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PubMed2006

Distribution and invasiveness of Streptococcus pneumoniae serotypes in Switzerland, a country with low antibiotic selection pressure, from 2001 to 2004.

To describe the serotype-specific epidemiology of colonizing and invasive Streptococcus pneumoniae isolates, which is important for vaccination strategies, we analyzed a total of 2,388 invasive and 1,540 colonizing S. pneumoniae isolates collected between January 2001 and December 2004 within two nationwide surveillance programs. We found that the relative rank orders of the most frequent serotypes (serotypes 1, 3, 4, 6B, 7F, 14, 19F, and 23F) differed among invasive and colonizing isolates. Serotypes 1, 4, 5, 7F, 8, 9V, and 14 had increased invasive potential, and serotypes/serogroups 3, 6A, 7, 10, 11, 19F, and 23F were associated with colonization. The proportion of pediatric serotypes was higher among children < 5 years old (48.5%) and persons > 64 years old (34.1%) than among other age groups (29.1%); it was also higher in West Switzerland (40.2%) than in other geographic regions (34.7%). Likewise, serotype-specific proportions of penicillin-resistant isolates for types 6B, 9V, 14, and 19F were significantly higher in West Switzerland. The relative frequency of pediatric serotypes corresponded with antibiotic consumption patterns. We conclude that the epidemiology of invasive and colonizing S. pneumoniae isolates is influenced by the serotype-specific potential for invasiveness, and therefore, surveillance programs should include colonizing and invasive S. pneumoniae isolates. Antibiotic selection pressure determines the serotype distribution in different age groups and geographic regions and therefore the expected direct and indirect effects of the 7-valent conjugate vaccine.

Adolescent↗
PubMed2001

Plasmodium falciparum: linkage disequilibrium between loci in chromosomes 7 and 5 and chloroquine selective pressure in Northern Nigeria.

In view of the recent discovery (Molecular Cell 6, 861-871) of a (Lys76Thr) codon change in gene pfcrt on chromosome 7 which determines in vitro chloroquine resistance in Plasmodium falciparum, we have re-examined samples taken before treatment in our study in Zaria, Northern Nigeria (Parasitology, 119, 343-348). Drug resistance was present in 5/5 cases where the pfcrt 76Thr codon change was seen (100% positive predictive value). Drug sensitivity was found in 26/28 cases where the change was absent (93% negative predictive value). Allele pfcrt 76Thr showed strong linkage disequilibrium with pfmdr1 Tyr86 on chromosome 5, more complete than that between pfcrt and cg2 alleles situated between recombination cross-over points on chromosome 7. Physical linkage of cg2 with pfcrt may account for linkage disequilibrium between their alleles but in the case of genes pfmdr1 and pfcrt, on different chromosomes, it is likely that this is maintained epistatically through the selective pressure of chloroquine.

ATP-Binding Cassette Transporters↗
PubMed2002

A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea.

The malaria vaccine Combination B comprises recombinant Plasmodium falciparum ring-infected erythrocyte surface antigen and 2 merozoite surface proteins (MSP1 and MSP2) formulated in oil-based adjuvant. A phase 1-2b double-blind, randomized, placebo-controlled trial in 120 children (5-9 years old) in Papua New Guinea demonstrated a 62% (95% confidence limits: 13%, 84%) reduction in parasite density in children not pretreated with sulfadoxine-pyrimethamine. Vaccinees had a lower prevalence of parasites carrying the MSP2-3D7 allelic form (corresponding to that in the vaccine) and a higher incidence of morbid episodes associated with FC27-type parasites. These results demonstrate functional activity of Combination B against P. falciparum in individuals with previous malaria exposure. The specific effects on parasites with particular msp2 genotypes suggest that the MSP2 component, at least in part, accounted for the activity. The vaccine-induced selection pressure exerted on the parasites and its consequences for morbidity strongly argue for developing vaccines comprising conserved antigens and/or multiple components covering all important allelic types.

Animals↗
PubMed1998

Strong selective pressure to use G:U to mark an RNA acceptor stem for alanine.

