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PubMed2000

A nuclease hypersensitive element in the human c-myc promoter adopts several distinct i-tetraplex structures.

Nucleic acid structure-function correlations are pivotal to major biological events like transcription, replication, and recombination. Depending on intracellular conditions in vivo and buffer composition in vitro, DNA appears capable of inexhaustible structure variation. At moderately acidic, or even neutral pH, DNA strands that are rich in cytosine bases can associate both inter- and intramolecularly to form i-tetraplexes. The hemiprotonated cytosine(+)-cytosine base pair constitutes the building block for the formation of i-tetraplexes, and motifs for their formation are frequent in vertebrate genomes. A major control element upstream of the human c-myc gene, which has been shown to interact sequence specifically with several transcription factors, becomes hypersensitive to nucleases upon c-myc expression. The control element is asymmetric inasmuch as that one strand is uncommonly rich in cytosines and exhibits multiple motifs for the formation of i-tetraplexes. To investigate the propensity for their formation we employ circular dichroism (CD) in combination with ultra violet (UV) spectroscopy and native gel electrophoresis. Our results demonstrate the cooperative formation of well-defined i-tetraplex structures. We conclude that i-tetraplex formation occurs in the promoter region of the human c-myc gene in vitro, and discuss implications of possible biological roles for i-tetraplex structures in vivo. Hypothetical formation of intramolecular fold-back i-tetraplexes is important to c-myc transcription, whereas chromosomal translocation events might involve the formation of bimolecular i-tetraplex structures.

Alleles↗
PubMed2006

Complete mitochondrial genome sequences for Crown-of-thorns starfish Acanthaster planci and Acanthaster brevispinus.

BACKGROUND: The crown-of-thorns starfish, Acanthaster planci (L.), has been blamed for coral mortality in a large number of coral reef systems situated in the Indo-Pacific region. Because of its high fecundity and the long duration of the pelagic larval stage, the mechanism of outbreaks may be related to its meta-population dynamics, which should be examined by larval sampling and population genetic analysis. However, A. planci larvae have undistinguished morphological features compared with other asteroid larvae, hence it has been difficult to discriminate A. planci larvae in plankton samples without species-specific markers. Also, no tools are available to reveal the dispersal pathway of A. planci larvae. Therefore the development of highly polymorphic genetic markers has the potential to overcome these difficulties. To obtain genomic information for these purposes, the complete nucleotide sequences of the mitochondrial genome of A. planci and its putative sibling species, A. brevispinus were determined and their characteristics discussed. RESULTS: The complete mtDNA of A. planci and A. brevispinus are 16,234 bp and 16,254 bp in size, respectively. These values fall within the length variation range reported for other metazoan mitochondrial genomes. They contain 13 proteins, 2 rRNA, and 22 tRNA genes and the putative control region in the same order as the asteroid, Asterina pectinifera. The A + T contents of A. planci and A. brevispinus on their L strands that encode the majority of protein-coding genes are 56.3% and 56.4% respectively and are lower than that of A. pectinifera (61.2%). The percent similarity of nucleotide sequences between A. planci and A. brevispinus is found to be highest in the CO2 and CO3 regions (both 90.6%) and lowest in ND2 gene (84.2%) among the 13 protein-coding genes. In the deduced putative amino acid sequences, CO1 is highly conserved (99.2%), and ATP8 apparently evolves faster any of the other protein-coding gene (85.2%). CONCLUSION: The gene arrangement, base composition, codon usage and tRNA structure of A. planci are similar to those of A. brevispinus. However, there are significant variations between A. planci and A. brevispinus. Complete mtDNA sequences are useful for the study of phylogeny, larval detection and population genetics.

Animals↗
PubMed1996

Mutational analysis of the human MAOA gene.

The monoamine oxidases (MAO-A and MAO-B) are the enzymes primarily responsible for the degradation of amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Wide variations in activity of these isozymes have been reported in control humans. The MAOA and MAOB genes are located next to each other in the p11.3-11.4 region of the human X chromosome. Our recent documentation of an MAO-A-deficiency state, apparently associated with impulsive aggressive behavior in males, has focused attention of genetic variations in the MAOA gene. In the present study variations in the coding sequence of the MAOA gene were evaluated by RT-PCR, SSCP, and sequencing a mRNA or genomic DNA in 40 control males with > 100-fold variations of MAO-A activity, as measured in cultured skin fibroblasts. Remarkable conservation of the coding sequence was found with only 5 polymorphisms observed. All but one of these were in the third codon position and thus did not alter the deduced amino acid sequence. The one amino acid alteration observed, lys --> arg, was neutral and should not affect the structure of the protein. This study demonstrates high conservation of coding sequence in the human MAOA gene in control males, and provides primer sets which can be used to search genomic DNA for mutations in this gene in males with neuropsychiatric conditions.

