Prog imperfective drift in ancient Greek? Reconsidering eimi 'be' with present participle

In this paper, I reconsider the diachrony of the Ancient Greek periphrastic construction of eimi 'be' with present participle by means of Bertinetto’s recently proposed model for the development of progressive grams (a process called ‘PROG imperfective drift’). While Bertinetto’s proposal sheds new light on the diachronic development of the construction, at the same time the evidence from Ancient Greek brings to light the need for modification and further refinement of the model (most importantly with regard to the role of what I call the ‘stative’ function, next to the diachronic source(s) of the construction). I furthermore show that eimi with present participle never fully developed a (focalized) progressive function, which can be explained in terms of ‘constructional competition’

Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer.

Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.This research was partly funded by the Institute of Cancer Research and by grants from Sarcoma UK (to B.E.T. [14.2014] and P.H.H. [3.2014]), Kent Cancer Trust (to M.M.), Hilfe fuer Krebskranke Kinder Frankfurt e.V. and Frankfurter Stiftung fuer Krebskranke Kinder (to J.C.), CRUK-CI Core Grant (C14303/A17197), and S.H.D. Fellowship (Wellcome Trust/Royal Society [107609]) (to M.D.R.). B.E.T. was supported by an ICR fellowship

Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation

<p>Abstract</p> <p>Background</p> <p>The anti-epileptic drug valproic acid (VPA) has attracted attention as an anti-cancer agent.</p> <p>Methods</p> <p>The present study investigated effects of VPA exposure on histone deacetylase (HDAC) inhibition, cell growth, cell speed, and the degree of Erk1/2 phosphorylation in 10 cell lines (BT4C, BT4Cn, U87MG, N2a, PC12-E2, CSML0, CSML100, HeLa, L929, Swiss 3T3).</p> <p>Results</p> <p>VPA induced significant histone deacetylase (HDAC) inhibition in most of the cell lines, but the degree of inhibition was highly cell type-specific. Moreover, cell growth, motility and the degree of Erk1/2 phosphorylation were inhibited, activated, or unaffected by VPA in a cell type-specific manner. Importantly, no relationship was found between the effects of VPA on HDAC inhibition and changes in the degree of Erk1/2 phosphorylation, cell growth, or motility. In contrast, VPA-induced modulation of the MAPK pathway downstream of Ras but upstream of MEK (i.e., at the level of Raf) was important for changes in cell speed.</p> <p>Conclusions</p> <p>These results suggest that VPA can modulate the degree of Erk1/2 phosphorylation in a manner unrelated to HDAC inhibition and emphasize that changes in the degree of Erk1/2 phosphorylation are also important for the anti-cancer properties of VPA.</p

The periphrastic perfect in Ancient Greek: a diachronic mental space analysis

In the present article, I apply Fauconniers mental spaces theory to the diachronic analysis of the Ancient Greek periphrastic perfect. I argue that the periphrastic construction started out as a resultative perfect, with FOCUS and EVENT located in the same mental space. I show that, contrary to what is sometimes believed, the construction was not limited to a purely stative meaning, but underwent the cross-linguistically attested semantic shift from resultative to anterior, whereby an additional non-FOCUS EVENT-space was constructed. In fourth-century Classical Greek, we witness the further extension of the periphrastic construction with regard to semantics, morphology and discourse context. I close the article with some remarks on the possible aoristicisation of the periphrastic perfect

The effects of ethanol and silymarin treatment during gestation on spatial working memory.

BACKGROUND: Using a rat model we have found that the bioflavonoid silymarin (SY) ameliorates some of the negative consequences of in utero exposure to ethanol (EtOH). In the current study our aim was to determine if spatial working memory (SWM) was impaired in offspring whose mothers were maintained on a liquid diet containing EtOH during different gestational weeks. We also determined if SWM was altered with a concomitant administration of SY with EtOH during specific gestational weeks. METHODS: We provided pregnant Fischer/344 rats with liquid diets containing 35% EtOH derived calories (EDC) during specific weeks of the gestational period. A silymarin/phospholipid compound containing 29.8% silybin co-administered with EtOH was also administered during specific weeks of the gestational period. We tested SWM of the offspring with a radial arm maze on postnatal day (PND) 60. After testing the rats were sacrificed and their brains perfused for later analysis. RESULTS: We observed SWM deficits, as well as a significantly lower brain weight in female offspring born of mothers treated with EtOH during the third week of gestation in comparison to mothers treated during either the first or second weeks of gestation. Rats from any group receiving EtOH in co-administration with SY showed no significant deficits in SWM. CONCLUSION: EtOH treatment during the last week of gestation had the greatest impact on SWM. The addition of SY to the EtOH liquid diet appeared to ameliorate the EtOH-induced learning deficits

Preprotein mature domains contain translocase targeting signals that are essential for secretion

