Characteristics of Ramachandran maps of L-alanine diamides as computed by various molecular mechanics, semiempirical and ab initio MO methods. A search for primary standard of peptide conformational stability

The optimized geometries and relative energies obtained by four force field and two semi-empirical methods were compared with ab initio results computed for formyl-L-alaninamide. Not all methods yielded the same number of minimum energy conformers. Furthermore, while the optimized geometries of the conformers found were comparable, the computed relative energies varied substantially. Also, the force field calculations produced Ramachandran maps that did not even have the appearance of the ab initio Ramachandran map. Correlating the ab initio relative energies (Delta E) or free energy (Delta G) with the log of relative populations, In(p(x)/p(gamma L)), led to linear relationships from which four conformers deviated; two of them (alpha(L) and epsilon(L)) were overly destabilized and two of them (gamma(L) and gamma(D)) were over-stabilized. It is suggested that, after such deviations are corrected, a primary standard may be obtained that might be useful in further investigations related to force-field parametrization as well as protein folding. (C) 1998 Elsevier Science B.V. All rights reserved

Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial

BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck

A mathematical and computational review of Hartree-Fock SCF methods in Quantum Chemistry

We present here a review of the fundamental topics of Hartree-Fock theory in Quantum Chemistry. From the molecular Hamiltonian, using and discussing the Born-Oppenheimer approximation, we arrive to the Hartree and Hartree-Fock equations for the electronic problem. Special emphasis is placed in the most relevant mathematical aspects of the theoretical derivation of the final equations, as well as in the results regarding the existence and uniqueness of their solutions. All Hartree-Fock versions with different spin restrictions are systematically extracted from the general case, thus providing a unifying framework. Then, the discretization of the one-electron orbitals space is reviewed and the Roothaan-Hall formalism introduced. This leads to a exposition of the basic underlying concepts related to the construction and selection of Gaussian basis sets, focusing in algorithmic efficiency issues. Finally, we close the review with a section in which the most relevant modern developments (specially those related to the design of linear-scaling methods) are commented and linked to the issues discussed. The whole work is intentionally introductory and rather self-contained, so that it may be useful for non experts that aim to use quantum chemical methods in interdisciplinary applications. Moreover, much material that is found scattered in the literature has been put together here to facilitate comprehension and to serve as a handy reference.Comment: 64 pages, 3 figures, tMPH2e.cls style file, doublesp, mathbbol and subeqn package

Relationships between crop yield and weed time of emergence/removal: modelling and parameter stability across environments

Seventeen Italian experiments relating to maize, soyabean and durum wheat were used to analyse the variability of duration of tolerated competition (DTC) and weed-free period (WFP) curves across reasonably homogeneous areas. The data sets were analysed by regression analysis using four models relating yield loss to weed density, time of emergence and removal. These models differ in the way they account for the effect of time of weed removal on potential competitiveness. A sigmoidal relationship between these two variables appears necessary. The model with the best overall performance was then used to test the stability of the parameters that give the shape of the curve in relation to time of emergence and removal. This was done by comparing a full model with shape parameters specific to each experiment and a reduced model with a common set of parameters for all the experiments referring to a specific crop. For all three crops, the residual sum of squares of the reduced model did not increase significantly, indicating that, across tested environments, the yield loss caused by mixed weed infestations can be expressed by a single set of parameters relating weed competitivity to time of emergence and removal. For a given area, it should therefore be possible to predict yield loss on the basis of a quite limited set of experiments, thus greatly simplifying the development and use of decision support systems (DSS)

Macrofossil floras of the Latady Basin, Antarctic Peninsula

New collections of plant material from the Merrick and Sweeney Mountains provide further evidence of Jurassic floral diversity in the Antarctic Peninsula. Eighteen taxa are recognised, including sphenophytes (Equisetum), ferns (Cladophlebis, Sphenopteris, Coniopteris), Bennettitales (Otozamites, Zamites, Ptilophyllum, Dicytozamites, Williamsonia), conifers (Pagiophyllum, Brachyphyllum, Elatocladus), and other seed plants (Taeniopteris, Archangelskya, Pachypteris). Many of these species occur in floras from the Botany Bay Group (Early–Middle Jurassic), and other Late Jurassic to Early Cretaceous sites across the Antarctic Peninsula. The plant material from the Latady Basin occurs in two main associations with distinct floristic compositions that reflect local environmental and taphonomic conditions. The richest localities occur in the deltaic settings, where paleosoil and leaf litter layers are preserved. In contrast, relatively little plant material is found in the wholly marine units such as those from the Hauberg Mountains

New Marsileaceous Fossils from the Late Cretaceous of South America and a Reevaluation of Marsileaceaephyllum.

Herein we report new macrofossils and associated microfossils representing the aquatic fern family Marsileaceae from the Campanian to Maastrichtian Cañadón del Irupé locality, La Colonia Formation, Chubut Province, Argentina. The macrofossils include compound leaves, detached leaflets, and sporocarps. The venation of the leaflets is consistent with the diagnosis of Marsileaceaephyllum, which we argue is poorly defined. Consequently, the circumscription and diagnosis of Marsileaceaephyllum are emended in order to limit the taxon to include only leaves or rhizomes bearing leaves with four leaflets that most resemble those of Marsilea among extant genera of Marsileaceae. The Cañadón del Irupé leaves and leaflets are assigned to the new genus Mirasolita, erected to encompass compound leaves bearing two petiolulate leaflets, each leaflet having a reniform lamina and reticulate venation. The architecture of Mirasolita leaves and leaflets is distinct from that of leaves of any of the living marsileaceous genera. The stalked sporocarps are assigned to the new genus Lugiomarsiglia. They are attributed to Marsileaceae because each has a sclerenchymatous wall surrounding circular bodies interpreted as sporangia. Associated megaspores are assigned to Molaspora lobata, a geographically widespread, primarily Late Cretaceous dispersed spore taxon. The co-occurrence of Molaspora lobata with an extinct marsileaceous leaf form fits a pattern wherein Cretaceous Regnellidium-like megaspores are associated with or found in situ within marsileaceous macrofossils that display a variety of morphologies.Fil: Hermsen, Elizabeth. Ohio State University; Estados Unidos de América;Fil: Gandolfo, Maria A.. Cornell University; Estados Unidos de América;Fil: Cuneo, Nestor Ruben. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Museo Paleontologico Egidio Feruglio; Argentin