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"Adams, Mark D"
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Superman : President Luthor
His fame bolstered after helping to rebuild Gotham City after an earthquake, billionaire Lex Luthor decides to run for the highest office in the land, the American presidency.
Book
Capsule carbohydrate structure determines virulence in Acinetobacter baumannii
Acinetobacter baumannii
is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in
A
.
baumannii
remain uncertain. By comparing genomes among a panel of
A
.
baumannii
strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene
gtr6
, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic
gtr6
mutants, we confirmed that
gtr6-
disrupted strains were protected from phagocytosis
in vitro
and displayed higher bacterial burden and lethality
in vivo
.
Gtr6
+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness
in vivo
. We found that the CR3 receptor mediated phagocytosis of
gtr6+
, but not
gtr6
-, strains in a complement-dependent manner. Furthermore, hypovirulent
gtr6+
strains demonstrated increased virulence
in vivo
when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple
A
.
baumannii
strains. Thus, capsular structure can determine virulence among
A
.
baumannii
strains by altering bacterial interactions with host complement-mediated opsonophagocytosis.
Journal Article
Antibiotic collateral sensitivity is contingent on the repeatability of evolution
Antibiotic resistance represents a growing health crisis that necessitates the immediate discovery of novel treatment strategies. One such strategy is the identification of collateral sensitivities, wherein evolution under a first drug induces susceptibility to a second. Here, we report that sequential drug regimens derived from in vitro evolution experiments may have overstated therapeutic benefit, predicting a collaterally sensitive response where cross-resistance ultimately occurs. We quantify the likelihood of this phenomenon by use of a mathematical model parametrised with combinatorially complete fitness landscapes for
Escherichia coli
. Through experimental evolution we then verify that a second drug can indeed stochastically exhibit either increased susceptibility or increased resistance when following a first. Genetic divergence is confirmed as the driver of this differential response through targeted and whole genome sequencing. Taken together, these results highlight that the success of evolutionarily-informed therapies is predicated on a rigorous probabilistic understanding of the contingencies that arise during the evolution of drug resistance.
The evolution of resistance to an antibiotic can render bacteria more susceptible, or more resistant, to a second antibiotic. Here, Nichol et al. provide evidence that the final outcome can be fairly stochastic and depends on the shape of the evolutionary fitness landscape.
Journal Article
A Metagenomic Framework for the Study of Airborne Microbial Communities
Understanding the microbial content of the air has important scientific, health, and economic implications. While studies have primarily characterized the taxonomic content of air samples by sequencing the 16S or 18S ribosomal RNA gene, direct analysis of the genomic content of airborne microorganisms has not been possible due to the extremely low density of biological material in airborne environments. We developed sampling and amplification methods to enable adequate DNA recovery to allow metagenomic profiling of air samples collected from indoor and outdoor environments. Air samples were collected from a large urban building, a medical center, a house, and a pier. Analyses of metagenomic data generated from these samples reveal airborne communities with a high degree of diversity and different genera abundance profiles. The identities of many of the taxonomic groups and protein families also allows for the identification of the likely sources of the sampled airborne bacteria.
