We study the dependence on the charm quark mass of the leading-order low-energy constants of the Delta S = 1 effective Hamiltonian, with the aim of elucidating the role of the charm mass scale in the ...Delta I = 1/2 rule for K arrow right pipi decay. To that purpose, finite-volume chiral perturbation theory predictions are matched to QCD simulations, performed in the quenched approximation with overlap fermions and mu = md = ms. Light quark masses range between a few MeV up to around one third of the physical strange mass, while charm masses range between mu and a few hundred MeV. Novel variance reduction techniques are used to obtain a signal for penguin contractions in correlation functions involving four-fermion operators. The important role played by the subtractions required to construct renormalized amplitudes for mc not = mu is discussed in detail. We find evidence that the moderate enhancement of the Delta I = 1/2 amplitude previously found in the GIM limit mc = mu increases only slightly as mc abandons the light quark regime. Hints of a stronger enhancement for even higher values of mc are also found, but their confirmation requires a better understanding of the subtraction terms.
Previous phylogenetic analyses of Ranunculales, which have mostly been focused on an individual family and were based on molecular data alone, have recovered three main clades within the order. ...However, support for relationships among these three clades was weak. Earlier hypotheses were often hampered by limited taxon sampling; to date less than one-tenth of the genera in the order have been sampled. In this study, we used a greatly enlarged taxon sampling (105 species, representing 99 genera of all seven families in the order). Our study is, furthermore, the first to employ morphology (65 characters) in combination with sequence data from four genomic regions, including plastid
rbcL,
matK and
trnL-F, and nuclear ribosomal 26S rDNA to reconstruct phylogenetic relationships within Ranunculales. Maximum parsimony and Bayesian inference were performed on the individual and combined data sets. Our analyses concur with those of previous studies, but in most cases provide stronger support and better resolution for relationships among the three main clades retrieved. The first, comprised solely of the monogeneric family Eupteleaceae, is the earliest-diverging lineage. The second clade is composed exclusively of taxa of Papaveraceae, which is sister to the third clade, the core Ranunculales, comprising the other five families of the order. Circaeasteraceae and Lardizabalaceae form a strongly supported clade.
Pteridophyllum is supported as sister to
Hypecoum, contradicting the viewpoint that the former is the earliest-diverging genus in Papaveraceae.
Glaucidium is basalmost in Ranunculaceae. Within this phylogenetic framework, the evolution of selected characters is inferred and diagnostic morphological characters at different taxonomic levels are identified and discussed. Based on both morphological and molecular evidence, a classification outline for Ranunculales is presented, including the proposal of two new subfamilies, Menispermoideae and Tinosporoideae in Menispermaceae and a new tribe, Callianthemeae, for the genus
Callianthemum (Ranunculaceae).
We discuss all-to-all quark propagator techniques in two (related) contexts within Lattice QCD: the computation of closed quark propagators, and applications to the so-called “eye diagrams” appearing ...in the computation of non-leptonic kaon decay amplitudes. Combinations of low-mode averaging and diluted stochastic volume sources that yield optimal signal-to-noise ratios for the latter problem are developed. We also apply a recently proposed probing algorithm to compute directly the diagonal of the inverse Dirac operator, and compare its performance with that of stochastic methods. At fixed computational cost the two procedures yield comparable signal-to-noise ratios, but probing has practical advantages which make it a promising tool for a wide range of applications in Lattice QCD.
The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards
. Nonetheless, our understanding of the complex relationship between age and cancer is ...still in its infancy
. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing
. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.
ABSTRACT
Objective
Three‐dimensional (3D) transperineal ultrasound has been shown to be a reliable and reproducible method for visualization of morphological changes in the female levator ani muscle. ...The aim of this study was to evaluate the relationship between persisting pelvic floor disorders 18–24 months after first delivery, biometric measurements of the pelvic floor and mode of delivery.