Base Sequence↗
PubMed2006

Simple sequence proteins in prokaryotic proteomes.

BACKGROUND: The structural and functional features associated with Simple Sequence Proteins (SSPs) are non-globularity, disease states, signaling and post-translational modification. SSPs are also an important source of genetic and possibly phenotypic variation. Analysis of 249 prokaryotic proteomes offers a new opportunity to examine the genomic properties of SSPs. RESULTS: SSPs are a minority but they grow with proteome size. This relationship is exhibited across species varying in genomic GC, mutational bias, life style, and pathogenicity. Their proportion in each proteome is strongly influenced by genomic base compositional bias. In most species simple duplications is favoured, but in a few cases such as Mycobacteria, large families of duplications occur. Amino acid preference in SSPs exhibits a trend towards low cost of biosynthesis. In SSPs and in non-SSPs, Alanine, Glycine, Leucine, and Valine are abundant in species widely varying in genomic GC whereas Isoleucine and Lysine are rich only in organisms with low genomic GC. Arginine is abundant in SSPs of two species and in the non-SSPs of Xanthomonas oryzae. Asparagine is abundant only in SSPs of low GC species. Aspartic acid is abundant only in the non-SSPs of Halobacterium sp NRC1. The abundance of Serine in SSPs of 62 species extends over a broader range compared to that of non-SSPs. Threonine(T) is abundant only in SSPs of a couple of species. SSPs exhibit preferential association with Cell surface, Cell membrane and Transport functions and a negative association with Metabolism. Mesophiles and Thermophiles display similar ranges in the content of SSPs. CONCLUSION: Although SSPs are a minority, the genomic forces of base compositional bias and duplications influence their growth and pattern in each species. The preferences and abundance of amino acids are governed by low biosynthetic cost, evolutionary age and base composition of codons. Abundance of charged amino acids Arginine and Aspartic acid is severely restricted. SSPs preferentially associate with cell surface and interface functions as opposed to metabolism, wherein proteins of high sequence complexity with globular structures are preferred. Mesophiles and Thermophiles are similar with respect to the content of SSPs. Our analysis serves to expand the commonly held views on SSPs.

Amino Acid Sequence↗
PubMed2026

Diploids derived from polyploids: genetic characteristics of four novel interspecific Sorghum populations.

Polyploidy has repeatedly shaped grass evolution, yet direct observations of how polyploid-derived chromosomes behave when returned to diploidy remain rare. Interspecific crosses between diploid Sorghum bicolor and tetraploid hybrids derived from Sorghum halepense generate mixed-ploidy progeny, providing an opportunity to examine chromosome transmission during the early stages of diploidization. Using genome-wide SNP markers, we characterized chromosomal inheritance patterns in 2 diploid and 2 tetraploid families derived from these crosses. Genotype-dosage profiles alone distinguished diploids from tetraploids with complete accuracy, reflecting strong ploidy-dependent differences in dosage-class distributions. Although diploid progeny retained much of the halepense-derived genomic background, several genomic intervals exhibited extended, nonrandom runs of S. bicolor homozygosity that remained polymorphic in corresponding tetraploid populations. These patterns, together with recurrent segregation distortion across independent families, suggest that the transition from tetraploidy to diploidy can expose allelic combinations that differ in transmission or viability. Analyses of flowering time further indicated that diploid and tetraploid derivatives possess distinct genomic architectures, with major association peaks occurring in different chromosomal regions across ploidy levels. Collectively, these results indicate that early diploidization involves nonrandom retention and loss of parental haplotypes shaped by both selective and structural constraints. The diploid extractions characterized here provide a rare empirical system for investigating the early stages of diploidization and a practical framework for studying and eventually mobilizing polyploid-derived variation for sorghum germplasm development. However, broader integration into elite breeding programs will require additional evaluation of cross-fertility, meiotic behavior, and chromosomal stability across diverse breeding backgrounds.

