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To understand diversity in enormous collections of genome sequences, we need computationally scalable tools that can quickly contextualize individual genomes based on their similarities and identify features of each genome that make them unique. We present WhatsGNU, a tool based on exact match proteomic compression that, in seconds, classifies any new genome and provides a detailed report of protein alleles that may have novel functional differences. We use this technique to characterize the total allelic diversity (panallelome) of Salmonella enterica , Mycobacterium tuberculosis , Pseudomonas aeruginosa, and Staphylococcus aureus . It could be extended to others. WhatsGNU is available from https://github.com/ahmedmagds/WhatsGNU .

Invasive Staphylococcus aureus infections cause high morbidity and mortality in children and adults. With rising antimicrobial resistance, optimal prevention strategies and novel therapeutics are needed. As an effective vaccine remains elusive, characterization of invasive isolates over time is required to identify determinants of invasive infection. S. aureus isolates recovered from children with invasive infection and those with colonization were obtained. Isolates were examined by whole genome sequencing to evaluate gene repertoire, sequence type, clonal complex, and phylogenetic characterization, and isolate characteristics were correlated to clinical data. 118 children with invasive S. aureus infections were enrolled; 56% of infections were caused by methicillin-susceptible S. aureus (MSSA). Methicillin-resistance (MRSA) was associated with increased inflammation, though clinical outcomes of MRSA vs MSSA did not differ. Colonization isolates exhibited higher sequence type diversity than invasive isolates. Nine distinct clonal complexes (CC) were identified among all isolates; CC8 and CC5 were associated with higher clinical severity scores. Accessory gene regulator locus type 1, Panton-Valentine Leukocidin, and arginine catabolic mobile element declined over time. Staphylokinase and leukocidin ED were associated with invasive infection, while enterotoxin B was more frequent in colonizing isolates. We observed a significant expansion in sequence type diversity among invasive clinical isolates over 12 years with the emergence of newly invasive clones in recent years. The presence of staphylokinase and LukED were associated with invasive infection over time. These findings provide insights into the pathogenesis of invasive S. aureus and may provide putative targets for immunologic approaches to prevention.

Chalcones are interesting anticancer drug candidates which have attracted much interest due to their unique structure and their extensive biological activity. Various functional modifications in chalcones have been reported, along with their pharmacological properties. In the current study, novel chalcone derivatives with the chemical base of tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-arylprop-2-en-1-one were synthesized, and the structure of their molecules was confirmed through NMR spectroscopy. The antitumor activity of these newly synthesized chalcone derivatives was tested on mouse (Luc-4T1) and human (MDA-MB-231) breast cancer cell lines. The antiproliferative effect was evaluated through SRB screening and the MTT assay after 48 h of treatment at different concentrations. Interestingly, among the tested chalcone derivatives, chalcone analogues with a methoxy group were found to have significant anticancer activity and displayed gradient-dependent inhibition against breast cancer cell proliferation. The anticancer properties of these unique analogues were examined further by cytometric analysis of the cell cycle, quantitative PCR, and the caspases-Glo 3/7 assay. Chalcone methoxy derivatives showed the capability of cell cycle arrest and increased Bax/Bcl2 mRNA ratios as well as caspases 3/7 activity. The molecular docking analysis suggests that these chalcone methoxy derivatives may inhibit anti-apoptotic proteins, particularly cIAP1, BCL2, and EGFRK proteins. In conclusion, our findings confirm that chalcone methoxy derivatives could be considered to be potent drug candidates against breast cancer.