The identity of alanine tRNAs is dependent on a G:U base pair at the 3:70 position of the acceptor helix. This system of molecular recognition is widely distributed from bacteria to human-cell cytoplasm. In contrast, some mitochondrial alanine acceptor helices are markedly different and contain nucleotides known to block aminoacylation by a nonmitochondrial enzyme. Thus, acceptor helix recognition may differ in these systems and may not depend on G:U. Here we report an example of a Caenorhabditis elegans mitochondrial system where the G:U pair is preserved but where proximal nucleotides known to block charging by a nonmitochondrial enzyme are also present. We show that, as expected, the mitochondrial substrate is not charged by the bacterial enzyme. In contrast, the cloned mitochondrial enzyme charged both mitochondrial and bacterial microhelices. Strikingly, charging of each required the G:U pair. Thus, G:U recognition persists even with an acceptor helix context that inactivates nonmitochondrial systems. The results suggest strong selective pressure to use G:U in a variety of contexts to mark an acceptor stem for alanine. Separate experiments also demonstrate that, at least for the mitochondrial enzyme, helix instability or irregularity is not important for recognition of G:U.

Acylation↗
PubMed1998

The influence of cell context on the selection pressure for p53 mutation in human cancer.

Although p53 mutation is, overall, by far the most frequent somatic genetic abnormality in human cancer, in some common tumour types, notably carcinoma of breast, it is seen only in a phenotypically-distinct sub-set of cases, often correlated with adverse prognosis. Conventionally, this is viewed as the consequence of random differences in acquired genetic events acting on a common cell. Here we develop a fundamentally different hypothesis, which proposes that the liability of a given tumour to exhibit p53 mutation is predetermined by the nature of its cell of origin and, more specifically, depends on the extent to which wild-type p53 forms a rate-limiting step in the control of proliferative lifespan in that cell. In other words, the phenotype of the cell of origin constrains both tumour phenotype and 'choice' of genetic events. This concept can be extended to tumour progression, where evidence particularly from thyroid tumorigenesis suggests that a switch in differentiation state can play a major causal role in tumour evolution by altering the selection pressure for p53 mutation. Finally, analysis of transformed thyroid cells has also revealed a novel physiological mechanism by which growth suppression by wild-type p53 may be evaded in cell types whose lifespan control is p53-independent.

Animals↗
PubMed2002

What impact will EPPO's new resistance risk assessment guideline have on selection pressure in the European Union?

This paper examines practical and regulatory implications, including both costs and benefits, resulting from implementation of EPPO's new resistance risk analysis guideline. Crop-protection companies operating in Europe are preparing risk analyses and management strategies, and are monitoring for resistance. However, this is a complex and expensive process involving technical, commercial and regulatory functions. The actual cost of filling these data gaps is consequently greater than many would have anticipated. The agrochemical industry has a vested interest in managing resistance and is committed to maintaining the essential contribution of crop-protection products to sustainable agriculture. However, with increasing regulatory costs, it is important that regulatory authorities concentrate requirements for resistance risk analyses, management strategies and monitoring where these are most needed. Should these requirements be applied indiscriminately, crop-protection companies will have to consider whether or not it is economically justifiable to make these investments, or whether to remove less profitable uses from product labels. In such situations, minor crops stand to be disproportionately effected. One year after publication, it is too early to measure the guideline's impact on selection pressure. It is already clear that the guideline represents an unprecedented step forward in the regulation and harmonisation of resistance management. There are, however, valid arguments against regulation of resistance management. One of the most important criticisms that is levelled against the latter approach is that, with the best motivation and with appropriate use restrictions on labels, these actions alone do not solve the problem. It is critical that all stakeholders in the crop protection process are made aware of the importance of resistance management and of complying with prescribed strategies.

Agriculture↗
PubMed2004

A two-plasmid system for stable, selective-pressure-independent expression of multiple extracellular proteins in mycobacteria.

