Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects.

Huntington's disease (HD), due to expansion of a CAG repeat in HTT , is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at HTT by a 5'-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.

Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer.

BACKGROUND: Therapeutic agents that specifically target patients with RAS mutant colorectal cancer (CRC) are needed. We sought potential drug targets by relating genome-wide association study and survival data in patients with advanced CRC profiled for mitogen-activated protein kinase (MAPK) pathway mutations. METHODS: In total, 694 patients from the clinical trials COIN and COIN-B had MAPK-activated CRCs (assigned as KRAS, NRAS, or BRAF mutant). Genome-wide single nucleotide polymorphism (SNP), gene, and gene-set analyses were performed to identify determinants of survival. For rs12028023 in RAS protein activator-like 2 (RASAL2), we studied its effect by MAPK pathway activation status (by comparing to 760 patients without MAPK-activated CRCs), MAPK gene mutation status, surface area of the primary tumor (as a marker of proliferation), and expression on RASAL2. RESULTS: In MAGMA genome-wide analyses, RASAL2 was the most significant gene associated with survival (p = 2.0 × 10-5 ). Patients carrying the minor (A) allele in the lead SNP, rs12028023 in intron 1 of RASAL2, had a median increase in survival of 167 days as compared with patients carrying the major allele. rs12028023 was predictive for survival by MAPK-activation status (pZ-test  = 2.1 × 10-3 ). Furthermore, rs12028023 improved survival in patients with RAS mutant (hazard ratio [HR] = 0.62, 95% confidence intervals [CI] = 0.5-0.8, p = 3.4 × 10-5 ) but not BRAF mutant (p = 0.87) CRCs. The rs12028023 A-allele was associated with reduced surface area of the primary tumor (Beta = -0.037, standard error [SE] = 0.017, p = 3.2 × 10-2 ) and reduced RASAL2 expression in cultured fibroblasts (p = 1.6 × 10-11 ). CONCLUSION: Our data demonstrate a prognostic role for RASAL2 in patients with MAPK-activated CRCs, with potential as a therapeutic target.

Relationship between 233 colorectal cancer risk loci and survival in 1926 patients with advanced disease.

Background: Genome, transcriptome and methylome-wide association studies have identified single-nucleotide polymorphisms (SNPs) or genes at 258 loci associated with colorectal cancer (CRC) risk. We studied the relationship between these and patient outcome. Methods: We studied 1926 unrelated patients with advanced CRC from COIN and COIN-B. Of 205 CRC-risk SNPs, 19 were directly genotyped and 162 were imputed, and of 53 risk genes, 52 were tested. An additive Cox model for overall survival was adjusted for known prognostic factors. For nominally significant SNPs or genes, we considered a recessive model with a Bonferroni corrected threshold of P = 2.1 × 10-4. We examined SNPs as expression quantitative trait loci (eQTL) and the relationship between gene expression in colorectal tumours and survival in 597 unrelated patients. Results: Eleven SNPs or genes were nominally associated with survival under an additive model. Only rs117079142 mapping to UTP23 and EIF3H (Hazard Ratio [HR] = 2.79, 95% Confidence Intervals [CI] = 1.70-4.58, P = 4.7 × 10-5) and rs9924886 mapping to CDH1 and CDH3 (HR = 1.24, 95% CI = 1.12-1.38, P = 5.2 × 10-5) passed the multiple testing threshold under a recessive model. rs117079142 was an eQTL for UTP23 and rs9924886 for CDH1, CDH3 and ZFP90. Decreased CDH1 expression in CRCs was associated with worse survival (HR = 2.18, 95% CI = 1.3-3.5, P = 1.8 × 10-3). Conclusion: rs117079142 and rs9924886 may represent potential prognostic biomarkers for CRC.

Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand-foot syndrome.