This paper investigates and benchmarks quadrotor navigation and hold autopilots’ global control performance using heuristic optimization algorithms. The compared methods offer advantages in terms of computational effectiveness and efficiency to tune the optimum controller gains for highly nonlinear systems. A nonlinear dynamical model of the quadrotor using the Newton–Euler equations is modeled and validated. Using a modified particle swarm optimization (MPSO) and genetic algorithm (GA) from the heuristic paradigm, an offline optimization problem is formulated and solved for three different controllers: a proportional–derivative (PD) controller, a nonlinear sliding-mode controller (SMC), and a nonlinear backstepping controller (BSC). It is evident through the simulation case studies that the utilization of heuristic optimization techniques for nonlinear controllers considerably enhances the quadrotor system response. The performance of the conventional PD controller, SMC, and BSC is compared with heuristic approaches in terms of stability and influence of internal and external disturbance, and system response using the MATLAB/SIMULINK environment. The simulation results confirm the reliability of the proposed tuned GA and MPSO controllers. The PD controller gives the best performance when the quadrotor system operates at the equilibrium point, while SMC and BSC approaches give the best performance when the system does an aggressive maneuver outside the hovering condition. The overall final results show that the GA-tuned controllers can serve as a benchmark for comparing the global performance of aerial robotic control loops.

Pasteurella multocida is the primary causative agent of a range of economically important diseases in animals, including haemorrhagic septicaemia (HS), a rapidly fatal disease of ungulates. There is limited information available on the diversity of P. multocida strains that cause HS. Therefore, we determined draft genome sequences of ten disease-causing isolates and two vaccine strains and compared these genomes using a range of bioinformatic analyses. The draft genomes of the 12 HS strains were between 2,298,035 and 2,410,300 bp in length. Comparison of these genomes with the North American HS strain, M1404, and other available P. multocida genomes (Pm70, 3480, 36950 and HN06) identified a core set of 1,824 genes. A set of 96 genes was present in all HS isolates and vaccine strains examined in this study, but absent from Pm70, 3480, 36950 and HN06. Moreover, 59 genes were shared only by the Asian B:2 strains. In two Pakistani isolates, genes with high similarity to genes in the integrative and conjugative element, ICEPmu1 from strain 36950 were identified along with a range of other antimicrobial resistance genes. Phylogenetic analysis indicated that the HS strains formed clades based on their country of isolation. Future analysis of the 96 genes unique to the HS isolates will aid the identification of HS-specific virulence attributes and facilitate the development of disease-specific diagnostic tests.

Background The Covid-19 pandemic has been characterized by the emergence of novel SARS-CoV-2 variants, each with distinct properties influencing transmission dynamics, immune escape, and virulence, which, in turn, influence their impact on local populations. Swift analysis of the properties of newly emerged variants is essential in the initial days and weeks to enhance readiness and facilitate the scaling of clinical and public health system responses. Methods This paper introduces a two-variant metapopulation compartmental model of disease transmission to simulate the dynamics of disease transmission during a period of transition to a newly dominant strain. Leveraging novel S-gene dropout analysis data and genomic sequencing data, combined with confirmed Covid-19 case data, we estimate the epidemiological characteristics of the Omicron variant, which replaced the Delta variant in late 2021 in Philadelphia, PA. We utilized a grid-search method to identify plausible combinations of model parameters, followed by an ensemble adjustment Kalman filter for parameter inference. Results The model successfully estimated key epidemiological parameters; we estimated the ascertainment rate of 0.22 (95% credible interval 0.15–0.29) and transmission rate of 5.0 (95% CI 2.4–6.6) for the Omicron variant. Conclusions The study demonstrates the potential for this model-inference framework to provide real-time insights during the emergence of novel variants, aiding in timely public health responses.

USA300 has remained the dominant community and healthcare associated methicillin-resistant (MRSA) clone in the United States and in northern South America for at least the past 20 years. In this time, it has experienced epidemic spread in both of these locations. However, its pre-epidemic evolutionary history and origins are incompletely understood. Large sequencing databases, such as NCBI, PATRIC, and Staphopia, contain clues to the early evolution of USA300 in the form of sequenced genomes of USA300 isolates that are representative of lineages that diverged prior to the establishment of the South American epidemic (SAE) clade and North American epidemic (NAE) clade. In addition, historical isolates collected prior to the emergence of epidemics can help reconstruct early events in the history of this lineage. Here, we take advantage of the accrued, publicly available data, as well as two newly sequenced pre-epidemic historical isolates from 1996, and a very early diverging ACME-negative NAE genome, to understand the pre-epidemic evolution of USA300. We use database mining techniques to emphasize genomes similar to pre-epidemic isolates, with the goal of reconstructing the early molecular evolution of the USA300 lineage. Phylogenetic analysis with these genomes confirms that the NAE and SAE USA300 lineages diverged from a most recent common ancestor around 1970 with high confidence, and it also pinpoints the independent acquisition events of the of the ACME and COMER loci with greater precision than in previous studies. We provide evidence for a North American origin of the USA300 lineage and identify multiple introductions of USA300 into South and North America. Notably, we describe a third major USA300 clade (the pre-epidemic branching clade; PEB1) consisting of both MSSA and MRSA isolates circulating around the world that diverged from the USA300 lineage prior to the establishment of the South and North American epidemics. We present a detailed analysis of specific sequence characteristics of each of the major clades, and present diagnostic positions that can be used to classify new genomes.