Methods
In this prospective observational study, we recruited on their second day after delivery 130 primiparous women. All were Caucasian and their pregnancies had been singleton with cephalic presentation. 3D transperineal ultrasound was performed, with standardized settings, on the second day (results published previously) and 18–24 months after delivery. Volumes were obtained at rest and on Valsalva maneuver and biometric measurements of the levator hiatus were determined in the axial plane. Obstetric and constitutional parameters were obtained from our clinical files and, 18–24 months after the delivery, a standardized questionnaire was used to evaluate persisting pelvic floor disorders. Ultrasound measurements at 18–24 months were compared according to clinical symptoms of pelvic floor disorders and mode of delivery, including a subgroup analysis of vaginal (spontaneous vs operative vaginal) and Cesarean (primary i.e. elective vs secondary i.e. after onset of labor) delivery groups.
Results
Seventy‐seven (59%) women had complete follow‐up at 18–24 months. Biometric measurements showed a significantly larger hiatal area in the vaginal delivery group than in the Cesarean section group 2 years after delivery (P < 0.01), whereas subgroup analysis within the vaginal and Cesarean delivery groups did not show significant differences. Although there was no statistical correlation between delivery mode and persisting stress urinary incontinence, women with persisting stress urinary incontinence 2 years after delivery had a larger hiatal area than did women without this clinical symptom (P < 0.01). There were no significant differences in hiatal dimensions in women with bladder urgency or dyspareunia.
Conclusions
3D transperineal ultrasound, which is easily accessible, can provide useful information on morphological changes of the female pelvic floor. Women with a spontaneous or operative vaginal first delivery had a significantly larger hiatal area and axial distension than did women whose first delivery was by Cesarean section, even 2 years after delivery. Performing 3D ultrasound after the first delivery may help to identify women at high risk for persisting pelvic floor disorders.
revised classification of the Apocynaceae s.l Endress, M.E. University of Zurich, Switzerland; Bruyns, P.V
The Botanical review,
2000, 20000101, 2000-1-00, Volume:
66, Issue:
1
Journal Article
Peer reviewed
Open access
The Asclepiadaceae, as traditionally defined, have repeatedly been shown to be an apomorphic derivative of the Apocynaceae. It has often been recommended that the Asclepiadaceae be subsumed within ...the Apocynaceae in order to make the latter monophyletic. To date, however, no comprehensive, unified classification has been established. Here we provide a unified classification for the Apocynaceae, which consists of 424 genera distributed among five subfamilies: Rauvolfioideae, Apocynoideae, Periplocoideae, Secamonoideae, and Asclepiadoideae. Keys to the subfamilies and tribes are provided, with lists of genera that (as far as we have been able to ascertain) are recognized in each tribe. /// Es wurde wiederholt festgestellt, dass die Asclepiadaceae in der traditionellen Umgrenzung ein apomorphes Derivat der Apocynaceae sind. Deshalb wurde oft vorgeschlagen, sie bei den Apocynaceae unterzubringen, damit die Apocynaceae eine monophyletische Gruppe darstellen. Bis jetzt wurde aber keine eingehende kombinierte Klassifikation publiziert. Hier stellen wir eine kombinierte Klassifikation vor für die Apocynaceae, mit 424 Gattungen, die in fünf Unterfamilien gegliedert sind: Rauvolfioideae, Apocynoideae, Periplocoideae, Secamonoideae und Asclepiadoideae. Schlüssel zu den Unterfamilien sowie den Triben werden gegeben. Die Gattungen, die zu jeder Tribus gehören (soweit bekannt) werden aufgelistet.
