Project description:Microorganisms can have a profound and varying effect on the chemical character of environments and, thereby, ecological health. Their capacity to consume or transform contaminants leads to contrasting outcomes, such as the dissipation of nutrient pollution via denitrification, the breakdown of spilled oil, or eutrophication via primary producer overgrowth. Recovering the genomes of organisms directly from the environment is useful to gain insights into resource usage, interspecies collaborations (producers and consumers), and trait acquisition. Microbial data can also be considered alongside the broader biological character of an environment through the co-recovery of eukaryotic DNA. The contributions of individual microorganisms (bacteria, archaea, and protists) to snapshots of ecosystem processes can be determined by integrating genomics with functional methods. This combined approach enables a detailed understanding of how microbial communities drive biogeochemical cycles, and although currently limited by scale, key attributes can be effectively extrapolated with lower-resolution methods to determine wider ecological relevance.
Project description:The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net.
Project description:PurposeThe identification of patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing.Experimental designWe apply this method to patients from two independent datasets: (i) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and (ii) TNBC patients who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973).ResultsWe find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score.ConclusionsOur analyses demonstrate that HRD can be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA1/2mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.
Project description:Mixture analysis is crucial in many areas of chemistry, and a wide variety of separation methods are in use. A common method for physical separation is high-performance liquid chromatography (HPLC), but resolution is a problem: chemically similar species coelute. An alternative approach is diffusion-ordered NMR spectroscopy (DOSY), in which the signals of mixture components are separated according to the diffusion coefficient. Again, separation is limited if species diffuse similarly or have overlap in their NMR spectra. Using the two techniques in combination can resolve both NMR spectra and the elution profiles of individual components, even where both techniques fail when used in isolation. Recording diffusion NMR data as a function of HPLC retention time gives a three-dimensional (3D) data set that can be analyzed using multiway statistical methods. PARAFAC analysis of diffusion NMR data measured from HPLC eluate for commercial "monoacetin" (a mixture of glycerol and its mono-, di-, and triacetates) yielded fully resolved and quantitative NMR spectra and elution profiles for all four components, whereas neither HPLC nor diffusion NMR applied independently was able to resolve the components.
Project description:Ultrafast cluster dynamics encompasses femtosecond nuclear dynamics, attosecond electron dynamics, and electron-nuclear dynamics in ultraintense laser fields (peak intensities 10(15)-10(20) W.cm(-2)). Extreme cluster multielectron ionization produces highly charged cluster ions, e.g., (C(4+)(D(+))(4))(n) and (D(+)I(22+))(n) at I(M) = 10(18) W.cm(-2), that undergo Coulomb explosion (CE) with the production of high-energy (5 keV to 1 MeV) ions, which can trigger nuclear reactions in an assembly of exploding clusters. The laser intensity and the cluster size dependence of the dynamics and energetics of CE of (D(2))(n), (HT)(n), (CD(4))(n), (DI)(n), (CD(3)I)(n), and (CH(3)I)(n) clusters were explored by electrostatic models and molecular dynamics simulations, quantifying energetic driving effects, and kinematic run-over effects. The optimization of table-top dd nuclear fusion driven by CE of deuterium containing heteroclusters is realized for light-heavy heteroclusters of the largest size, which allows for the prevalence of cluster vertical ionization at the highest intensity of the laser field. We demonstrate a 7-orders-of-magnitude enhancement of the yield of dd nuclear fusion driven by CE of light-heavy heteroclusters as compared with (D(2))(n) clusters of the same size. Prospective applications for the attainment of table-top nucleosynthesis reactions, e.g., (12)C(P,gamma)(13)N driven by CE of (CH(3)I)(n) clusters, were explored.
Project description:While national parochialism is commonplace, individual differences explain more variance in it than cross-national differences. Global consciousness (GC), a multi-dimensional concept that includes identification with all humanity, cosmopolitan orientation, and global orientation, transcends national parochialism. Across six societies (N = 11,163), most notably the USA and China, individuals high in GC were more generous allocating funds to the other in a dictator game, cooperated more in a one-shot prisoner's dilemma, and differentiated less between the ingroup and outgroup on these actions. They gave more to the world and kept less for the self in a multi-level public goods dilemma. GC profiles showed 80% test-retest stability over 8 months. Implications of GC for cultural evolution in the face of trans-border problems are discussed.
Project description:To examine mutational pathways that lead to CXCR4 use of HIV-1, we analyzed the genotypic and phenotypic characteristics of envelope sequences from a large panel of patient virus populations and individual clones containing different V3 mutations. Basic amino acid substitutions at position 11 were strong determinants of CXCR4-mediated entry but required multiple compensatory mutations to overcome associated reductions in infectivity. In contrast, basic amino acid substitutions at position 25, or substitutions at positions 6-8 resulting in the loss of a potential N-linked glycosylation site, contributed to CXCR4-mediated entry but required additional substitutions acting cooperatively to confer efficient CXCR4 use. Our assumptions, based upon examination of patient viruses, were largely confirmed by characterizing the coreceptor utilization of five distinct panels of isogenic envelope sequences containing V3 amino acid substitutions introduced by site-directed mutagenesis. These results further define the mutational pathways leading to CXCR4 use and their associated genetic barriers.
Project description:It is unclear whether naturally acquired immunity to Plasmodium falciparum results from the acquisition of antibodies to multiple, diverse antigens or to fewer, highly conserved antigens. Moreover, the specific antibody functions required for malaria immunity are unknown, and hence informative immunological assays are urgently needed to address these knowledge gaps and guide vaccine development. In this study, we investigated whether merozoite-opsonizing antibodies are associated with protection from malaria in a strain-specific or strain-transcending manner by using a novel field isolate and an immune plasma-matched cohort from Papua New Guinea with our validated assay of merozoite phagocytosis. Highly correlated opsonization responses were observed across the 15 parasite strains tested, as were strong associations with protection (composite phagocytosis score across all strains in children uninfected at baseline: hazard ratio of 0.15, 95% confidence interval of 0.04 to 0.63). Opsonizing antibodies had a strong strain-transcending component, and the opsonization of transgenic parasites deficient for MSP3, MSP6, MSPDBL1, or P. falciparum MSP1-19 (PfMSP1-19) was similar to that of wild-type parasites. We have provided the first evidence that merozoite opsonization is predominantly strain transcending, and the highly consistent associations with protection against diverse parasite strains strongly supports the use of merozoite opsonization as a correlate of immunity for field studies and vaccine trials. These results demonstrate that conserved domains within merozoite antigens targeted by opsonization generate strain-transcending immune responses and represent promising vaccine candidates.
Project description:The enigmatic observation that the rapidly evolving influenza A (H3N2) virus exhibits, at any given time, a limited standing genetic diversity has been an impetus for much research. One of the first generative computational models to successfully recapitulate this pattern of consistently constrained diversity posits the existence of a strong and short-lived strain-transcending immunity. Building on that model, we explored a much broader set of scenarios (parameterizations) of a transient strain-transcending immunity, ran long-term simulations of each such scenario, and assessed its plausibility with respect to a set of known or estimated influenza empirical measures. We evaluated simulated outcomes using a variety of measures, both epidemiological (annual attack rate, epidemic duration, reproductive number, and peak weekly incidence), and evolutionary (pairwise antigenic diversity, fixation rate, most recent common ancestor, and kappa, which quantifies the potential for antigenic evolution). Taking cumulative support from all these measures, we show which parameterizations of strain-transcending immunity are plausible with respect to the set of empirically derived target values. We conclude that strain-transcending immunity which is milder and longer lasting than previously suggested is more congruent with the observed short- and long-term behavior of influenza.