Journal Article
Assessing the Evolutionary Impact of Amino Acid Mutations in the Human Genome
Quantifying the distribution of fitness effects among newly arising mutations in the human genome is key to resolving important debates in medical and evolutionary genetics. Here, we present a method for inferring this distribution using Single Nucleotide Polymorphism (SNP) data from a population with non-stationary demographic history (such as that of modern humans). Application of our method to 47,576 coding SNPs found by direct resequencing of 11,404 protein coding-genes in 35 individuals (20 European Americans and 15 African Americans) allows us to assess the relative contribution of demographic and selective effects to patterning amino acid variation in the human genome. We find evidence of an ancient population expansion in the sample with African ancestry and a relatively recent bottleneck in the sample with European ancestry. After accounting for these demographic effects, we find strong evidence for great variability in the selective effects of new amino acid replacing mutations. In both populations, the patterns of variation are consistent with a leptokurtic distribution of selection coefficients (e.g., gamma or log-normal) peaked near neutrality. Specifically, we predict 27-29% of amino acid changing (nonsynonymous) mutations are neutral or nearly neutral (|s|<0.01%), 30-42% are moderately deleterious (0.01%<|s|<1%), and nearly all the remainder are highly deleterious or lethal (|s|>1%). Our results are consistent with 10-20% of amino acid differences between humans and chimpanzees having been fixed by positive selection with the remainder of differences being neutral or nearly neutral. Our analysis also predicts that many of the alleles identified via whole-genome association mapping may be selectively neutral or (formerly) positively selected, implying that deleterious genetic variation affecting disease phenotype may be missed by this widely used approach for mapping genes underlying complex traits.
Journal Article
Historical perspective on the influence of wildfire policy, law, and informal institutions on management and forest resilience in a multiownership, frequent-fire, coupled human and natural system in Oregon, USA
We examine the influence of wildfire institutions on management and forest resilience over time, drawing on research from a multiownership, frequent-fire, coupled human and natural system (CHANS) in the eastern Cascades of Oregon, USA. We constructed social-ecological histories of the study area’s three main landowner groups (national forest, private corporate, and tribal) using a historical framework (1905–2010). Our findings highlight two infrequently recognized linkages of multiownership, frequentfire CHANS: (1) informal institutions (e.g., cultural norms, knowledge system and fire paradigm) and institutional history often influence wildfire management adaptation (changes in forest fuel treatment, harvest fuel treatment, and wildfire incident response) through interactions with formal institutions (e.g., policy, law) and consequent effects on managers’ decision-making flexibility; (2) institutional interactions over time can influence forest resilience, thereby contributing to forest structural variation in multiownership landscapes. Consequently, the factors that contribute to maladaptive wildfire management are heterogeneously distributed across ownerships and the landscape. The timing of institutional dynamics also matters: manager flexibility to respond adaptively to wildfire hazard change seems to depend on synchronicity in evolution between informal and formal institutions, whereas asynchronous evolution (e.g., policy change, coupled with delayed shift in cultural norms or fire paradigms) may generate a time lag between unanticipated ecological feedbacks and management response. Thus, interventions that promote informal institutional evolution in tandem with developments in policy and law may shorten time lags, accelerating adaptation. A historical perspective can facilitate broad-scale, adaptive responses to wildfire-related ecological feedbacks in several ways: by providing insight into how informal institutions and institutional history interact with formal institutions to influence wildfire management behavior; by providing a historical baseline and system stages that contextualize current management behavior, ecological conditions, and policy options; and by illuminating historical sources of variation among ownerships and how they might be addressed.
Journal Article
Active and Passive Immunization Protects against Lethal, Extreme Drug Resistant-Acinetobacter baumannii Infection
Extreme-drug-resistant (XDR) Acinetobacter baumannii is a rapidly emerging pathogen causing infections with unacceptably high mortality rates due to inadequate available treatment. New methods to prevent and treat such infections are a critical unmet medical need. To conduct a rational vaccine discovery program, OmpA was identified as the primary target of humoral immune response after intravenous infection by A. baumannii in mice. OmpA was >99% conserved at the amino acid level across clinical isolates harvested between 1951 and 2009 from cerebrospinal fluid, blood, lung, and wound infections, including carbapenem-resistant isolates, and was ≥89% conserved among other sequenced strains, but had minimal homology to the human proteome. Vaccination of diabetic mice with recombinant OmpA (rOmpA) with aluminum hydroxide adjuvant markedly improved survival and reduced tissue bacterial burden in mice infected intravenously. Vaccination induced high titers of anti-OmpA antibodies, the levels of which correlated with survival in mice. Passive transfer with immune sera recapitulated protection. Immune sera did not enhance complement-mediated killing but did enhance opsonophagocytic killing of A. baumannii. These results define active and passive immunization strategies to prevent and treat highly lethal, XDR A. baumannii infections.