Urinary tract infection (UTI) is an extremely common infectious condition affecting people throughout the world. Increasing antibiotic resistance in pathogens causing UTI threatens our ability to continue to treat patients in the clinics. Urinary tract infection (UTI) is one of the most common infectious conditions affecting people in the United States and around the world. Our knowledge of the host-pathogen interaction during UTI caused by Gram-positive bacterial uropathogens is limited compared to that for Gram-negative pathogens. Here, we investigated whether copper and the primary copper-containing protein, ceruloplasmin, are mobilized to urine during naturally occurring UTI caused by Gram-positive uropathogens in patients. Next, we probed the role of copper resistance in the fitness of methicillin-resistant Staphylococcus aureus (MRSA) during experimental UTI in a murine model. Our findings demonstrate that urinary copper and ceruloplasmin content are elevated during UTI caused by Enterococcus faecalis , S. aureus , S. epidermidis , and S. saprophyticus . MRSA strains successfully colonize the urinary tract of female CBA mice with selective induction of inflammation in the kidneys but not the bladder. MRSA mutants lacking CopL, a copper-binding cell surface lipoprotein, and the ACME genomic region containing copL , exhibit decreased fitness in the mouse urinary tract compared to parental strains. Copper sensitivity assays, cell-associated copper and iron content, and bioavailability of iron during copper stress demonstrate that homeostasis of copper and iron is interlinked in S. aureus . Importantly, relative fitness of the MRSA mutant lacking the ACME region is further decreased in mice that receive supplemental copper compared to the parental strain. In summary, copper is mobilized to the urinary tract during UTI caused by Gram-positive pathogens, and copper resistance is a fitness factor for MRSA during UTI. IMPORTANCE Urinary tract infection (UTI) is an extremely common infectious condition affecting people throughout the world. Increasing antibiotic resistance in pathogens causing UTI threatens our ability to continue to treat patients in the clinics. Better understanding of the host-pathogen interface is critical for development of novel interventional strategies. Here, we sought to elucidate the role of copper in host- Staphylococcus aureus interaction during UTI. Our results reveal that copper is mobilized to the urine as a host response in patients with UTI. Our findings from the murine model of UTI demonstrate that copper resistance is involved in the fitness of methicillin-resistant S. aureus (MRSA) during interaction with the host. We also establish a critical link between adaptation to copper stress and iron homeostasis in S. aureus .

