Combretazet-3 a novel synthetic cis-stable combretastatin-A4-azetidinone hybrid with enhanced stabilityand therapeutic efficacy in colon cancer

In recent years an extensive series of synthetic combretastatin A-4 (CA-4)-azetidinone (β-lactam) hybrids were designed and synthesised with a view to improve the stability, therapeutic efficacy and aqueous solubility of CA-4. Lead compounds containing a 3,4,5-trimethoxy aromatic ring at position 1 and a variety of substitution patterns at positions 3 and 4 of the β-lactam ring were screened in three adenocarcinoma-derived colon cancer cell lines (CT-26, Caco-2 and the CA-4 resistant cell line, HT-29). In both CT-26 and Caco-2 cells all β-lactam analogues analysed displayed potent therapeutic efficacy within the nanomolar range. Substitution of the ethylene bridge of CA-4 with the β-lactam ring together with the aforementioned aryl substitutions improved the therapeutic efficacy of CA-4 up to 300‑fold in the combretastatin refractory HT-29 cells. The lead compound combretazet-3 (CAZ-3); chemical name [4-(3-hydroxy-4-methoxyphenyl)-3-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one] demonstrated improved chemical stability together with enhanced therapeutic efficacy as compared with CA-4 whilst maintaining the natural biological properties of CA-4. Furthermore, CAZ-3 demonstrated significant tumour inhibition in a murine model of colon cancer. Our results suggest that combretastatin-azetidinone hybrids represent an effective novel therapy for the treatment of combretastatin resistant carcinomas

Large-scale phylogenomic analysis reveals the phylogenetic position of the problematic taxon Protocruzia and unravels the deep phylogenetic affinities of the ciliate lineages

The Ciliophora is one of the most studied protist lineages because of its important ecological role in the microbial loop. While there is an abundance of molecular data for many ciliate groups, it is commonly limited to the 18S ribosomal RNA locus. There is a paucity of data when it comes to availability of protein-coding genes especially for taxa that do not belong to the class Oligohymenophorea. To address this gap, we have sequenced EST libraries for 11 ciliate species. A supermatrix was constructed for phylogenomic analysis based on 158 genes and 42,158 characters and included 16 ciliates, four dinoflagellates and nine apicomplexans. This is the first multigene-based analysis focusing on the phylum Ciliophora. Our analyses reveal two robust superclades within the Intramacronucleata; one composed of the classes Spirotrichea, Armophorea and Litostomatea (SAL) and another with Colpodea and Oligohymenophorea. Furthermore, we provide corroborative evidence for removing the ambiguous taxon Protocruzia from the class Spirotrichea and placing it as incertae sedis in the phylum Ciliophora

Time-resolved infra-red studies of photo-excited porphyrins in the presence of nucleic acids and in HeLa tumour cells: insights into binding site and electron transfer dynamics

Cationic porphyrins based on the 5,10,15,20-meso-(tetrakis-4-N-methylpyridyl) core (TMPyP4) have been studied extensively over many years due to their strong interactions with a variety of nucleic acid structures, and their potential use as photodynamic therapeutic agents and telomerase inhibitors. In this paper, the interactions of metal-free TMPyP4 and Pt(II)TMPyP4 with guanine-containing nucleic acids are studied for the first time using time-resolved infrared spectroscopy (TRIR). In D2O solution (where the metal-free form exists as D2TMPyP4) both compounds yielded similar TRIR spectra (between 1450–1750 cm−1) following pulsed laser excitation in their Soret B-absorption bands. Density functional theory calculations reveal that vibrations centred on the methylpyridinium groups are responsible for the dominant feature at ca. 1640 cm−1. TRIR spectra of D2TMPyP4 or PtTMPyP4 in the presence of guanosine 5'-monophosphate (GMP), double-stranded {d(GC)5}2 or {d(CGCAAATTTGCG)}2 contain negative-going signals, ‘bleaches’, indicative of binding close to guanine. TRIR signals for D2TMPyP4 or PtTMPyP bound to the quadruplex-forming cMYC sequence {d(TAGGGAGGG)}2T indicate that binding occurs on the stacked guanines. For D2TMPyP4 bound to guanine-containing systems, the TRIR signal at ca. 1640 cm−1 decays on the picosecond timescale, consistent with electron transfer from guanine to the singlet excited state of D2TMPyP4, although IR marker bands for the reduced porphyrin/oxidised guanine were not observed. When PtTMPyP is incorporated into HeLa tumour cells, TRIR studies show protein binding with time-dependent ps/ns changes in the amide absorptions demonstrating TRIR's potential for studying light-activated molecular processes not only with nucleic acids in solution but also in biological cells

