Triaminotriazine DNA helicase inhibitors with antibacterial activity

Screening of a chemical library in a DNA helicase assay involving the Pseudomonas aeruginosa DnaB helicase provided a triaminotriazine inhibitor with good antibacterial activity but associated cytotoxicity toward mammalian cells. Synthesis of analogs provided a few inhibitors that retained antibacterial activity and demonstrated a significant reduction in cytotoxicity. The impact of serum and initial investigations toward a mode of action highlight several features of this class of compounds as antibacterials.     

Has the kouprey (Bos sauveli Urbain, 1937) been domesticated in Cambodia?

The kouprey (Bos sauveli Urbain, 1937) is a very rare bovid species of Cambodia, which may be extinct in the wild, as no living specimen has been observed for a long time. Here, we describe a complete taxidermy mount, which presents astonishing morphological similarities with the kouprey. The animal was mounted in 1871 at the National Museum of Natural History in Paris, where it was referenced as No. 1871-576. It was deposited at the Natural History Museum of Bourges, France, in 1931, where it is still conserved today. To clarify the taxonomic status of the specimen of Bourges, DNA was extracted from a piece of bone taken on the mandible, and two different fragments of the mitochondrial cytochrome b gene were independently amplified and sequenced. The phylogenetic analyses show that the specimen of Bourges is robustly associated with the holotype of the kouprey, and that both are related to other wild species of Bos found in Indochina, i.e., banteng (B. javanicus) and gaur (B. frontalis). Because of doubts for sexing the animal, we applied a molecular test based on the PCR amplification of a DNA fragment specific to the Y chromosome. The results indicate that the specimen of Bourges is a male. The comparisons with male kouprey previously described in the literature reveal important differences concerning the body size, general coloration and horns. As these differences involve phenotypic traits that are strongly selected in case of domestication, we suggest that the specimen of Bourges was a domestic ox. This implies therefore that the kouprey may have been domesticated in Cambodia, and that several extant local races may be directly related to the kouprey.     

Nucleoside Modifications Affect the Structure and Stability of the Anticodon of tRNALys,3

Abstract

NMR spectroscopy was used to determine the solution structures of RNA oligonucleotides comprising the anticodon domain of tRNA^Lys,3. The structural effects of the pseudouridine modification at position 39 were investigated and are well correlated with changes in thermodynamic parameters. The loop conformation differs from that seen in tRNA^Phe and provides an explanation of the critical role of modification in this tRNA.     

Pharmacological targeting of the ephrin receptor kinase signalling by GLPG1790 in vitro and in vivo reverts oncophenotype,induces myogenic differentiation and radiosensitizes embryonal rhabdomyosarcoma cells

Background

EPH (erythropoietin-producing hepatocellular) receptors are clinically relevant targets in several malignancies. This report describes the effects of GLPG1790, a new potent pan-EPH inhibitor, in human embryonal rhabdomyosarcoma (ERMS) cell lines.

Methods

EPH-A2 and Ephrin-A1 mRNA expression was quantified by real-time PCR in 14 ERMS tumour samples and in normal skeletal muscle (NSM). GLPG1790 effects were tested in RD and TE671 cell lines, two in vitro models of ERMS, by performing flow cytometry analysis, Western blotting and immunofluorescence experiments. RNA interfering experiments were performed to assess the role of specific EPH receptors. Radiations were delivered using an x-6 MV photon linear accelerator. GLPG1790 (30 mg/kg) in vivo activity alone or in combination with irradiation (2 Gy) was determined in murine xenografts.

Results

Our study showed, for the first time, a significant upregulation of EPH-A2 receptor and Ephrin-A1 ligand in ERMS primary biopsies in comparison to NSM. GLPG1790 in vitro induced G1-growth arrest as demonstrated by Rb, Cyclin A and Cyclin B1 decrease, as well as by p21 and p27 increment. GLPG1790 reduced migratory capacity and clonogenic potential of ERMS cells, prevented rhabdosphere formation and downregulated CD133, CXCR4 and Nanog stem cell markers. Drug treatment committed ERMS cells towards skeletal muscle differentiation by inducing a myogenic-like phenotype and increasing MYOD1, Myogenin and MyHC levels. Furthermore, GLPG1790 significantly radiosensitized ERMS cells by impairing the DNA double-strand break repair pathway. Silencing of both EPH-A2 and EPH-B2, two receptors preferentially targeted by GLPG1790, closely matched the effects of the EPH pharmacological inhibition. GLPG1790 and radiation combined treatments reduced tumour mass by 83% in mouse TE671 xenografts.

Conclusions

Taken together, our data suggest that altered EPH signalling plays a key role in ERMS development and that its pharmacological inhibition might represent a potential therapeutic strategy to impair stemness and to rescue myogenic program in ERMS cells.