Journal Article
Novel recurrently mutated genes in African American colon cancers
Significance Colorectal cancer is a leading cause of cancer-related deaths world-wide. African Americans exhibit the highest colon cancer incidence and mortality among all ethnic groups in the United States. Despite this finding, there is a dearth of knowledge on the genetic mechanisms underlying colon carcinogenesis in African Americans. We thus initiated this study to characterize the mutational landscapes of African American colon cancers. We identified new genes that are significantly mutated in colon cancer and that are highly preferentially targeted for mutations in colon cancers arising in African Americans as compared with Caucasians. These findings suggest differences in routes of colon carcinogenesis between the different ethnic groups and also may have implications for the ethnicity associated differences in tumor incidence and outcome.
We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 ( EPHA6 ) and folliculin ( FLCN ), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors.
Journal Article
The Success of Acinetobacter Species; Genetic, Metabolic and Virulence Attributes
An understanding of why certain Acinetobacter species are more successful in causing nosocomial infections, transmission and epidemic spread in healthcare institutions compared with other species is lacking. We used genomic, phenotypic and virulence studies to identify differences between Acinetobacter species. Fourteen strains representing nine species were examined. Genomic analysis of six strains showed that the A. baumannii core genome contains many genes important for diverse metabolism and survival in the host. Most of the A. baumannii core genes were also present in one or more of the less clinically successful species. In contrast, when the accessory genome of an individual A. baumannii strain was compared to a strain of a less successful species (A. calcoaceticus RUH2202), many operons with putative virulence function were found to be present only in the A. baumannii strain, including the csu operon, the acinetobactin chromosomal cluster, and bacterial defence mechanisms. Phenotype microarray analysis showed that compared to A. calcoaceticus (RUH2202), A. baumannii ATCC 19606(T) was able to utilise nitrogen sources more effectively and was more tolerant to pH, osmotic and antimicrobial stress. Virulence differences were also observed, with A. baumannii ATCC 19606(T), A. pittii SH024, and A. nosocomialis RUH2624 persisting and forming larger biofilms on human skin than A. calcoaceticus. A. baumannii ATCC 19606(T) and A. pittii SH024 were also able to survive in a murine thigh infection model, whereas the other two species were eradicated. The current study provides important insights into the elucidation of differences in clinical relevance among Acinetobacter species.
Journal Article
An Analysis of the Epidemic of Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae: Convergence of Two Evolutionary Mechanisms Creates the “Perfect Storm”
Abstract
Background
Carbapenem resistance is a critical healthcare challenge worldwide. Particularly concerning is the widespread dissemination of Klebsiella pneumoniae carbapenemase (KPC). Klebsiella pneumoniae harboring blaKPC (KPC-Kpn) is endemic in many areas including the United States, where the epidemic was primarily mediated by the clonal dissemination of Kpn ST258. We postulated that the spread of blaKPC in other regions occurs by different and more complex mechanisms. To test this, we investigated the evolution and dynamics of spread of KPC-Kpn in Colombia, where KPC became rapidly endemic after emerging in 2005.
Methods
We sequenced the genomes of 133 clinical isolates recovered from 24 tertiary care hospitals located in 10 cities throughout Colombia, between 2002 (before the emergence of KPC-Kpn) and 2014. Phylogenetic reconstructions and evolutionary mapping were performed to determine temporal and genetic associations between the isolates.
Results
Our results indicate that the start of the epidemic was driven by horizontal dissemination of mobile genetic elements carrying blaKPC-2, followed by the introduction and subsequent spread of clonal group 258 (CG258) isolates containing blaKPC-3.
Conclusions
The combination of 2 evolutionary mechanisms of KPC-Kpn within a challenged health system of a developing country created the “perfect storm” for sustained endemicity of these multidrug-resistant organisms in Colombia.
Journal Article