Secretory proteins are only temporary cytoplasmic residents. They are typically synthesized as preproteins, carrying signal peptides N-terminally fused to their mature domains. In bacteria secretion largely occurs posttranslationally through the membrane-embedded SecA-SecYEG translocase. Upon crossing the plasma membrane, signal peptides are cleaved off and mature domains reach their destinations and fold. Targeting to the translocase is mediated by signal peptides. The role of mature domains in targeting and secretion is unclear. We now reveal that mature domains harbor their own independent targeting signals (mature domain targeting signals [MTSs]). These are multiple, degenerate, interchangeable, linear or 3D hydrophobic stretches that become available because of the unstructured states of targeting-competent preproteins. Their receptor site on the cytoplasmic face of the SecYEG-bound SecA is also of hydrophobic nature and is located adjacent to the signal peptide cleft. Both the preprotein MTSs and their receptor site on SecA are essential for protein secretion. Evidently, mature domains have their own previously unsuspected distinct roles in preprotein targeting and secretion

Incidence of childhood leukaemia in the vicinity of nuclear sites in France, 1990–1998

Overall, 670 cases (O) of childhood leukaemia were diagnosed within 20 km of the 29 French nuclear installations between 1990 and 1998 compared to an expected number (E) of 729.09 cases (O/E=0.92, 95% confidence interval (CI)=[0.85-0.99]). Each of the four areas defined around the sites showed non significant deficits of cases (0-5 km: O=65, O/E=0.87, CI=[0.67-1.10]; 5-10 km: O=165, O/E=0.95, CI=[0.81-1.10]; 10-15 km: O=220, O/E=0.88, CI=[0.77-1.00]; 15-20 km: O=220, O/E=0.96, CI=[0.84-1.10]). There was no evidence of a trend in standardised incidence ratio with distance from the sites for all children or for any of the three age groups studied. Similar results were obtained when the start-up year of the electricity-generating nuclear sites and their electric nuclear power were taken into account. No evidence was found of a generally increased risk of childhood leukaemia around the 29 French nuclear sites under study during 1990-1998

Parent-Of-Origin Effects in Autism Identified through Genome-Wide Linkage Analysis of 16,000 SNPs

Autism is a common heritable neurodevelopmental disorder with complex etiology. Several genome-wide linkage and association scans have been carried out to identify regions harboring genes related to autism or autism spectrum disorders, with mixed results. Given the overlap in autism features with genetic abnormalities known to be associated with imprinting, one possible reason for lack of consistency would be the influence of parent-of-origin effects that may mask the ability to detect linkage and association.We have performed a genome-wide linkage scan that accounts for potential parent-of-origin effects using 16,311 SNPs among families from the Autism Genetic Resource Exchange (AGRE) and the National Institute of Mental Health (NIMH) autism repository. We report parametric (GH, Genehunter) and allele-sharing linkage (Aspex) results using a broad spectrum disorder case definition. Paternal-origin genome-wide statistically significant linkage was observed on chromosomes 4 (LOD(GH) = 3.79, empirical p<0.005 and LOD(Aspex) = 2.96, p = 0.008), 15 (LOD(GH) = 3.09, empirical p<0.005 and LOD(Aspex) = 3.62, empirical p = 0.003) and 20 (LOD(GH) = 3.36, empirical p<0.005 and LOD(Aspex) = 3.38, empirical p = 0.006).These regions may harbor imprinted sites associated with the development of autism and offer fruitful domains for molecular investigation into the role of epigenetic mechanisms in autism

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine

Background: More effective chemotherapies are urgently needed for bladder cancer, a major cause of morbidity and mortality worldwide. We therefore explored the efficacy of the combination of gemcitabine and AZD7762, a checkpoint kinase 1/2 (CHK1/2) inhibitor, for bladder cancer. Methods: Viability, clonogenicity, cell cycle distribution and apoptosis were assessed in urothelial cancer cell lines and various non-malignant urothelial cells treated with gemcitabine and AZD7762. DNA damage was assessed by ?H2A.X and 53-BP1 staining and checkpoint activation was followed by Western blotting. Pharmacological inhibition of CHK1 and CHK2 was compared to downregulation of either CHK1 or CHK2 using siRNAs. Results: Combined use of gemcitabine and AZD7762 synergistically reduced urothelial carcinoma cell viability and colony formation relative to either single treatment. Non-malignant urothelial cells were substantially less sensitive to this drug combination. Gemcitabine plus AZD7762 inhibited cell cycle progression causing cell accumulation in S-phase. Moreover, the combination induced pronounced levels of apoptosis as indicated by an increase in the fraction of sub-G1 cells, in the levels of cleaved PARP, and in caspase 3/7 activity. Mechanistic investigations showed that AZD7762 treatment inhibited the repair of gemcitabine-induced double strand breaks by interference with CHK1, since siRNA-mediated depletion of CHK1 but not of CHK2 mimicked the effects of AZD7762. Conclusions: AZD7762 enhanced sensitivity of urothelial carcinoma cells to gemcitabine by inhibiting DNA repair and disturbing checkpoints. Combining gemcitabine with CHK1 inhibition holds promise for urothelial cancer therapy