Cancer patients treated with capecitabine and oxaliplatin (XELOX) often develop hand-foot syndrome (HFS) or palmar-plantar erythrodysesthesia. Genetic variation in ST6GAL1 is a risk factor for type-2 diabetes (T2D), a disease also associated with HFS. We analysed genome-wide association data for 10 toxicities in advanced colorectal cancer (CRC) patients from the COIN and COIN-B trials. One thousand and fifty-five patients were treated with XELOX ± cetuximab and 745 with folinic acid, fluorouracil and oxaliplatin ± cetuximab. We also analysed rs6783836 in ST6GAL1 with HFS in CRC patients from QUASAR2. Using UK Biobank data, we sought to confirm an association between ST6GAL1 and T2D (17 384 cases, 317 887 controls) and analysed rs6783836 against markers of diabetes, inflammation and psoriasis. We found that 68% of patients from COIN and COIN-B with grade 2-3 HFS responded to treatment as compared to 58% with grade 0-1 HFS (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.02-1.2, P = 2.0 × 10-4 ). HFS was also associated with improved overall survival (hazard ratio = 0.92, 95% CI = 0.84-0.99, P = 4.6 × 10-2 ). rs6783836 at ST6GAL1 was associated with HFS in patients treated with XELOX (OR = 3.1, 95% CI = 2.1-4.6, P = 4.3 × 10-8 ) and was borderline significant in patients receiving capecitabine from QUASAR2, but with an opposite allele effect (OR = 0.66, 95% CI = 0.42-1.03, P = .05). ST6GAL1 was associated with T2D (lead SNP rs3887925, OR = 0.94, 95% CI = 0.92-0.96, P = 1.2 × 10-8 ) and the rs6783836-T allele was associated with lowered HbA1c levels (P = 5.9 × 10-3 ) and lymphocyte count (P = 2.7 × 10-3 ), and psoriasis (P = 7.5 × 10-3 ) beyond thresholds for multiple testing. In conclusion, HFS is a biomarker of treatment outcome and rs6783836 in ST6GAL1 is a potential biomarker for HFS with links to T2D and inflammation.

A genome-wide search for determinants of survival in 1926 patients with advanced colorectal cancer with follow-up in over 22,000 patients.

BACKGROUND: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome. PATIENTS AND METHODS: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10-5), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas. RESULTS: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10-7). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10-2) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10-8). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10-2). CONCLUSIONS: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.

Genome-wide association studies of toxicity to oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab in 1800 patients with advanced colorectal cancer.

Chemotherapies administered at normal therapeutic dosages can cause significant side-effects and may result in early treatment discontinuation. Inter-individual variation in toxicity highlights the need for biomarkers to personalise treatment. We sought to identify such biomarkers by conducting 40 genome-wide association studies, together with gene and gene set analyses, for any toxicity and 10 individual toxicities in 1800 patients with advanced colorectal cancer treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab from the MRC COIN and COIN-B trials (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). Single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome-wide or suggestive significance were validated in independent patient groups. We found that MROH5 was significantly associated with neutropenia in MAGMA gene analyses in patients treated with XELOX (P = 6.6 × 10-7 ) and was independently validated in those receiving XELOX + cetuximab; pooled P = 3.7 × 10-7 . rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (odds ratio = 5.0, 95% confidence interval = 3.0-8.3, P = 9.8 × 10-10 ) but was not independently replicated. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five of these were independently validated (rs6030266 with diarrhoea, rs1546161 with hand-foot syndrome, rs9601722 with neutropenia, rs13413764 with lethargy and rs4600090 with nausea; all with pooled P's < 5.0 × 10-6 ). In conclusion, the association of MROH5 with neutropenia and five other putative biomarkers warrant further investigation for their potential clinical utility. Despite our comprehensive genome-wide analyses of large, well-characterised, clinical trials, we found a lack of common variants with modest effect sizes associated with toxicities.

Interactions between all pairs of neighboring trees in 16 forests worldwide reveal details of unique ecological processes in each forest, and provide windows into their evolutionary histories.