Recombinant mycobacteria expressing Mycobacterium tuberculosis extracellular proteins are leading candidates for new vaccines against tuberculosis and other mycobacterial diseases, and important tools both in antimycobacterial drug development and basic research in mycobacterial pathogenesis. Recombinant mycobacteria that stably overexpress and secrete major extracellular proteins of M. tuberculosis in native form on plasmids pSMT3 and pNBV1 were previously constructed by the authors. To enhance the versatility of this plasmid-based approach for mycobacterial protein expression, the Escherichia coli/mycobacteria shuttle plasmid pGB9 was modified to accommodate mycobacterial genes expressed from their endogenous promoters. Previous studies showed that the modified plasmid, designated pGB9.2, derived from the cryptic Mycobacterium fortuitum plasmid pMF1, was present at a low copy number in both E. coli and mycobacteria, and expression of recombinant M. tuberculosis proteins was found to be at levels paralleling its copy number, that is, approximating their endogenous levels. Plasmid pGB9.2 was compatible with the shuttle vectors pSMT3 and pNBV1 and in combination with them it simultaneously expressed the M. tuberculosis 30 kDa extracellular protein FbpB. Plasmid pGB9.2 was stably maintained in the absence of selective pressure in three mycobacterial species: Mycobacterium bovis BCG, M. tuberculosis and M. smegmatis. Plasmid pGB9.2 was found to be self-transmissible between both fast- and slow-growing mycobacteria, but not from mycobacteria to E. coli or between E. coli strains. The combination of two compatible plasmids in one BCG strain allows expression of recombinant mycobacterial proteins at different levels, a potentially important factor in optimizing vaccine potency.

Acyltransferases↗
PubMed1998

Lack of strong immune selection pressure by the immunodominant, HLA-A*0201-restricted cytotoxic T lymphocyte response in chronic human immunodeficiency virus-1 infection.

Despite detailed analysis of the HIV-1-specific cytotoxic T lymphocyte response by various groups, its relation to viral load and viral sequence variation remains controversial. We analyzed HLA-A*0201 restricted cytotoxic T lymphocyte responses in 17 HIV-1-infected individuals with viral loads ranging from < 400 to 221,000 HIV RNA molecules per milliliter of plasma. In 13 out of 17 infected subjects, CTL responses against the SLYNTVATL epitope (p17 Gag; aa 77-85) were detectable, whereas two other HLA-A*0201 restricted epitopes (ILKEPVHGV, IV9; and VIYQYMDDL, VL9) were only recognized by six and five individuals out of 17 individuals tested, respectively. Naturally occurring variants of the SL9 epitope were tested for binding to HLA-A*0201 and for recognition by specific T cell clones generated from five individuals. Although these variants were widely recognized, they differed by up to 10,000-fold in terms of variant peptide concentrations required for lysis of target cells. A comparison of viral sequences derived from 10 HLA-A*0201-positive individuals to sequences obtained from 11 HLA-A*0201-negative individuals demonstrated only weak evidence for immune selective pressure and thus question the in vivo efficacy of immunodominant CTL responses present during chronic HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Enhancement of host fitness by the sul2-coding plasmid p9123 in the absence of selective pressure.

OBJECTIVES: Despite a 97% reduction in clinical sulphonamide usage, the prevalence of sulphonamide resistance among Escherichia coli has remained constant in the UK. Genetic linkage of sulphonamide resistance to other resistances is thought important for this maintenance, but the finding also implies that sulphonamide resistance exerts little fitness cost. To test this hypothesis, we examined the fitness impact of four naturally occurring sul2-coding plasmids upon their hosts. METHODS: The fitness impact of the plasmids upon E. coli was determined by pairwise growth competition in a minimal medium. The DNA sequence of plasmid p9123 was obtained by primer walking and PCR. RESULTS: Three of the four sul2-coding plasmids studied imposed fitness costs on their hosts. The fourth plasmid, a 6.2 kb resistance element carrying sul2, strA and strB designated p9123, conferred a 4% fitness advantage upon its original clinical host and also on E. coli K12 JM109. The complete sequence of p9123 revealed eight open reading frames, including five of unknown function. There was no obvious gene to which the fitness advantage might be attributed. CONCLUSIONS: The novel finding that p9123 can improve host fitness may explain why this plasmid and its close relatives are so widespread among enteric bacteria. In addition to other factors such as co-selection of sulphonamide resistance by other agents, the fitness advantage conferred by plasmids such as p9123 may have contributed to the maintenance of sulphonamide resistance in the UK in the absence of clinical selection pressure. These data indicate that once antibiotic resistance has been established on mobile genetic elements, it may be difficult to eliminate.

Anti-Infective Agents↗
PubMed1994

Changing the substrate specificity of penicillin G acylase from Kluyvera citrophila through selective pressure.