Become the best coach you can be: the role of coach training and coaching experience in workplace coaching quality and quality control

This paper explores whether coach training or coaching experience leads to better coaching quality and quality control. In two large studies, both coaches (N1 = 2267) and personnel managers who book coaches for their company (N2 = 754) answered questions about coaching quality and quality control. The results show that more coach training leads to not only a better self-perceived coaching quality (Study 1) but also a better other-perceived coaching-quality (Study 2); moreover, more coach training positively affects quality control. It is remarkable that coaching experience showed no significant relation regarding other-perceived coaching quality and quality control. Study 2 further revealed that references lead to more recommendations but not to a better coaching quality or quality control. Thus, coach training is an essential factor when selecting organizational coaches. Further research is needed to understand the impact of different approaches to coach trainings on coaching outcomes

Observation of the Bc+_\mathrm{c}^+ Meson in Pb-Pb and pp Collisions at sNN\sqrt{s_{\mathrm{NN}}} = 5.02 TeV and Measurement of its Nuclear Modification Factor

The B$_\mathrm{c}^+$ meson is observed for the first time in heavy ion collisions. Data from the CMS detector are used to study the production of the B$_\mathrm{c}^+$ meson in lead-lead (Pb-Pb) and proton-proton (pp) collisions at a center-of-mass energy per nucleon pair of $\sqrt{s_{\mathrm{NN}}}$ = 5.02 TeV , via the B$_\mathrm{c}^+$ → (J/ψ → μ$^+$μ$^−$)μ$^+$ν$_μ$ decay. The B$_\mathrm{c}^+$ nuclear modification factor, derived from the PbPb-to-pp ratio of production cross sections, is measured in two bins of the trimuon transverse momentum and of the PbPb collision centrality. The B$_\mathrm{c}^+$meson is shown to be less suppressed than quarkonia and most of the open heavy-flavor mesons, suggesting that effects of the hot and dense nuclear matter created in heavy ion collisions contribute to its production. This measurement sets forth a promising new probe of the interplay of suppression and enhancement mechanisms in the production of heavy-flavor mesons in the quark-gluon plasma

Measurement of W±^{±}γ differential cross sections in proton-proton collisions at s\sqrt{s} = 13 TeV and effective field theory constraints

Differential cross section measurements of W±γ production in proton-proton collisions at $\sqrt{s}$ =13  TeV are presented. The data set used in this study was collected with the CMS detector at the CERN LHC in 2016–2018 with an integrated luminosity of 138  fb−1. Candidate events containing an electron or muon, a photon, and missing transverse momentum are selected. The measurements are compared with standard model predictions computed at next-to-leading and next-to-next-to-leading orders in perturbative quantum chromodynamics. Constraints on the presence of TeV-scale new physics affecting the WWγ vertex are determined within an effective field theory framework, focusing on the O3W operator. A simultaneous measurement of the photon transverse momentum and the azimuthal angle of the charged lepton in a special reference frame is performed. This two-dimensional approach provides up to a factor of ten more sensitivity to the interference between the standard model and the O3W contribution than using the transverse momentum alone

Search for invisible decays of the Higgs boson produced via vector boson fusion in proton-proton collisions at s\sqrt{s} = 13 TeV

A search for invisible decays of the Higgs boson produced via vector boson fusion (VBF) has been performed with 101  fb$^{-1}$ of proton-proton collisions delivered by the LHC at $\sqrt{s}$ =13  TeV and collected by the CMS detector in 2017 and 2018. The sensitivity to the VBF production mechanism is enhanced by constructing two analysis categories, one based on missing transverse momentum and a second based on the properties of jets. In addition to control regions with Z and W boson candidate events, a highly populated control region, based on the production of a photon in association with jets, is used to constrain the dominant irreducible background from the invisible decay of a Z boson produced in association with jets. The results of this search are combined with all previous measurements in the VBF topology, based on data collected in 2012 (at $\sqrt{s}$ =8  TeV), 2015, and 2016, corresponding to integrated luminosities of 19.7, 2.3, and 36.3  fb$^{-1}$, respectively. The observed (expected) upper limit on the invisible branching fraction of the Higgs boson is found to be 0.18 (0.10) at the 95% confidence level, assuming the standard model production cross section. The results are also interpreted in the context of Higgs-portal models