Sorghum↗
PubMed1996

Use of competitive PCR to assay copy number of repetitive elements in banana.

Banana is one of the most important subtropical fruit crops. Genetic improvement by traditional breeding strategies is difficult and better knowledge of genomic structure is needed. Repeated sequences are powerful markers for genetic fingerprinting. The method proposed here to determine the copy number of nuclear repetitive elements is based on competitive reverse transcription-polymerase chain reaction and can also be used for quantifying cytosolic sequences. The reliability of this method was investigated on crude preparations of total DNA. Variations due to the heterogeneity of crude DNA extracts showed that a single locus reference is needed for accurate quantification. A mapped microsatellite locus was used to normalize copy number measurements. Copy number assay of repetitive elements using this method clearly distinguishes between the two banana subspecies investigated: Musa acuminata spp. banskii and M. acuminata spp. malaccensis. Two repetitive sequence families, pMaCIR1115 and pA9-26, were assayed that cover up to 1% of the M. acuminata genome. Their copy number varied up to six fold between the two subspecies. Furthermore, sequence quantification showed that mitochondrial genomes are present in crude leaf-extracted banana DNA at up to 40 copies per cell.

Blotting, Southern↗
PubMed1996

Comparison of the human genomic structure of the Runt domain-encoding PEBP2/CBFalpha gene family.

We cloned the human cDNA corresponding to the cDNA (PEBP2alphaB-451) encoding the mouse polyomavirus enhancer-binding protein 2alphaB-451, representing a major splice variant from acute myeloid leukemia gene 1 (AML1). Genomic DNA clones of AML1 were also isolated and the exon/intron structure was determined. Furthermore, we determined and compared the genomic structures of three mammalian Runt domain-containing genes, PEBP2alphaA,AML/PEBE2alphaB and PEBP2alphaC.

Acute Disease↗
PubMed1991

Genetic variants of collagen III and abdominal aortic aneurysm.

Collagens provide the tensile strength of the aortic wall. Variations in collagen structure are recognised in Ehlers Danlos syndrome type IV and could also be associated with a predisposition to aortic aneurysm. The frequency of some minor genetic variants of type III collagen, present in the normal population, can be detected by restriction enzyme digestion of genomic DNA from peripheral leucocytes. The frequency of a minor collagen type III allele demonstrated with the restriction enzyme Ava II was compared in patients with abdominal aortic aneurysm (n = 70) and aortoiliac stenosis (n = 47). The frequency of the minor allele was significantly higher in aneurysm patients (0.30) compared with patients with aortoiliac stenosis (0.17), p less than 0.05. The presence of the minor allele was associated with a less elastic aneurysm wall (median pressure strain elastic modulus 4575, n = 7), compared with patients homozygous for the common allele (median pressure strain elastic modulus 1990, n = 6), p less than 0.05. These results indicate that genetic variants of type III collagen may influence the extensile properties of the aortic wall and that mutations in the type III collagen gene may be associated with aortic aneurysms.

Aged↗
PubMed2006

Natural variation in a subtelomeric region of Arabidopsis: implications for the genomic dynamics of a chromosome end.

We investigated genome dynamics at a chromosome end in the model plant Arabidopsis thaliana through a study of natural variation in 35 wild accessions. We focused on the single-copy subtelomeric region of chromosome 1 north (approximately 3.5 kb), which represents the relatively simple organization of subtelomeric regions in this species. PCR fragment-length variation across the subtelomeric region indicated that the 1.4-kb distal region showed elevated structural variation relative to the centromere-proximal region. Examination of nucleotide sequences from this 1.4-kb region revealed diverse DNA rearrangements, including an inversion, several deletions, and an insertion of a retrotransposon LTR. The structures at the deletion and inversion breakpoints are characteristic of simple deletion-associated nonhomologous end-joining (NHEJ) events. There was strong linkage disequilibrium between the distal subtelomeric region and the proximal telomere, which contains degenerate and variant telomeric repeats. Variation in the proximal telomere was characterized by the expansion and deletion of blocks of repeats. Our sample of accessions documented two independent chromosome-healing events associated with terminal deletions of the subtelomeric region as well as the capture of a scrambled mitochondrial DNA segment in the proximal telomeric array. This natural variation study highlights the variety of genomic events that drive the fluidity of chromosome termini.