When Darwin visited the Galapagos archipelago, he observed that, in spite of the islands' physical similarity, members of species that had dispersed to them recently were beginning to diverge from each other. He postulated that these divergences must have resulted primarily from interactions with sets of other species that had also diverged across these otherwise similar islands. By extrapolation, if Darwin is correct, such complex interactions must be driving species divergences across all ecosystems. However, many current general ecological theories that predict observed distributions of species in ecosystems do not take the details of between-species interactions into account. Here we quantify, in sixteen forest diversity plots (FDPs) worldwide, highly significant negative density-dependent (NDD) components of both conspecific and heterospecific between-tree interactions that affect the trees' distributions, growth, recruitment, and mortality. These interactions decline smoothly in significance with increasing physical distance between trees. They also tend to decline in significance with increasing phylogenetic distance between the trees, but each FDP exhibits its own unique pattern of exceptions to this overall decline. Unique patterns of between-species interactions in ecosystems, of the general type that Darwin postulated, are likely to have contributed to the exceptions. We test the power of our null-model method by using a deliberately modified data set, and show that the method easily identifies the modifications. We examine how some of the exceptions, at the Wind River (USA) FDP, reveal new details of a known allelopathic effect of one of the Wind River gymnosperm species. Finally, we explore how similar analyses can be used to investigate details of many types of interactions in these complex ecosystems, and can provide clues to the evolution of these interactions.

Comparison of Acute Kidney Injury During Treatment with Vancomycin and either Piperacillin-Tazobactam or Meropenem.

CONTEXT: Empiric antibiotics are often required in hospitalized patients with serious infections who may be septic and at risk for drug resistant organisms. The purpose of this study was to evaluate the observed incidence of acute kidney injury (AKI) in a sample of adult patients receiving either piperacillin-tazobactam and vancomycin or meropenemvancomycin for at least 72 hours. METHODS: Single-center, retrospective matched cohort at a 200-bed Regional Community Medical Center. Adult patients were included in the sample if they were without preexisting renal dysfunction and admitted over an 18-month time period to receive either the combination of piperacillin-tazobactam and vancomycin or meropenem-vancomycin. Sample patients were evaluated for AKI. This condition was defined by the authors as an increase in serum creatinine of 0.5mg/ml or an increase of 50% above baseline during the duration of antibiotic treatment. RESULTS: A total of 266 patients receiving either combination of antibiotics were evaluated for AKI. The incidence of AKI was significantly higher in the piperacillin-tazobactam and vancomycin group (n = 74/292, 25%) compared with the meropenem-vancomycin group (n=8/74, 9.5%, p=0.008). CONCLUSIONS: The results of this study suggest that the combination of piperacillin-tazobactam and vancomycin is associated with an increased incidence of AKI. Higher vancomycin trough concentrations were associated with increased risk for development of AKI.

Correction: Persistence of Neighborhood Demographic Influences over Long Phylogenetic Distances May Help Drive Post-Speciation Adaptation in Tropical Forests.

[This corrects the article DOI: 10.1371/journal.pone.0156913.].

Persistence of Neighborhood Demographic Influences over Long Phylogenetic Distances May Help Drive Post-Speciation Adaptation in Tropical Forests.

