Plethora of Resistance Genes in Carbapenem-Resistant Gram-Negative Bacteria in Greece: No End to a Continuous Genetic Evolution

Carbapenem-resistant Gram-negative bacteria are a public health threat that requires urgent action. The fact that these pathogens commonly also harbor resistance mechanisms for several other antimicrobial classes further reduces patient treatment options. The present study aimed to provide information regarding the multidrug resistance genetic background of carbapenem-resistant Gram-negative bacteria in Central Greece. Strains from a tertiary care hospital, collected during routine practice, were characterized using a DNA microarray-based assay. Various different resistance determinants for carbapenems, other beta-lactams, aminoglycosides, quinolones, trimethoprim, sulfonamides and macrolides were detected among isolates of the same sequence type. Eighteen different multidrug resistance genomic profiles were identified among the twenty-four K. pneumoniae ST258, seven different profiles among the eight K. pneumoniae ST11, four profiles among the six A. baumannii ST409 and two among the three K. oxytoca. This report describes the multidrug resistance genomic background of carbapenem-resistant Gram-negative bacteria from a tertiary care hospital in Central Greece, providing evidence of their continuous genetic evolution.

Molecular Epidemiology and Genetic Evolution of Canine Parvovirus Type 2 in Diarrheic Dogs in Serbia From 2008 To 2020

Canine Parvovirus 2 (CPV2) is a causal agent of an infectious disease with the highest fatality rate among dogs. However, in Serbia, it has never been investigated thoroughly. This study was conducted on samples originating from dogs with diarrhea in anamnesis, stored in the sample bank, submitted for various reasons to the Institute of Veterinary Medicine of Serbia. In total, 50 rectal swab samples were collected from the period 2008 to 2020, and consequently tested. Out of 50 rectal swab samples, the CPV2 genome was detected in 14 (28%). This retrospective study showed the presence of three different variants of CPV2 in diarrheic dogs during the last 12 years in Serbia. CPV2a was the most prevalent variant (60%) followed by CPV2b (30%), and CPV2c (10%). Interestingly, CPV2a had been the predominantly detected variant up until 2018. Nevertheless in 2019, there was the first detected occurrence of the CPV2b variant, followed by the first detection of the CPV2c in 2020. This study reports the evidence and distribution of CPV2 throughout the time-lapse from 2008 to 2020, providing new information about the presence and the prevalence of virus strains in Serbia.

Genome-Wide Characterization of Zebrafish Endogenous Retroviruses Reveals Unexpected Diversity in Genetic Organizations and Functional Potentials

Endogenous retroviruses (ERVs) are relics of past infection that constitute up to 8% of the human genome. Understanding the genetic evolution of the ERV family and the interplay of ERVs and encoded RNAs and proteins with host function has become a new frontier in biology.

Continuation Newton methods with deflation techniques and quasi-genetic evolution for global optimization problems

The global minimum point of an optimization problem is of interest in engineering fields and it is difficult to be solved, especially for a nonconvex large-scale optimization problem. In this article, we consider the continuation Newton method with the deflation technique and the quasi-genetic evolution for this problem. Firstly, we use the continuation Newton method with the deflation technique to find the stationary points from several determined initial points as many as possible. Then, we use those found stationary points as the initial evolutionary seeds of the quasi-genetic algorithm. After it evolves into several generations, we obtain a suboptimal point of the optimization problem. Finally, we use the continuation Newton method with this suboptimal point as the initial point to obtain the stationary point, and output the minimizer between this final stationary point and the found suboptimal point of the quasi-genetic algorithm. Finally, we compare it with the multi-start method (the built-in subroutine GlobalSearch.m of the MATLAB R2020a environment) and the differential evolution algorithm (the DE method, the subroutine de.m of the MATLAB Central File Exchange 2021), respectively. Numerical results show that the proposed method performs well for the large-scale global optimization problems, especially the problems of which are difficult to be solved by the known global optimization methods.

Development and selective grain make plasticity 'take the lead' in adaptive evolution

Background Biological evolution exhibits an extraordinary capability to adapt organisms to their environments. The explanation for this often takes for granted that random genetic variation produces at least some beneficial phenotypic variation in which natural selection can act. Such genetic evolvability could itself be a product of evolution, but it is widely acknowledged that the immediate selective gains of evolvability are small on short timescales. So how do biological systems come to exhibit such extraordinary capacity to evolve? One suggestion is that adaptive phenotypic plasticity makes genetic evolution find adaptations faster. However, the need to explain the origin of adaptive plasticity puts genetic evolution back in the driving seat, and genetic evolvability remains unexplained. Results To better understand the interaction between plasticity and genetic evolvability, we simulate the evolution of phenotypes produced by gene-regulation network-based models of development. First, we show that the phenotypic variation resulting from genetic and environmental perturbation are highly concordant. This is because phenotypic variation, regardless of its cause, occurs within the relatively specific space of possibilities allowed by development. Second, we show that selection for genetic evolvability results in the evolution of adaptive plasticity and vice versa. This linkage is essentially symmetric but, unlike genetic evolvability, the selective gains of plasticity are often substantial on short, including within-lifetime, timescales. Accordingly, we show that selection for phenotypic plasticity can be effective in promoting the evolution of high genetic evolvability. Conclusions Without overlooking the fact that adaptive plasticity is itself a product of genetic evolution, we show how past selection for plasticity can exercise a disproportionate effect on genetic evolvability and, in turn, influence the course of adaptive evolution.