Methicillin-resistant Staphylococcus aureus (MRSA) poses a substantial threat to human health worldwide and evolves rapidly by acquiring mobile genetic elements, such as plasmids. Here we investigate how the copB - mco copper hypertolerance operon carried on a mobile genetic element contributes to the virulence potential of clinical isolates of MRSA. Copper is a key component of innate immune bactericidal defenses. Here we show that copper hypertolerance genes enhance the survival of S. aureus inside primed macrophages and in whole human blood. The copB and mco genes are carried by clinical isolates responsible for invasive infections across Europe, and more broadly among three successful clonal lineages of S. aureus . Our findings show that a gain of copper hypertolerance genes increases the resistance of MRSA to phagocytic killing by host immune cells and imply that acquisition of this mobile genetic element can contribute to the success of MRSA. Pathogens are exposed to toxic levels of copper during infection, and copper tolerance may be a general virulence mechanism used by bacteria to resist host defenses. In support of this, inactivation of copper exporter genes has been found to reduce the virulence of bacterial pathogens in vivo . Here we investigate the role of copper hypertolerance in methicillin-resistant Staphylococcus aureus (MRSA). We show that a copper hypertolerance operon ( copB-mco ), carried on a mobile genetic element (MGE), is prevalent in a collection of invasive S. aureus strains and more widely among clonal complex 22, 30, and 398 strains. The copB and mco genes encode a copper efflux pump and a multicopper oxidase, respectively. Isogenic mutants lacking copB or mco had impaired growth in subinhibitory concentrations of copper. Transfer of a copB-mco- carrying plasmid to a naive clinical isolate resulted in a gain of copper hypertolerance and enhanced bacterial survival inside primed macrophages. The copB and mco genes were upregulated within infected macrophages, and their expression was dependent on the copper-sensitive operon repressor CsoR. Isogenic copB and mco mutants were impaired in their ability to persist intracellularly in macrophages and were less resistant to phagocytic killing in human blood than the parent strain. The importance of copper-regulated genes in resistance to phagocytic killing was further elaborated using mutants expressing a copper-insensitive variant of CsoR. Our findings suggest that the gain of mobile genetic elements carrying copper hypertolerance genes contributes to the evolution of virulent strains of S. aureus that are better equipped to resist killing by host immune cells. IMPORTANCE Methicillin-resistant Staphylococcus aureus (MRSA) poses a substantial threat to human health worldwide and evolves rapidly by acquiring mobile genetic elements, such as plasmids. Here we investigate how the copB - mco copper hypertolerance operon carried on a mobile genetic element contributes to the virulence potential of clinical isolates of MRSA. Copper is a key component of innate immune bactericidal defenses. Here we show that copper hypertolerance genes enhance the survival of S. aureus inside primed macrophages and in whole human blood. The copB and mco genes are carried by clinical isolates responsible for invasive infections across Europe, and more broadly among three successful clonal lineages of S. aureus . Our findings show that a gain of copper hypertolerance genes increases the resistance of MRSA to phagocytic killing by host immune cells and imply that acquisition of this mobile genetic element can contribute to the success of MRSA.

Toxin production by Clostridioides difficile damages the colonic epithelium and leads to a robust inflammatory response. This disruption of the epithelial barrier markedly alters the nutritional landscape in the C. difficile- infected gut. The impact of toxin-mediated nutritional remodeling during C. difficile infection (CDI) on resident microbiota remains largely unexplored. One group of opportunistic pathogens, the enterococci, thrive during CDI, but it is unclear what strategies they employ to survive in this altered environment. Here, we demonstrate that Enterococcus faecalis , a heme auxotroph, takes advantage of C. difficile toxin-mediated damage to acquire host heme for enhanced fitness. Specifically, heme acquired from the C. difficile- infected gut is used by E. faecalis to populate a heme-dependent cytochrome and aerobically respire. This fitness advantage is specific to C. difficile toxin-mediated damage, as infection with a toxin-null strain of C. difficile does not provide E. faecalis with a fitness advantage. Finally, targeted disruption of the E. faecalis cytochrome ( cydABDC ) operon leads to a fitness defect in the C. difficile- infected gut. Together, this work demonstrates that C. difficile toxin remodels the gut ecosystem and improves the fitness of E. faecalis in a cydABDC -dependent manner. These data further highlight growing evidence of a cooperative partnership between C. difficile and enterococci that has implications on susceptibility to and severity of CDI. Clostridioides difficile and Enterococcus faecalis are two pathogens of great public health importance. Both bacteria colonize the human gastrointestinal tract where they are known to interact in ways that worsen disease outcomes. We show that the damage associated with C. difficile infection (CDI) releases nutrients that benefit E. faecalis . One particular nutrient, heme, allows E. faecalis to use oxygen to generate energy and grow better in the gut. Understanding the mechanisms of these interspecies interactions could inform therapeutic strategies for CDI.