Arabidopsis↗
PubMed2002

[The mitochondrial genome and human mitochondrial diseases].

To date, more than 100 point mutations and several hundreds of structural rearrangements of mitochondrial DNA (mtDNA) are known too be connected with characteristic neuromuscular and other mitochondrial syndromes varying form those causing death at the neonatal stage to diseases with late ages of onset. The immediate cause of mitochondrial disorders is a defective oxidative phosphorylation. Wide phenotypic variation and the heteroplasmy phenomenon, which some authors include in mutation load, are characteristic of human mitochondrial diseases. As the numbers of cases identified and pedigrees described increase, data on the genotype--phenotype interaction and the structure and frequency of pathogenic and conditionally pathogenic mtDNA mutations in human populations are rapidly accumulated. The data on the genetics and epidemiology of mitochondrial diseases are not only important for differential diagnosis and genetic counseling. Since both neutral and mildly pathogenic mutations of mtDNA are progressively accumulated in maternal phyletic lines, molecular analysis of these mutations permits not only reconstruction of the genealogical tree of modern humans, but also estimation of the role that these mutations play in natural selection.

DNA, Mitochondrial↗
PubMed1998

Microsatellite analysis of the population structure of a vancouver island sockeye salmon (Oncorhynchus nerka) stock complex using nondenaturing gel electrophoresis

Variation at four microsatellite loci, Omy77, Ots100, Ots3, and Ots103, was characterized for three populations of sockeye salmon (Oncorhynchus nerka) found within 50 km of each other in the Barkley Sound region of Southwest Vancouver Island, British Columbia. We used a simple polyacrylamide gel electrophoresis technique to analyze microsatellite alleles amplified from total genomic DNA extracts of liver and archived scales. Classes from several years were examined for each population, with little significant interannual variability detected. Each microsatellite locus was highly polymorphic with 10 alleles at Omy77, 12 alleles at Ots100, 16 alleles at Ots3, and 17 alleles at Ots103; average observed heterozygosities were also high at 75%, 76%, 69%, and 85% respectively. Fst values and pairwise tests indicated that the populations had significantly different allele frequencies, suggesting that the three populations are reproductively isolated. Our results suggested that microsatellite loci can be analyzed with a simple technique to reveal population structure of sockeye salmon on a small geographic scale.

Journal Article↗
PubMed2006

The association of DNA sequence variation at the MAOA genetic locus with quantitative behavioural traits in normal males.

Monoamine oxidase A (MAOA) catalyses the oxidative deamination of biogenic amines including neurotransmitters, mainly norepinephrine and serotonin in the brain and peripheral tissues. A nonsense mutation in the gene was shown to be involved in a rare X-linked behavioural syndrome, which includes impaired impulse control, aggression and borderline mental retardation (Brunner syndrome). Several recent studies have shown the association of genetic variation of a VNTR in the gene promoter with various pathological behavioural traits. In the present study the association of MAOA genetic variation with a large set of quantitative behavioural traits in normal individuals has been examined. DNA samples from 421 unrelated males were genotyped for 14 SNPs and for the promoter VNTR at the MAOA locus. An additional 16 SNPs were genotyped at apparently neutral loci across the X chromosome to serve as a genomic control for possible false positive associations due to population structure. Behavioural traits were measured using the NEO psychometric questionnaire, which is based on a 5-axis model of personality, and consists of 30 different quantitative traits. There was a robust association of the A2 ("straightforwardness") facet with common allelic variants at the promoter VNTR. Most of the tested traits were not associated with the VNTR despite reasonable power, thus demonstrating that the VNTR influence on quantitative behavioural traits in normal males may be very specific. In contrast, several traits of the C ("conscientiousness") axis were associated with less common SNP-defined haplotypes. Hence, it appears that common genetic variation at the VNTR contributes to the behavioural attribute of "straightforwardness", while rare haplotypes defined by SNPs downstream of the transcription start site may contribute to "conscientiousness". This study is used to address the validation, interpretation and limitation of genetic association studies of quantitative behavioural traits.

Black or African American↗
PubMed2005

Sex-specific quantitative trait loci contribute to normal variation in bone structure at the proximal femur in men.