Escherichia coli (muT, mutD, Leu-) cells transformed with plasmid pYKD59 harbouring the pac gene encoding penicillin acylase (PA) from Kluyvera citrophila ATCC 21285 were exposed to environmental conditions that made expression of this enzyme essential for growth. Under these conditions, spontaneous mutants were isolated that used adipyl-L-leucine as the sole source of L-leucine. DNA sequencing of the mutant pac genes identified a transversion mutation of thymine to guanine at position 1163. This mutation was located in the beta-subunit of the enzyme and resulted in conversion of Phe-360 to valine. The assignment of this mutation to the shift in substrate specificity was further confirmed by site-directed mutagenesis. Secondary-structure prediction of the region surrounding Phe-360 suggests that this mutation should not produce any significant structural change. The purified mutant acylase was able to hydrolyse adipyl-, glutaryl-, valeryl-, caproyl-, heptanoyl- and phenoxyacetyl-L-leucine at pH 5 with greater efficiency than the wild-type enzyme. However, the mutant enzyme was not able to hydrolyse glutaryl-7-aminocephalosporanic acid and had lost 90% and 50% of activity on penicillin G and phenylacetyl-L-leucine respectively. Nevertheless, mutant PA retained its original activity on 6-nitro-3-phenylacetamidobenzoate and p-nitrophenylphenylacetate, suggesting that the binding specificity of PA by the acyl and amine moieties of the substrate are not independent phenomena. The small differences observed between the c.d. spectra of the mutant enzyme recorded at pH 5 and 8 suggest the existence of different conformational states at the two pH values, but these differences were indistinguishable from those observed in the native enzyme and cannot be correlated with the shift in substrate specificity. Our results demonstrate that it is possible to change the specificity of PA by laboratory evolution and use it to identify the amino acids involved in substrate recognition. However, the synchronous participation of the alpha- and beta-subunits in the complex induced-fit-like mechanism of acylases suggests that, to obtain new enzymes for industrial application, the selection pressure should be specifically designed for the compound of interest.

Amino Acid Sequence↗
PubMed2006

Elevated pressure selectively blunts flow-evoked vasodilatation in rat mesenteric small arteries.

BACKGROUND AND PURPOSE: The present study investigated mechanisms underlying impaired endothelium-dependent vasodilatation elicited by elevating the intraluminal pressure in rat mesenteric small arteries. EXPERIMENTAL APPROACH: Arterial segments (internal diameter 316+/-2 microm, n=86) were mounted in a pressure myograph. The effect of elevating pressure from 50 to 120 mmHg for 1 h before resetting it to 50 mmHg was studied on endothelium-dependent vasodilatation. KEY RESULTS: In arteries constricted with U46619 in the presence of indomethacin, shear stress generated by flow, evoked vasodilatation that was abolished by an inhibitor of nitric oxide (NO) synthase, asymmetric dimethylarginine (1 mM), whereas acetylcholine-induced vasodilatation was unchanged. After elevation of intraluminal pressure for 1 h and then resetting it to 50 mmHg, vasodilatation induced by shear stress and the NO donor, S-nitrosopenicillamine was inhibited, while vasodilatation induced by a guanylyl cyclase activator, BAY 412272, and acetylcholine was unaltered. Superoxide levels sensitive to polyethylene glycol superoxide dismutase were increased in segments exposed to elevated pressure. A superoxide scavenger, tempol (300 microM), a general endothelin receptor antagonist, SB 217242 and the selective ET(A) receptor antagonist, BQ 123 preserved shear stress-evoked vasodilatation. CONCLUSIONS AND IMPLICATIONS: The present study shows that transient exposure to an elevated intraluminal pressure selectively inhibits flow-evoked NO-mediated vasodilatation, probably through activation of endothelin receptors and increased formation of superoxide. In contrast, elevation of pressure did not affect the acetylcholine-evoked endothelium-derived hyperpolarizing factor type vasodilatation in mesenteric small arteries.

Acetylcholine↗
PubMed1997

Positive Darwinian selection on two homologous fertilization proteins: what is the selective pressure driving their divergence?