Studies of forest dynamics plots (FDPs) have revealed a variety of negative density-dependent (NDD) demographic interactions, especially among conspecific trees. These interactions can affect growth rate, recruitment and mortality, and they play a central role in the maintenance of species diversity in these complex ecosystems. Here we use an equal area annulus (EAA) point-pattern method to comprehensively analyze data from two tropical FDPs, Barro Colorado Island in Panama and Sinharaja in Sri Lanka. We show that these NDD interactions also influence the continued evolutionary diversification of even distantly related tree species in these FDPs. We examine the details of a wide range of these interactions between individual trees and the trees that surround them. All these interactions, and their cumulative effects, are strongest among conspecific focal and surrounding tree species in both FDPs. They diminish in magnitude with increasing phylogenetic distance between heterospecific focal and surrounding trees, but do not disappear or change the pattern of their dependence on size, density, frequency or physical distance even among the most distantly related trees. The phylogenetic persistence of all these effects provides evidence that interactions between tree species that share an ecosystem may continue to promote adaptive divergence even after the species' gene pools have become separated. Adaptive divergence among taxa would operate in stark contrast to an alternative possibility that has previously been suggested, that distantly related species with dispersal-limited distributions and confronted with unpredictable neighbors will tend to converge on common strategies of resource use. In addition, we have also uncovered a positive density-dependent effect: growth rates of large trees are boosted in the presence of a smaller basal area of surrounding trees. We also show that many of the NDD interactions switch sign rapidly as focal trees grow in size, and that their cumulative effect can strongly influence the distributions and species composition of the trees that surround the focal trees during the focal trees' lifetimes.

Multifrequency cw-EPR and DFT Studies of an Apparent Compressed Octahedral Cu(II) Complex.

The syntheses and single-crystal X-ray structures of the mononuclear complexes [Cu(bmet)](ClO4)2·H2O, [Cu(bmet)]Br2·2MeCN, and [Zn(bmet)](ClO4)2·H2O (bmet = N,N'-bis(2,2'-bipyridin-6-ylmethyl)ethane-1,2-diamine) are described. All three complexes feature a central metal ion bound to all six N atoms of the bmet ligand, which displays a meridional-facial-facial-meridional (mffm) configuration. The three complexes show one N-M-N axis to be significantly shorter than the others in agreement with an apparent compressed octahedral geometry. The X-ray structures of a single crystal of [Cu(bmet)](ClO4)2·0.375H2O resolved from data recorded at different temperatures display no remarkable structural modifications. However, they all display both as a powder and, in solution, an axial g1 > g2 ≳ g3 > g(e) electron paramagnetic resonance (EPR) pattern at low temperature, which is indicative of tetragonally elongated octahedra, while at room temperature the Q-band EPR spectra display a more rhombic g1 ≳ g2 > g3 > g(e) pattern. The fully density functional theory optimized structure of the Cu(II) complexes displays significant structural modifications only along one N(imine)-M-N(amine) axis resulting in an elongated octahedral structure. Furthermore, the EPR parameters predicted from this structure are comparable to those determined experimentally from the axial EPR signal recorded at low temperature, consistent with the unpaired electron residing mainly in the {3d(x(2)-y(2))} orbital. The structural and electronic properties of [Cu(bmet)](2+) are different from those in other previously described dynamic Jahn-Teller systems. We propose that these data can be rationalized by a dynamic Jahn-Teller effect perturbed by the strain of the hexadentate bmet ligand.

Analysis of simple sequence repeats in mammalian cell cycle genes.

Simple sequence repeats (SSRs), or microsatellites are hyper-mutable and can lead to disorders. Here we explore SSR distribution in cell cycle-associated genes [grouped into: checkpoint; regulation; replication, repair, and recombination (RRR); and transition] in humans and orthologues of eight mammals. Among the gene groups studied, transition genes have the highest SSR density. Trinucleotide repeats are not abundant and introns have higher repeat density than exons. Many repeats in human genes are conserved; however, CG motifs are conserved only in regulation genes. SSR variability in cell cycle genes represents a genetic Achilles' heel, yet SSRs are common in all groups of genes. This tolerance many be due to i) positions in introns where they do not disrupt gene function, ii) essential roles in regulation, iii) specific value of adaptability, and/or iv) lack of negative selection pressure. Present study may be useful for further exploration of their medical relevance and potential functionality.

Genetic and phenotypic consequences of introgression between humans and Neanderthals.

