from previouslyincorporated 3H-thymidine, immunological probes.DNA strand breaks: 1• Many of these techniques can measure either SSB or DSB by manipulation of the pH. 2• High pH (alkaline conditions) will denature DNA (separate the two trands). 3• Neutral conditions: double strands remain intact.Sucrose gradient sedimentation: 1• cells carefully lysed on top of sucrose gradient, 2• centrifuged at high speed, 3• the larger fragments will migrate further into the gradientFilter elution: 1• DNA prelabeled by growing cells in radioactive DNA precursors (3H or 14C thymidine). Cells lysed gently on the filter. 2• Elution through pores in a filter using a pump and fraction collector. 3• The amount of DNA eluted as a function of time is proportional to radiation damage.
  7. 7. Dr.N.sangeetha 7 Radiation Biology Unit 4 4• Larger fragments elute more slowly. 5• Neutral conditions or alkaline conditions can be used. Gel electrophoresis: 1• Separation of DNA fragments according to size (and shape) in a gel of acrylamide or agarose when exposed to an applied electric field. 2• Cannot resolve very large fragments. 3• A variation known as pulsed field gel electrophoresis can resolve much larger fragments. The electric field is pulsed and alternated in orientation. 4• Methods to quantitate the amount of DNA migrating out of the well either radiolabeling or fluorescence (expressed as fraction of activity released, FAR).Comet assay: 1• Single-cell gel electrophoresis. 2• Cells embedded in gel, lysed to remove proteins, then subjected to electric field. 3• Smaller DNA fragments migrate further making a “tail” that can be stained and viewed under a fluorescent microscope.Difficulties with Double Strand BreaksDouble strand breaks (DSBs) are difficult problems for the cell to repair. The two ends maydissociate, although the histone molecules may provide some structual support. If sevearl breaksare formed in a cell, then the cell may unite the strands incorrectly. The final problem is thatthere may not be an appropriate template to repair the damage, particularly in G1 and early Sphases.Double Strand Break RepairDSB repair is performed by two cellular processes: Homologous Recombination and Non-Homologous End JoiningHomologous Recombination (HR)This is the ideal repair pathway, but it requries an undamaged copy of the DNA to function. Thisundamaged copy is only present after DNA replication has occured: ie, in late S phase, G2 phaseand in early mitosis. This means that homologous recombination only occurs after duplicationof the DNA has occured in preparation for mitosis.The first step in HR is the detection of the double strand break. This is performed by theATM/ATR gene products, as well as the MRN complex. When activated, these proteins signal
  8. 8. Dr.N.sangeetha 8 Radiation Biology Unit 4numerous other molecules (including TP53), inducing a cell cycle arrest. The ends of thedamaged DNA strand are processed and damaged bases are removed. The resulting repairprocess attracts the sister chromatid, unwinds it and uses the undamaged DNA strand of the sisterchromatid to fill in gap left by the double strand break.Homologous Recombination is the more accurate of the DSB repair pathways, as it uses anundamaged template to replace the damaged section.Non-Homologous End Joining (NHEJ)Non-homologous end joining is used in all phases of the cell cycle, as it does not require a sisterchromatid to function. Each side of the double strand break is recognised by XRCC5 andXRCC6 (Ku-70 / Ku-80). These attract PRKDC to the break, which bridges the gap and notifiesthe cell that damage has occured through phosphorylation of numerous signalling molecules. Acollection of NHEJ related proteins then processes each end before ligating the ends together.Other DNA repair mechanismsRadiation also induces a number of other errors in the DNA strand, which are more easilyrepaired.Base Excision Repair (BER)BER is perhaps the most straightforward of the repair pathways. It is used when a single base hasbeen damaged. This is recognised by DNA glycosolase, which excises the base. The DNA isthen nicked by the AP endonuclease enzyme, leaving a single strand break.The alternative method of arriving at this situation is when radiation induces a single strandbreak, which is then recognised by the PARP protein. The ends are processed to leave a cleansingle strand break, similar to the scenario that arises from base damage and excision.These cleaned single strand breaks are then repaired by patch repair, either short or long. Shortpatch repair replaces the damaged base, whereas long patch repair involves the removal ofseveral bases and then filling in of the gap by DNA polymerase and ligation of the ends.Nucleotide Excision Repair (NER)NER is used when a stretch of DNA has been damaged. It is particularly important in theresponse to ultraviolet radiation, which can cause bulky DNA adducts. The DNA is incised attwo points distant from the lesion by 5 - 10 bases, and the entire section of DNA is replaced. Thegap in the DNA is then copied from the undamaged side of the DNA strand and ligated onto thefree ends.