Sex, drugs and pupusas Morales, J. Francisco; Endress, Mary E.; Liede-Schumann, Sigrid
Taxon,
June 2017, Volume:
66, Issue:
3
Journal Article
Peer reviewed
Echiteae (Apocynaceae) comprises about 200 species divided among 19 genera, 16 of which are restricted to the Neotropics, the other 3 to the Paleotropics. There are two large genera, Prestonia and ...Parsonsia, in the Neotropics and Paleotropics, respectively, whereas three-fourths of the genera contain only one to four species. In this study DNA of 82 species was extracted and amplified for four molecular markers: three plastid (trnL intron + trnL-trnF intergenic spacer, rpl16 intron, matK + 5′/3′ trnK intron) and the nuclear ribosomal region ITS. The ingroup comprised 70 species from 17 genera in the tribe, and included representatives of all subtribes; the outgroup included 5 species each from the two putatively most closely related tribes, Odontadenieae and Mesechiteae, as well as 2 rooting species. Phylogenetic analyses were conducted using Bayesian inference and maximum likelihood approaches. Echiteae and four of its subtribes (Echitinae, Parsonsiinae, Peltastinae, Prestoniinae) as currently circumscribed were shown to be non-monophyletic. The fifth subtribe, Pentalinoninae, though monophyletic, does not belong to Echiteae; it was resolved as sister to a clade of Odontadenieae, where it fits better, since in both the characteristic secondary compounds are cardenolides. Prestonia and Temnadenia were resolved as polyphyletic, with P. riedelii grouped with Rhodocalyx and T. ornata nested within Prestonia. Fernaldia is nested within Echites and Peltastes is nested in Macropharynx. Fourteen genera are maintained. The new subtribe Laubertiinae is proposed, as are the combinations resulting from the merging of Fernaldia and Peltastes and the transfer of P. riedelii and T. ornata to Rhodocalyx and Prestonia, respectively. In the ancestors of Echiteae, we hypothesize that an evolutionary shift took place in which steroidal alkaloids and/or cardenolides, characteristic for apocynoids, were replaced by parsonsine-type pyrrolizidine alkaloids as the predominant defense compounds.
BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their ...potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents. We also uncovered functional similarities and differences among BRD2, BRD4, and BRD7. Although deletion of BRD2 enhances sensitivity to BBDIs, BRD7 loss leads to gain of TEAD-YAP chromatin binding and luminal features associated with BBDI resistance. Single-cell RNA-seq, ATAC-seq, and cellular barcoding analysis of BBDI responses in sensitive and resistant cell lines highlight significant heterogeneity among samples and demonstrate that BBDI resistance can be pre-existing or acquired.
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•Synthetic lethal and resistance interactions with BET inhibitors in TNBC•Multiple independent unbiased screens identify the same genes and pathways•CDK4/6 inhibitors and paclitaxel have top synergies with BET bromodomain inhibitors•Deletion of SNF/SWI complex components leads to BET inhibitor resistance
Shu et al. conducted integrated comprehensive molecular profiling and functional screens to identify synthetic lethal and resistance interactions with BET bromodomain inhibitors. CDK4 and BRD2 are top synthetic lethal hits, whereas deletion of BRD7 leads to resistance because of activation of genes suppressed by BET inhibitors in sensitive cells.
Cells are subjected to oxidative stress during the initiation and progression of tumors, and this imposes selective pressure for cancer cells to adapt mechanisms to tolerate these conditions. Here, ...we examined the dependency of cancer cells on glutathione (GSH), the most abundant cellular antioxidant. While cancer cell lines displayed a broad range of sensitivities to inhibition of GSH synthesis, the majority were resistant to GSH depletion. To identify cellular pathways required for this resistance, we carried out genetic and pharmacologic screens. Both approaches revealed that inhibition of deubiquitinating enzymes (DUBs) sensitizes cancer cells to GSH depletion. Inhibition of GSH synthesis, in combination with DUB inhibition, led to an accumulation of polyubiquitinated proteins, induction of proteotoxic stress, and cell death. These results indicate that depletion of GSH renders cancer cells dependent on DUB activity to maintain protein homeostasis and cell viability and reveal a potentially exploitable vulnerability for cancer therapy.
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•Most cancer cell lines are largely insensitive to GSH depletion•Deubiquitinases (DUBs) protect cancer cells upon inhibition of GSH synthesis•Inhibition of DUBs and GSH synthesis causes ER and proteotoxic stress and cell death•Combined targeting of DUBs and GSH blocks tumor growth
Tumor initiation and progression lead to highly oxidative stress conditions. Harris et al. show that upon glutathione depletion, cancer cells rely on deubiquitinating enzymes to maintain protein homeostasis and cell viability. Combined inhibition of deubiquitinases and glutathione synthesis leads to proteotoxic and ER stress and cell death.
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