Chromatin Accessibility Analysis Reveals Epigenetic Evolution Is a Common Mechanism of Relapse in Acute Myeloid Leukemia

Introduction: Acute myeloid leukemia (AML) is associated with a poor prognosis and high rates of relapse despite aggressive treatments including high dose chemotherapy. To understand the clonal dynamics and genetic evolution of relapsed AML, we analyzed a cohort of 142 previously published genotyped and paired diagnosis-relapse AML samples. 40% of queried cases exhibited no major changes in somatic mutations upon relapse, and genetically stable clonal structure correlated with increased relapse probability. Thus, we hypothesized epigenetic reprogramming plays a role in these cases and AML relapse in general. Here, we examine the epigenetic landscape of relapsed AML and characterize the cis and trans regulatory elements that correlate with AML relapse in the presence or absence of genetic evolution. Methods: We identified 27 viable cryopreserved paired diagnosis and relapse samples from the same patient treated at Stanford with high-dose chemotherapy. Leukemic blasts and (when possible) leukemia stem cell (LSC) enriched populations were FACS purified and prepared for genotyping with a myeloid malignancy targeted sequencing panel as well as ATAC-seq for chromatin accessibility profiling. Single-cell ATAC-seq was further performed on select samples to investigate regulatory reprogramming in cell subpopulations. We then performed integrative analysis to uncover the interplay between genetic lesions, epigenetic regulatory programs, and gene accessibility in relapsed AML. Results: Genotyping analysis of these AML specimens revealed that 40% of samples exhibited no changes in AML-related genetic alterations upon relapse (hereby referred to as "stable" samples). Chromatin accessibility analysis revealed these stable samples had a distinct epigenetic signature, modulating similar gene accessibility programs and sharing enhancer loci that become accessible across all stable relapse samples. These sequences included genes involved in chromatin organization and compaction, as well as those involved in transcriptional control of hematopoietic differentiation and myeloid cell maturation. We also observed several regulatory signatures present at relapse specific for AML subtypes, including NPM1/FLT3 double mutant AML and those with mutations in transcription factors such as CEBPA or RUNX1. We then performed single-cell ATAC-seq on genetically stable samples to further characterize the sub-clonal epigenetic dynamics between the diagnosis and relapse cells. Several samples exhibited regulatory heterogeneity in multiple cell subpopulations that changed significantly at relapse. One subpopulation of interest was characterized by increased GATA and RUNX family transcription factor motif accessibility at relapse, indicating a shift toward a less differentiated progenitor cell phenotype. In addition, we identified a subpopulation of cells at diagnosis that were epigenetically similar to the major epigenetic states present at relapse, indicating that selection for specific epigenetic subclones may occur in AML patients during therapy in the absence of additional genetic lesions. Finally, given the critical role of LSCs in AML pathogenesis and their possible role as a reservoir for AML relapse, we analyzed LSC-enriched subpopulations in a subset of our cohort. ATAC-seq analysis indicated these cells shared several LSC-specific epigenetic features between samples, are distinguished from leukemia blasts by distinct regulatory programs, and undergo epigenetic remodeling between initial diagnosis and relapse. Gene accessibility analysis also revealed a shared LSC gene expression signature that also shifted at relapse. These data indicate a specific, distinct epigenomic signature for LSC enriched cell populations, and that epigenetic evolution at relapse occurs intracellularly, rather than reflecting heterogeneity in cellular subpopulations upon AML relapse. Conclusion: This study reveals that epigenetic remodeling in the absence of genetic evolution is a mechanism through which AML relapse occurs. We show that chromatin reorganization of genes and regulatory sequences occurs in these AML cells, leading to a permissive cell state that might be resistant to conventional treatment. Ongoing work includes dissecting the subclonal structure of these AML cells and identifying the relationship between gene regulatory networks that contribute to relapse. Disclosures Ediriwickrema: Nanosive SAS: Patents & Royalties. Majeti: BeyondSpring Inc.: Membership on an entity's Board of Directors or advisory committees; CircBio Inc.: Membership on an entity's Board of Directors or advisory committees; Kodikaz Therapeutic Solutions Inc.: Membership on an entity's Board of Directors or advisory committees; Coherus Biosciences: Membership on an entity's Board of Directors or advisory committees; Acuta Capital Partners: Consultancy; Gilead: Patents & Royalties: inventor on a number of patents related to CD47 cancer immunotherapy licensed to Gilead Sciences, Inc..

‘All sorts of wonderful impossibilities’: Tracing the Genesis of John McGahern’s ‘Doorways’

It is well known by now that John McGahern was a scrupulous reviser of his own work, even if this insight into his compositional methods has not been accompanied by a substantial body of research on the archive and the revisions themselves. This essay aims to address this anomaly by focusing on the genetic evolution of McGahern's short story ‘Doorways’. Specifically, it will concentrate on the earliest handwritten drafts when the work is at its most provisional. The consensus view of McGahern's writing practices is of an artist committed to ideals of Flaubertian perfectionism, but implicit in this view is a bias towards the more granular work of late-stage refinement. The approach this essay takes shows McGahern at his most distant from the Flaubertian perfectionist that he is best known as, thus opening up new ways to reconsider how those works achieve their distinctive appearance of refined delicacy and simplicity.

Individual-based modeling of genome evolution in haplodiploid organisms

Ants, bees, wasps, bark beetles, and other species have haploid males and diploid females. Although such haplodiploid species play key ecological roles and are threatened by environmental changes, no general framework exists for simulating their genetic evolution. Here, we use the SLiM simulation environment to build a novel model for individual-based forward simulation of genetic evolution in haplodiploid populations. We compare the fates of adaptive and deleterious mutations and find that selection is more effective in haplodiploid species than in diploid species. Our open-source model will help understand the evolution of sociality and how ecologically important species may adapt to changing environments.