  9. 9. Dr.N.sangeetha 9 Radiation Biology Unit 4Mismatch RepairMismatch repair is important in carcinogenesis and was described in the DNA Replication topic.Proteins are able to detect abnormal shapes in the DNA due to incorrect pairing of bases. Theseabnormal bases are excised with a small margin of bases on either side. The gap is then filled byDNA polymerase and the ends ligated.Human genetic diseases can be caused by defective DNA repair mechanisms. Thiswas first discovered by Cleaver (1968), who showed that cells from patients withxeroderma pigmentosum (XP) were defective for the ability to remove ultraviolet(UV)-induced lesions from their genome.Types- 1. Nucleotide excision repair diseases (NER diseases)Lesions that cause gross distortions on the DNA double helix, such as pyrimidinedimers induced by UV irradiation, are recognized and excised from DNA by acomplex mechanism known as nucleotide excision repair.Three human genetic disorders are associated with defects on nucleotide excisionrepair:- xeroderma pigmentosum- Cockayne syndrome- trichothiodystrophy
  10. 10. Dr.N.sangeetha 10 Radiation Biology Unit 4http://ghr.nlm.nih.gov/geneXeroderma pigmentosum, which is commonly known as XP, is an inherited conditioncharacterized by an extreme sensitivity to ultraviolet (UV) rays from sunlight. This conditionmostly affects the eyes and areas of skin exposed to the sun. Some affected individuals also haveproblems involving the nervous system.The signs of xeroderma pigmentosum usually appear in infancy or early childhood. Manyaffected children develop a severe sunburn after spending just a few minutes in the sun. Thesunburn causes redness and blistering that can last for weeks. Other affected children do not getsunburned with minimal sun exposure, but instead tan normally. By age 2, almost all childrenwith xeroderma pigmentosum develop freckling of the skin in sun-exposed areas (such as theface, arms, and lips); this type of freckling rarely occurs in young children without the disorder.In affected individuals, exposure to sunlight often causes dry skin (xeroderma) and changes inskin coloring (pigmentation). This combination of features gives the condition its name,xeroderma pigmentosum.Xeroderma pigmentosum is caused by mutations in genes that are involved in repairing damagedDNA. DNA can be damaged by UV rays from the sun and by toxic chemicals such as thosefound in cigarette smoke. Normal cells are usually able to fix DNA damage before it causesproblems. However, in people with xeroderma pigmentosum, DNA damage is not repairednormally. As more abnormalities form in DNA, cells malfunction and eventually becomecancerous or die.Many of the genes related to xeroderma pigmentosum are part of a DNA-repair process knownas nucleotide excision repair (NER). The proteins produced from these genes play a variety ofroles in this process. They recognize DNA damage, unwind regions of DNA where the damagehas occurred, snip out (excise) the abnormal sections, and replace the damaged areas with thecorrect DNA. Inherited abnormalities in the NER-related genes prevent cells from carrying outone or more of these steps. The POLH gene also plays a role in protecting cells from UV-induced DNA damage, although it is not involved in NER; mutations in this gene cause thevariant type of xeroderma pigmentosum.The major features of xeroderma pigmentosum result from a buildup of unrepaired DNAdamage. When UV rays damage genes that control cell growth and division, cells can either dieor grow too fast and in an uncontrolled way. Unregulated cell growth can lead to thedevelopment of cancerous tumors. Neurological abnormalities are also thought to result from anaccumulation of DNA damage, although the brain is not exposed to UV rays. Researchers
  11. 11. Dr.N.sangeetha 11 Radiation Biology Unit 4suspect that other factors damage DNA in nerve cells. It is unclear why some people withxeroderma pigmentosum develop neurological abnormalities and others do not.Inherited mutations in at least eight genes have been found to cause xeroderma pigmentosum.More than half of all cases in the United States result from mutations in the XPC, ERCC2, orPOLH genes. Mutations in the other genes generally account for a smaller percentage of cases.Read more about the ERCC2, ERCC3, POLH, XPA, and XPC genes.Cockayne syndrome is a rare disorder characterized by short stature and an appearance of prematureaging. Features of this disorder include a failure to gain weight and grow at the expected rate (failure tothrive), abnormally small head size (microcephaly), and