Strong evidence for introgression of Neanderthal genes into parts of the modern human gene pool has recently emerged. The evidence indicates that some populations of modern humans have received infusions of genes from two different groups of Neanderthals. One of these Neanderthal groups lived in the Middle East and Central Europe and the other group (the Denisovans) is known to have lived in Central Asia and was probably more widespread. This review examines two questions. First, how were these introgressions detected and what does the genetic evidence tell us about their nature and extent? We will see that an unknown but possibly large fraction of the entire Neanderthal gene complement may have survived in modern humans. Even though each modern European and Asian carries only a few percent of genes that can be traced back to Neanderthals, different individuals carry different subgroups of these introgressed genes. Second, what is the likelihood that this Neanderthal genetic legacy has had phenotypic effects on modern humans? We examine evidence for and against the possibility that some of the surviving fragments of Neanderthal genomes have been preserved by natural selection, and we explore the ways in which more evidence bearing on this question will become available in the future.

Rapid recent human evolution and the accumulation of balanced genetic polymorphisms.

All evolutionary change can be traced to alterations in allele frequencies in populations over time. DNA sequencing on a massive scale now permits us to follow the genetic consequences as our species has diverged from our close relatives and as we have colonized different parts of the world and adapted to them. But it has been difficult to disentangle natural selection from many other factors that alter frequencies. These factors include mutation and intragenic reciprocal recombination, gene conversion, segregation distortion, random drift, and gene flow between populations (these last two are greatly influenced by splits and coalescences of populations over time). The first part of this review examines recent studies that have had some success in dissecting out the role of natural selection, especially in humans and Drosophila. Among many examples, these studies include those that have followed the rapid evolution of traits that may permit adaptation to high altitude in Tibetan and Andean populations. In some cases, directional selection has been so strong that it may have swept alleles close to fixation in the span of a few thousand years, a rapidity of change that is also sometimes encountered in other organisms. The second part of the review summarizes data showing that remarkably few alleles have been carried completely to fixation during our recent evolution. Some of the alleles that have not reached fixation may be approaching new internal equilibria, which would indicate polymorphisms that are maintained by balancing selection. Finally, the review briefly examines why genetic polymorphisms, particularly those that are maintained by negative frequency dependence, are likely to have played an important role in the evolution of our species. A method is suggested for measuring the contribution of these polymorphisms to our gene pool. Such polymorphisms may add to the ability of our species to adapt to our increasingly complex and challenging environment.

Sm/Lsm genes provide a glimpse into the early evolution of the spliceosome.

The spliceosome, a sophisticated molecular machine involved in the removal of intervening sequences from the coding sections of eukaryotic genes, appeared and subsequently evolved rapidly during the early stages of eukaryotic evolution. The last eukaryotic common ancestor (LECA) had both complex spliceosomal machinery and some spliceosomal introns, yet little is known about the early stages of evolution of the spliceosomal apparatus. The Sm/Lsm family of proteins has been suggested as one of the earliest components of the emerging spliceosome and hence provides a first in-depth glimpse into the evolving spliceosomal apparatus. An analysis of 335 Sm and Sm-like genes from 80 species across all three kingdoms of life reveals two significant observations. First, the eukaryotic Sm/Lsm family underwent two rapid waves of duplication with subsequent divergence resulting in 14 distinct genes. Each wave resulted in a more sophisticated spliceosome, reflecting a possible jump in the complexity of the evolving eukaryotic cell. Second, an unusually high degree of conservation in intron positions is observed within individual orthologous Sm/Lsm genes and between some of the Sm/Lsm paralogs. This suggests that functional spliceosomal introns existed before the emergence of the complete Sm/Lsm family of proteins; hence, spliceosomal machinery with considerably fewer components than today's spliceosome was already functional.

Testing metabolic ecology theory for allometric scaling of tree size, growth and mortality in tropical forests.