Most examples of positive selection inferred from nucleotide sequence data involve hostpathogen interactions. However, positive selection also promotes the divergence of proteins mediating sperm-egg recognition in marine invertebrates. The abalone spermatozoon has a large acrosomal vesicle containing two proteins of 16 kDa and 18 kDa. Lysin, the 16-kDa protein, exhibits species-specificity in dissolving a hole in the egg vitelline envelope through which the sperm swims to reach the egg plasma membrane. The 18-kDa protein coats the sperm acrosomal process and probably mediates fusion of the two gametes. In this review, we compare sequences of both proteins from five species of California abalones. Both proteins show extensive divergence which has been promoted by positive Darwinian selection. The ratios of nonsynonymous to synonymous nucleotide substitutions may be the highest yet discovered for full-length sequences. Although extensive divergence has occurred, there is conservation of the shape and polarity of residues in both proteins. The two acrosomal proteins arose by a gene duplication followed by their extensive divergence. Five hypotheses are presented which attempt to explain the nature of the unknown selective force responsible for the robust positive selection. The positive selection may, in some unknown way, be related to the establishment of prezygotic barriers to reproduction. Because positive selection promotes the divergence of unrelated, species-specific gamete recognition proteins in both abalones and sea urchins, we predict that positive selection may be a general phenomenon in the evolution of gamete recognition systems in marine invertebrates.

Amino Acid Sequence↗
PubMed1992

Directional mutation pressure, selective constraints, and genetic equilibria.

Rates of substitution mutations in two directions, v [from an A-T or T-A nucleotide pair (AT-pair) to a G-C or C-G nucleotide pair (GC-pair)] and u [from a GC-pair to an AT-pair], are usually not the same. The net effect, v/(u + v), has previously been defined as directional mutation pressure (mu D), which explains the wide interspecific variation and narrow intragenomic heterogeneity of DNA G + C content in bacteria. In this article, first, a theory of the evolution of DNA G + C content is presented that is based on the equilibrium among three components: directional mutation pressure, DNA G + C content, and selective constraints. According to this theory, consideration of both u and v as well as selective constraints is essential to explain the molecular evolution of the DNA base composition and sequence. Second, the theory of directional mutation pressure is applied to the analysis of the wide intragenomic heterogeneity of DNA G + C content in multicellular eukaryotes. The theory explains the extensive intragenomic heterogeneity of G + C content of higher eukaryotes primarily as the result of the intragenomic differences of directional mutation pressure and selective constraints rather than the result of positive selections for functional advantages of the DNA G + C content itself.

Animals↗
PubMed1998

Selective-pressure single impression procedure for tooth-mucosa-supported removable partial dentures.

This article describes a method of making impressions for tooth-mucosa-supported removable partial dentures using a single impression procedure. Through the use of border-molded custom trays, selectively relieved, and application of pressure on residual ridge areas, the objectives of maximum tissue coverage and selective tissue placement of primary stress-bearing areas are fulfilled. With a single impression procedure, treatment time is reduced and laboratory errors commonly encountered with the altered cast impression technique can be minimized or eliminated.

Dental Impression Materials↗
PubMed1993

Stable continuous constitutive expression of a heterologous protein in Saccharomyces cerevisiae without selection pressure.

The stability of heterologous protein expression in Saccharomyces cerevisiae during continuous culture without selection for plasmid-containing cells was investigated. The protein chosen was the leech thrombin inhibitor desulphato-hirudin, which is tolerated well by S. cerevisiae when over-expressed. Expression was from a 2-mu derived multicopy vector containing a synthetic hirudin gene under control of the constitutive glyceraldehyde-3-phosphate dehydrogenase derived GAPFL promoter. The behaviour of the system was studied at three dilution rates (D) corresponding to approximately 30% (0.06 h-1), 60% (0.12 h-1) and 90% (0.17 h-1) of the estimated maximum D. The level of plasmid loss was low at all Ds, with only 5-10% plasmid-free cells observed at 75 generations. The plasmid was most stably maintained at the intermediate D of 0.12 h-1, where the rate of loss was comparable to the loss of the native 2-mu plasmid. Hirudin expression was also highest at D = 0.12 h-1, possibly as a result of cell lysis at D = 0.06 h-1 and D = 0.17 h-1, leading to the release of vacuolar proteases and subsequent proteolysis of hirudin. Differences in expression levels were not a result of changes in plasmid copy number, which was in the range 40-60 throughout all three experiments. The high stability of this system at all Ds investigated shows that heterologous protein expression is not a burden to S. cerevisiae when the protein expressed is tolerated well.