impaired development of the nervous system.Affected individuals have an extreme sensitivity to sunlight (photosensitivity), and even a small amountof sun exposure can cause a sunburn. Other possible signs and symptoms include hearing loss, eyeabnormalities, severe tooth decay, bone abnormalities, and changes in the brain that can be seen onbrain scans.Cockayne syndrome can result from mutations in either the ERCC6 gene (also known as the CSB gene) orthe ERCC8 gene (also known as the CSA gene). These genes provide instructions for making proteins thatare involved in repairing damaged DNA. DNA can be damaged by ultraviolet (UV) rays from the sun andby toxic chemicals, radiation, and unstable molecules called free radicals. Cells are usually able to fixDNA damage before it causes problems. However, in people with Cockayne syndrome, DNA damage isnot repaired normally. As more abnormalities build up in DNA, cells malfunction and eventually die. Theincreased cell death likely contributes to the features of Cockayne syndrome, such as growth failure andpremature aging.the ERCC6 gene provides instructions for making a protein commonly called the Cockaynesyndrome B (CSB) protein. This protein is involved in repairing damaged DNA and appears toassist with gene transcription, which is the first step in protein production. Although the role ofthe CSB protein is not clearly understood, this protein might help to start (initiate) genetranscription and then monitor its progress.DNA can be damaged by ultraviolet (UV) rays from the sun and by toxic chemicals, radiation,and unstable molecules called free radicals. If left uncorrected, DNA damage accumulates,which causes cells to malfunction and ultimately to die. Although DNA damage occursfrequently, normal cells are usually able to fix it before it can cause problems. Cells have severalmechanisms to correct DNA damage; one such mechanism involves the CSB protein. Thisprotein specializes in repairing damaged DNA within active genes (those genes undergoing genetranscription). When DNA in active genes is damaged, the enzyme that carries out genetranscription (RNA polymerase) gets stuck, and the process stalls. Researchers think that the
  12. 12. Dr.N.sangeetha 12 Radiation Biology Unit 4CSB protein helps remove RNA polymerase from the damaged site, so the DNA can be repaired.The CSB protein may also assist in restarting gene transcription after the damage is corrected.Ataxia-telangiectasia is a rare inherited disorder that affects the nervous system, immune system, andother body systems. This disorder is characterized by progressive difficulty with coordinatingmovements (ataxia) beginning in early childhood, usually before age 5. Affected children typicallydevelop difficulty walking, problems with balance and hand coordination, involuntary jerkingmovements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy).The movement problems typically cause people to require wheelchair assistance by adolescence. Peoplewith this disorder also have slurred speech and trouble moving their eyes to look side-to-side(oculomotor apraxia). Small clusters of enlarged blood vessels called telangiectases, which occur in theeyes and on the surface of the skin, are also characteristic of this condition.Mutations in the ATM gene cause ataxia-telangiectasia. The ATM gene provides instructions for makinga protein that helps control cell division and is involved in DNA repair. This protein plays an importantrole in the normal development and activity of several body systems, including the nervous system andimmune system. Mutations in the ATM gene reduce or eliminate the function of the ATM protein.Without this protein, cells become unstable and die inappropriately, particularly affecting cells in a partof the brain involved in coordinating movements (the cerebellum). The loss of these brain cells causesthe movement problems characteristic of ataxia-telangiectasia. Mutations in the ATM gene also preventcells from responding correctly to DNA damage, which allows breaks in DNA strands to accumulate andcan lead to the formation of cancerous tumors.Bloom syndrome is an inherited disorder characterized by short stature, sun-sensitive skin changes, anincreased risk of cancer, and other health problems. People with Bloom syndrome have low birth weightand length. They remain much shorter and thinner than others in their family, growing to an adultheight of less than 5 feet. Affected individuals usually develop dilated blood vessels and reddening in theskin, particularly in response to sun exposure. These changes typically appear as a butterfly-shapedpatch of reddened skin across the nose and cheeks. The skin changes may also affect the hands andarms. People with Bloom syndrome have an increased risk of cancer. They can develop any of thecancers found in the general population, but the cancers arise unusually early in life, and affectedindividuals often develop more than one type of cancer.Individuals with this disorder often have a high-pitched voice and distinctive facial features including along, narrow face; a small lower jaw; a large nose; and prominent ears. Other features affecting some