     

Adapting test timing to the sleep-wake schedule: effects on diurnal neurobehavioral performance changes in young evening and older morning chronotypes

The synchrony effect refers to the beneficial impact of temporal matching between the timing of cognitive task administration and preferred time-of-day for diurnal activity. Aging is often associated with an advance in sleep-wake timing and concomitant optimal performance levels in the morning. In contrast, young adults often perform better in the evening hours. So far, the synchrony effect has been tested at fixed clock times, neglecting the individual's sleep-wake schedule and thus introducing confounds, such as differences in accumulated sleep pressure or circadian phase, which may exacerbate synchrony effects. To probe this hypothesis, the authors tested older morning and young evening chronotypes with a psychomotor vigilance and a Stroop paradigm once at fixed morning and evening hours and once adapting testing time to their preferred sleep-wake schedule in a within-subject design. The authors observe a persistence of synchrony effects for overall median reaction times during a psychomotor vigilance task, even when testing time is adapted to the specific individual's sleep-wake schedule. However, data analysis also indicates that time-of-day modulations are weakened under those conditions for incongruent trials on Stroop performance and the slowest reaction times on the psychomotor vigilance task. The latter result suggests that the classically observed synchrony effect may be partially mediated by a series of parameters, such as differences in socio-professional timing constraints, the amount of accumulated sleep need, or circadian phase, all leading to differential arousal levels at testing.     

Professional exposure to goats increases the risk of pneumonic-type lung adenocarcinoma: results of the IFCT-0504-Epidemio study

Pneumonic-type lung adenocarcinoma (P-ADC) represents a distinct subset of lung cancer with specific clinical, radiological, and pathological features. Given the weak association with tobacco-smoking and the striking similarities with jaagsiekte sheep retrovirus (JSRV)-induced ovine pulmonary adenocarcinoma, it has been suggested that a zoonotic viral agent infecting pulmonary cells may predispose to P-ADC in humans. Our objective was to explore whether exposure to domestic small ruminants may represent a risk factor for P-ADC. We performed a multicenter case-control study recruiting patients with P-ADC as cases and patients with non-P-ADC non-small cell lung cancer as controls. A dedicated 356-item questionnaire was built to evaluate exposure to livestock. A total of 44 cases and 132 controls were included. At multivariate analysis, P-ADC was significantly more associated with female gender (Odds-ratio (OR)?=?3.23, 95% confidence interval (CI): 1.32-7.87, p?=?0.010), never-smoker status (OR?=?3.57, 95% CI: 1.27-10.00, p?=?0.015), personal history of extra-thoracic cancer before P-ADC diagnosis (OR?=?3.43, 95% CI: 1.10-10.72, p?=?0.034), and professional exposure to goats (OR?=?5.09, 95% CI: 1.05-24.69, p?=?0.043), as compared to other subtypes of lung cancer. This case-control suggests a link between professional exposure to goats and P-ADC, and prompts for further epidemiological evaluation of potential environmental risk factors for P-ADC.     

An axiomatic method for goal-dependent allocation in life cycle assessment

The International Journal of Life Cycle Assessment - How to apply allocation in an life cycle assessment (LCA) is a long-running and controversial debate. Consensus seems to exist on the fact that...     

On the causes of trends in the seasonal amplitude of atmospheric CO2

No consensus has yet been reached on the major factors driving the observed increase in the seasonal amplitude of atmospheric CO₂ in the northern latitudes. In this study, we used atmospheric CO₂ records from 26 northern hemisphere stations with a temporal coverage longer than 15 years, and an atmospheric transport model prescribed with net biome productivity (NBP) from an ensemble of nine terrestrial ecosystem models, to attribute change in the seasonal amplitude of atmospheric CO₂. We found significant (p < .05) increases in seasonal peak‐to‐trough CO₂ amplitude (AMP_P‐T) at nine stations, and in trough‐to‐peak amplitude (AMP_T‐P) at eight stations over the last three decades. Most of the stations that recorded increasing amplitudes are in Arctic and boreal regions (>50°N), consistent with previous observations that the amplitude increased faster at Barrow (Arctic) than at Mauna Loa (subtropics). The multi‐model ensemble mean (MMEM) shows that the response of ecosystem carbon cycling to rising CO₂ concentration (eCO₂) and climate change are dominant drivers of the increase in AMP_P‐T and AMP_T‐P in the high latitudes. At the Barrow station, the observed increase of AMP_P‐T and AMP_T‐P over the last 33 years is explained by eCO₂ (39% and 42%) almost equally than by climate change (32% and 35%). The increased carbon losses during the months with a net carbon release in response to eCO₂ are associated with higher ecosystem respiration due to the increase in carbon storage caused by eCO₂ during carbon uptake period. Air‐sea CO₂ fluxes (10% for AMP_P‐T and 11% for AMP_T‐P) and the impacts of land‐use change (marginally significant 3% for AMP_P‐T and 4% for AMP_T‐P) also contributed to the CO₂ measured at Barrow, highlighting the role of these factors in regulating seasonal changes in the global carbon cycle.