Animals↗
PubMed2002

Response of Escherichia coli hypermutators to selection pressure with antimicrobial agents from different classes.

The responses of hypermutable Escherichia coli strains to selection with antibiotics having different endogenous resistance potentials were determined. Selections with rifampicin or ciprofloxacin at 4 x MIC, i.e. conditions where they act as single target agents against RpoB and GyrA, respectively, demonstrated that some hypermutators generated resistant mutants with frequencies up to 1000-fold higher than normal strains. Furthermore, individual mutants recovered from hypermutable hosts often exhibited higher levels of resistance to the drugs than mutants arising in normal hosts. Exposure to ciprofloxacin at 16 x MIC, i.e. conditions where it has low endogenous resistance potential, failed to select resistant mutants in hypermutable or normal hosts (mutation frequency <10(-11)). Consistent with these findings, the highest estimated mutation frequency for selection at 16 x MIC in a hypermutable host would be 4.4 x 10(-15) (mutT), calculated by determining the individual mutation frequencies for first-step ciprofloxacin resistance and second-step resistance arising in hosts already harbouring single first-step mutations in gyrA at codons 83 or 87. The frequency with which second-step ciprofloxacin resistance mutations arose was suppressed in hypermutators and demonstrated at most a 10-fold increase in mutation rate compared with non-hypermutator hosts. Second-step mutants may contain mutations in mar, since a survey of 170 second-step ciprofloxacin-resistant mutants derived from both hypermutator and non-hypermutator parents demonstrated that they all possessed increased resistance to chloramphenicol, a phenotype associated with mar mutations. Exposure to 4 x MIC of D-cycloserine, cefotaxime or polymyxin B (agents with multiple targets or membrane activity) failed to select resistant mutants in normal or hypermutator hosts (mutation frequency <10(-11)); however, continuous culture in the presence of sub-lethal concentrations of D-cycloserine (0.25 x MIC) selected resistant mutants in hypermutators after c. 33 generations, compared with c. 44 generations in normal hosts. Since hypermutable bacteria occur naturally, our data emphasize that successful new drugs will need to possess low endogenous resistance potentials.

Anti-Bacterial Agents↗
PubMed2002

Increased positive selection pressure in persistent (SSPE) versus acute measles virus infections.

We compared the extent of positive selection acting on acute and persistent strains of measles virus (MV). Far stronger positive selection was found in the fusion (F) and haemagglutinin (H) genes from subacute sclerosing panencephalitis (SSPE) compared to acute MV cases. Most of the positively selected sites identified in these surface glycoprotein genes from SSPE cases correspond to structural, functional or antigenic areas, and could not be explained by the effects of cell passaging. The correlations between selected sites and functional studies of MV are discussed in detail with reference to the maintenance of persistent infection. No positive selection was found in the matrix (M) gene from acute cases of MV and the effects of including hypermutated SSPE M gene sequences in phylogenetic inference were also explored. Finally, using H gene data, we estimated the rate of molecular evolution for SSPE strains as 3.4 x 10(-4) substitutions/site/year, which is similar to previous estimates obtained for acute strains.

Evolution, Molecular↗
PubMed1997

Mutations of the HIV type 1 V3 loop under selection pressure with neutralizing monoclonal antibody NM-01.

Variants of human immunodeficiency virus type 1 (HIV-1) were selected for resistance to the neutralizing monoclonal antibody (MAb) NM-01. MAb NM-01 recognizes the center of the third hypervariable domain (V3 loop) of the envelope gp120, and neutralizes diverse HIV-1 strains. In the continuous presence of MAb NM-01, transmission and propagation of molecularly cloned HIV-1 were performed in vitro to isolate escape variants. The polymerase chain reaction-single-strand conformation polymorphism and sequence analyses of these variants indicated that the antigenic change against MAb NM-01 is due to a single base substitution resulting in one amino acid interchange within the recognition site of MAb NM-01 in the V3 loop. Mutational analyses also demonstrated a nonrandom event of variability and the existence of mutational hot spots in the V3 loop. The bias of variability could be interpreted by the specificity of error-prone replication by HIV-1 reverse transcriptase. Furthermore, the results suggest that distribution of mutability might correlate closely with the stability of the secondary structure of RNA encoding the V3 loop region.

Antibodies, Monoclonal↗