Bone structure is an important determinant of osteoporotic fracture. In women, bone structure is highly heritable, and several quantitative trait loci (QTL) have been reported. There are few comparable data in men. This study in men aimed at establishing the heritability of bone structure at the proximal femur, identifying QTL contributing to normal variation in bone structure, and determining which QTL might be sex-specific. Bone structure at the proximal femur was measured in 205 pairs of brothers age 18-61. Heritability was calculated, and linkage analysis performed on phenotypes at the proximal femur. Heritability estimates ranged from 0.99 to 0.39. A genome wide scan identified suggestive QTL (LOD>2.2) for femoral shaft width on chromosome 14q (LOD=2.69 at position 99 cM), calcar femorale at chromosome 2p (LOD=3.97 at position 194 cM) and at the X chromosome (LOD=3.01 at position 77 cM), femoral neck width on chromosome 5p (LOD=2.28 at position 0 cM), femoral head width on chromosome 11q (LOD=2.30 at position 131 cM) and 15q (LOD=3.11 at position 90 cM), and pelvic axis length on chromosome 4q (LOD=4.16 at position 99 cM) and 17q (LOD=2.80 at position 112 cM). Comparison with published data in 437 pairs of premenopausal sisters from the same geographical region suggested that 3 of the 7 autosomal QTL were male-specific. This study demonstrates that bone structure at the proximal femur in healthy men is highly heritable. The occurrence of sex-specific genes in humans for bone structure has important implications for the pathogenesis and treatment of osteoporosis.

Adult↗
PubMed2004

Detecting gradients of asymmetry in site-specific substitutions in mitochondrial genomes.

During mitochondrial replication, spontaneous mutations occur and accumulate asymmetrically during the time spent single stranded by the heavy strand (DssH). The predominant mutations appear to be deaminations from adenine to hypoxanthine (A --> H, which leads to an A --> G substitution) and cytosine to thymine (C --> T). Previous findings indicated that C --> T substitutions accumulate rapidly and then saturate at high DssH, suggesting protection or repair, whereas A --> G accumulates linearly with DssH. We describe here the implementation of a simple hidden Markov model (HMM) of among-site rate correlations to provide an almost continuous profile of the asymmetry in substitution response for any particular substitution type. We implement this model using a phylogeny-based Bayesian Markov chain Monte Carlo (MCMC) approach. We compare and contrast the relative asymmetries in all 12 possible substitution types, and find that the observed transition substitution responses determined using our new method agree quite well with previous predictions of a saturating curve for C --> T transition substitutions and a linear accumulation of A --> G transitions. The patterns seen in transversion substitutions show much lower among-site variation, and are nonlinear and more complex than those seen in transitions. We also find that, after accounting for the principal linear effect, some of the residual variation in A --> G/G --> A response ratios is explained by the average predicted nucleic acid secondary structure propensity at a site, possibly due to protection from mutation when secondary structure forms.

Genome↗
PubMed2000

Porcine lung surfactant protein D: complementary DNA cloning, chromosomal localization, and tissue distribution.

Porcine organs and lung surfactant have medically important applications in both xenotransplantation and therapy. We have started to characterize porcine lung surfactant by cloning the cDNA of porcine surfactant protein D (SP-D). SP-D and SP-A are important mediators in innate immune defense for the lung and possibly other mucosal surfaces. Porcine SP-D will also be an important reagent for use in existing porcine animal models for human lung infections. The complete cDNA sequence of porcine SP-D, including the 5' and 3' untranslated regions, was determined from two overlapping bacteriophage clones and by PCR cloning. Three unique features were revealed from the porcine sequence in comparison to SP-D from other previously characterized species, making porcine SP-D an intriguing species addition to the SP-D/collectin family. The collagen region contains an extra cysteine residue, which may have important structural consequences. The other two differences, a potential glycosylation site and an insertion of three amino acids, lie in the loop regions of the carbohydrate recognition domain, close to the carbohydrate binding region and thus may have functional implications. These variations were ruled out as polymorphisms or mutations by confirming the sequence at the genomic level in four different pig breeds. Porcine SP-D was shown to localize primarily to the lung and with less abundance to the duodenum, jejunum, and ileum. The genes for SP-D and SP-A were also shown to colocalize to a region of porcine chromosome 14 that is syntenic with the human and murine collectin loci.