The theory of metabolic ecology predicts specific relationships among tree stem diameter, biomass, height, growth and mortality. As demographic rates are important to estimates of carbon fluxes in forests, this theory might offer important insights into the global carbon budget, and deserves careful assessment. We assembled data from 10 old-growth tropical forests encompassing censuses of 367 ha and > 1.7 million trees to test the theory's predictions. We also developed a set of alternative predictions that retained some assumptions of metabolic ecology while also considering how availability of a key limiting resource, light, changes with tree size. Our results show that there are no universal scaling relationships of growth or mortality with size among trees in tropical forests. Observed patterns were consistent with our alternative model in the one site where we had the data necessary to evaluate it, and were inconsistent with the predictions of metabolic ecology in all forests.

Comparing tropical forest tree size distributions with the predictions of metabolic ecology and equilibrium models.

Tropical forests vary substantially in the densities of trees of different sizes and thus in above-ground biomass and carbon stores. However, these tree size distributions show fundamental similarities suggestive of underlying general principles. The theory of metabolic ecology predicts that tree abundances will scale as the -2 power of diameter. Demographic equilibrium theory explains tree abundances in terms of the scaling of growth and mortality. We use demographic equilibrium theory to derive analytic predictions for tree size distributions corresponding to different growth and mortality functions. We test both sets of predictions using data from 14 large-scale tropical forest plots encompassing censuses of 473 ha and > 2 million trees. The data are uniformly inconsistent with the predictions of metabolic ecology. In most forests, size distributions are much closer to the predictions of demographic equilibrium, and thus, intersite variation in size distributions is explained partly by intersite variation in growth and mortality.

Nonrandom processes maintain diversity in tropical forests.

An ecological community's species diversity tends to erode through time as a result of stochastic extinction, competitive exclusion, and unstable host-enemy dynamics. This erosion of diversity can be prevented over the short term if recruits are highly diverse as a result of preferential recruitment of rare species or, alternatively, if rare species survive preferentially, which increases diversity as the ages of the individuals increase. Here, we present census data from seven New and Old World tropical forest dynamics plots that all show the latter pattern. Within local areas, the trees that survived were as a group more diverse than those that were recruited or those that died. The larger (and therefore on average older) survivors were more diverse within local areas than the smaller survivors. When species were rare in a local area, they had a higher survival rate than when they were common, resulting in enrichment for rare species and increasing diversity with age and size class in these complex ecosystems.

Molecular analysis of adenovirus isolates from vaccinated and unvaccinated young adults.

Infections of adenovirus type 4 (Ad4) and Ad7 were discovered among previously vaccinated individuals through febrile respiratory illness surveillance at military recruit camps. Genetic analysis was performed on these isolates and a sample of adenovirus isolates from unvaccinated patients. Antigenic regions of the adenovirus hexon gene from 21 vaccinated and 31 unvaccinated patients were sequenced and compared to homologous regions of Ad4 and Ad7 vaccine strains and of other representative hexon sequences archived in GenBank. The phylogenetic distribution of sequences from vaccinated individuals closely resembled those from unvaccinated individuals. The most common Ad7 strain was the Ad7d2 hexon genotype, and the most common Ad4 strain was a genotype nearly identical to the recently discovered Z-G 95-873 Ad4 variant. Near exclusive isolation of Ad4 since 1999 indicates that the Ad4 variant is currently responsible for the vast majority of adenovirus morbidity in military recruit camps. Different ratios of nonsynonymous to synonymous nucleotide substitution rates in known antigenic regions compared to nonantigenic regions indicated positive selection for diversity in the antigenic regions and purifying selection in the nonantigenic regions.

Fatal Saccharomyces cerevisiae aortic graft infection.

Saccharomyces cerevisiae is a yeast commonly used in baking and a frequent colonizer of human mucosal surfaces. It is considered relatively nonpathogenic in immunocompetent adults (J. N. Aucott, J. Fayan, H. Grossnicklas, A. Morrissey, M. M. Lederman, and R. A. Salata, Rev. Infect. Dis. 12:406-411, 1990). We present a case of S. cerevisiae fungemia and aortic graft infection in an immunocompetent adult. This is the first reported case of S. cerevisiae fungemia where the identity of the pathogen was confirmed by rRNA sequencing.