  13. 13. Dr.N.sangeetha 13 Radiation Biology Unit 4people with Bloom syndrome include learning disabilities, an increased risk of diabetes, chronicobstructive pulmonary disease (COPD), and recurrent infections of the upper respiratory tract, ears, andlungs during infancy. Men with Bloom syndrome usually do not produce sperm, and as a result areunable to father children (infertile). Women with the disorder generally have reduced fertility andexperience menopause earlier than usual.Mutations in the BLM gene cause Bloom syndrome. The BLM gene provides instructions for making amember of a protein family called RecQ helicases. Helicases are enzymes that bind to DNA andtemporarily unwind the two spiral strands (double helix) of the DNA molecule. This unwinding isnecessary for copying (replicating) DNA in preparation for cell division, and for repairing damaged DNA.Because RecQ helicases maintain the structure and integrity of DNA, they are known as the "caretakersof the genome."BLM gene mutations prevent the BLM protein from performing its function in maintaining genomicstability. As a result of the altered BLM protein activity, the frequency of sister chromatid exchangeincreases about 10-fold, which is a hallmark of Bloom syndrome. Increased sister chromatid exchange isan indicator of chromosome instability. It is associated with gaps and breaks in the genetic material thatimpair normal cell activities and cause the health problems associated with this condition. Cancer resultsfrom genetic changes that allow cells to divide in an uncontrolled way. Altered BLM protein activity mayalso lead to an increase in cell death, resulting in slow growth in affected individuals.Werner syndrome is characterized by the dramatic, rapid appearance of features associated withnormal aging. Individuals with this disorder typically grow and develop normally until theyreach puberty. Affected teenagers usually do not have a growth spurt, resulting in short stature.The characteristic aged appearance of individuals with Werner syndrome typically begins todevelop when they are in their twenties and includes graying and loss of hair; a hoarse voice; andthin, hardened skin. They may also have a facial appearance described as "bird-like." Manypeople with Werner syndrome have thin arms and legs and a thick trunk due to abnormal fatdeposition.As Werner syndrome progresses, affected individuals may develop disorders of aging early inlife, such as cloudy lenses (cataracts) in both eyes, skin ulcers, type 2 diabetes, diminishedfertility, severe hardening of the arteries (atherosclerosis), thinning of the bones (osteoporosis),and some types of cancer. It is not uncommon for affected individuals to develop multiple, rarecancers during their lifetime. People with Werner syndrome usually live into their late forties orearly fifties. The most common causes of death are cancer and atherosclerosis.Mutations in the WRN gene cause Werner syndrome. The WRN gene provides instructions for producingthe Werner protein, which is thought to perform several tasks related to the maintenance and repair ofDNA. This protein also assists in the process of copying (replicating) DNA in preparation for cell division.Mutations in the WRN gene often lead to the production of an abnormally short, nonfunctional Werner
  14. 14. Dr.N.sangeetha 14 Radiation Biology Unit 4protein. Research suggests that this shortened protein is not transported to the cells nucleus, where itnormally interacts with DNA. Evidence also suggests that the altered protein is broken down morequickly in the cell than the normal Werner protein. Researchers do not fully understand how WRNmutations cause the signs and symptoms of Werner syndrome. Cells with an altered Werner proteinmay divide more slowly or stop dividing earlier than normal, causing growth problems. Also, the alteredprotein may allow DNA damage to accumulate, which could impair normal cell activities and cause thehealth problems associated with this condition.