Amino Acid Sequence↗
PubMed1993

Studies on the evolution and function of different forms of the mouse myogenic gene Myo-D1 and upstream flanking region.

The product of the murine Myo-D1 gene is able to initiate the complete sequence of genetic events required for formation of skeletal muscle. Because efficiency of regeneration of skeletal muscle is more pronounced in SJL/J mice, as compared to other strains, differences in the structure of Myo-D1 and the upstream regulatory region were sought to determine whether efficiency of tissue repair was influenced by the structure of the gene itself. Analysis of the restriction-fragment length polymorphism (RFLP) of genomic DNA from SJL/J and different sub-strains of mouse indicated that there are at least three different structural forms of Myo-D1, one of which is unique to SJL/J mice and may have been derived from a double recombinational event involving founder forms of Myo-D1. The unique form of Myo-D1 in SJL/J mice also exhibits a PvuII RFLP upstream from the gene, which may reflect some form of rearrangement or variation in methylation of a potential Myo-D1-binding region. Reference to the size of fragments hybridising with the Myo-D1 probe, following digestion of genomic DNA with TaqI, suggests that in most tissues, adenine residues within Myo-D1 may be extensively methylated. Segregation of Myo-D1 allotypes with response to mechanical injury to skeletal muscle in F2 offspring derived from SJL/J and BALB/c parental strains reveals that increased efficiency of tissue repair is associated with the SJL/J type of Myo-D1 gene. These observations provide new approaches to investigation of genetic control of tissue regeneration and cellular differentiation and proliferation in general.

Adenine↗
PubMed1999

Nucleotide sequence of UK and Australian isolates of feline calicivirus (FCV) and phylogenetic analysis of FCVs.

We have determined the first complete genome sequence and capsid gene sequences of feline calicivirus (FCV) isolates from the UK and Australia. These were compared with other previously published sequences. The viruses used in the comparisons were isolated between 1957 and 1995 from various geographical locations and obtained from cats showing a range of clinical signs. Despite these diverse origins, comparisons between all strains showed a similar degree of sequence variation within both ORF1 (non-structural polyprotein) and ORF2 (major capsid protein) (amino acid distances of 7.7-13.0% and 8.8-18.6%, respectively). In contrast, ORF3 (putative minor structural protein) sequences indicated a more heterogenous distribution of FCV relatedness (amino acid distances of 1.9-17.9%). Phylogenetic analysis suggested that, unlike some other caliciviruses, FCV isolates within the current data set fall into one diverse genogroup. Within this group, there was an overall lack of geographic or temporal clustering which may be related to the epidemiology of FCV infection in cats. Analysis of regions of variability in the genome has shown that, as well as the previously identified variable regions in ORF2, similar domains exist within ORFs 1 and 3 also, although to a lesser extent. In ORF1, these variable domains largely fall between the putative non-structural protein functional domains.

Amino Acid Sequence↗
PubMed2005

Characterization of hypervariable region in hepatitis C virus envelope protein during acute and chronic infection.

Hepatitis C virus (HCV) causes persistent infection in most patients. To clarify the mechanisms underlying establishment of this persistent infection, nucleotide sequences of the E1/E2 region were characterized in 5 patients with acute and chronic HCV infection. We used direct DNA sequencing methods to identify the major sequence of HCV in each patient. Each HCV genome displayed a high frequency of nucleotide sequence variation in the hypervariable region (HVR) of E2. However, patient-specific conserved nucleotide sequences were identified in the E1/E2 region during the course of infection and conserved the higher-order protein structure. In the acute phase HCV infection, amino acid substitution in HVR-1 as the monthly rate of amino acids substitution per site (%) between each point exceeded 10.2%. In the chronic phase HCV infection, a significantly lower rate of amino acid substitution was observed in patients. The host immune responses to HVR-1 of each HCV isolates from all clinical courses were characterized using synthetic peptides and ELISA. One chronic patient serum (genotype 1b) did not react at all to its own HVR-1 peptides, however another patient (genotype 2b) reacted to all clinical course. These results indicated that HVR-1 might not always exhibit neutralizing epitopes of HCV infection. The sequence variation in HVR-1 may instead indicate the existence of various clones in acute phase infection and the adaption of these clones is thought to have caused persistent and chronic infection in each patient.

Acute Disease↗