miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response

Although there is evidence that redox regulation has an essential role in malignancies, its impact on tumor prognosis remains unclear. Here we show crosstalk between oxidative stress and the miR-200 family of microRNAs that affects tumorigenesis and chemosensitivity. miR-141 and miR-200a target p38α and modulate the oxidative stress response. Enhanced expression of these microRNAs mimics p38α deficiency and increases tumor growth in mouse models, but it also improves the response to chemotherapeutic agents. High-grade human ovarian adenocarcinomas that accumulate miR-200a have low concentrations of p38α and an associated oxidative stress signature. The miR200a-dependent stress signature correlates with improved survival of patients in response to treatment. Therefore, the role of miR-200a in stress could be a predictive marker for clinical outcome in ovarian cancer. In addition, although oxidative stress promotes tumor growth, it also sensitizes tumors to treatment, which could account for the limited success of antioxidants in clinical trials.     

Infestation of the invasive mollusc <Emphasis Type="Italic">Crepidula fornicata</Emphasis> by the native shell borer <Emphasis Type="Italic">Cliona celata</Emphasis>: a case of high parasite load without detrimental effects

The temporal prevalence of the widespread boring sponge Cliona celata and its effects were analysed in a population of the invasive mollusc Crepidula fornicata. This mollusc produces extra shell material when infested with the endolithic sponge, suggesting that infestation may be detrimental for C. fornicata growth and/or reproduction. For 37 months, size, sex, female reproductive status and sponge-infestation stage were recorded for 300 individuals sampled every month in the Bay of Morlaix (France). In the 12,049 individuals examined, the prevalence of C. celata was high with a monthly average of 43.1% of the individuals hosting the sponge. The relative proportion of heavily infested individuals generally increased over time. Nevertheless, a cyclic decrease occurred every 10 months, suggesting putative episodes of mortality of heavily infested individuals. The gregarious behaviour of the mollusc seemed to promote the high prevalence of the sponge, which may propagate through contact between neighbouring C. fornicata individuals. Due to the sex-size relationship in protandrous C. fornicata, females were far more infested than males. We did not find evidence for a cost of producing extra shell material on somatic growth or on female fertility, and the boring sponge is unlikely to substantially affect the sex-change patterns in C. fornicata. The limited effects of the endolithic sponge on C. fornicata contrasts with the documented damage to some local species, including commercially exploited shellfish, suggesting that C. fornicata may alter the infestation dynamics in the surrounding native community. Dedicated studies are now needed to investigate the extent and mechanisms of these species interactions.     

Mixed Magnetism for Refrigeration and Energy Conversion

The efficient coupling between lattice degrees of freedom and spin degrees of freedom in magnetic materials can be used for refrigeration and energy conversion. This coupling is enhanced in materials exhibiting the giant magnetocaloric effect. First principle electronic structure calculations on hexagonal MnFe(P, Si) reveal a new form of magnetism: the coexistence of strong and weak magnetism in alternate atomic layers. The weak magnetism of Fe layers (disappearance of local magnetic moments at the Curie temperature) is responsible for a strong coupling with the crystal lattice while the strong magnetism in adjacent Mn‐layers ensures Curie temperatures high enough to enable operation at and above room temperature. Varying the composition on these magnetic sublattices gives a handle to tune the working temperature and to achieve a strong reduction of the undesired thermal hysteresis. In this way we design novel materials based on abundantly available elements with properties matched to the requirements of an efficient refrigeration or energy‐conversion cycle.     

Nucleosome-remodelling machines and other molecular motors observed at the single-molecule level

Through its capability to transiently pack and unpack our genome, chromatin is a key player in the regulation of gene expression. Single-molecule approaches have recently complemented conventional biochemical and biophysical techniques to decipher the complex mechanisms ruling chromatin dynamics. Micromanipulations with tweezers (magnetic or optical) and imaging with molecular microscopy (electron or atomic force) have indeed provided opportunities to handle and visualize single molecules, and to measure the forces and torques produced by molecular motors, along with their effects on DNA or nucleosomal templates. By giving access to dynamic events that tend to be blurred in traditional biochemical bulk experiments, these techniques provide critical information regarding the mechanisms underlying the regulation of gene activation and deactivation by nucleosome and chromatin structural changes. This minireview describes some single-molecule approaches to the study of ATP-consuming molecular motors acting on DNA, with applications to the case of nucleosome-remodelling machines.     

Predictive integration of gene functional similarity and co-expression defines treatment response of endothelial progenitor cells

Background  

Endothelial progenitor cells (EPCs) have been implicated in different processes crucial to vasculature repair, which may offer the basis for new therapeutic strategies in cardiovascular disease. Despite advances facilitated by functional genomics, there is a lack of systems-level understanding of treatment response mechanisms of EPCs. In this research we aimed to characterize the EPCs response to adenosine (Ado), a cardioprotective factor, based on the systems-level integration of gene expression data and prior functional knowledge. Specifically, we set out to identify novel biosignatures of Ado-treatment response in EPCs.     

113Cd nmr study of the metal cluster structure of human liver metallothionein

Cadmium-113 nuclear magnetic resonance (¹¹³Cd nmr) was used to elucidate the structural properties of the cadmium binding sites in human liver metallothionein. The isotopically labeled ¹¹³Cd-metallothionein was prepared by the in vitro exchange of the native metals (greater than 94% zinc) for ¹¹³CdCl₂ during isolation. The two isoproteins, MT-1 and MT-2, showed ¹¹³Cd nmr resonances in the chemical shift range 610–670 ppm. The multiplet structure of the resonances is due to two bond scalar interactions between adjacent ¹¹³Cd ions linked by cysteine thiolate ligands. Homonuclear ¹¹³Cd decoupling experiments allowed the determination of the metal cluster structure, which, similar to the rabbit liver metallothionein, consists of a four- and a three-metal cluster designated cluster A and cluster B, respectively. Chemical shift similarities in the ¹¹³Cd nmr spectra of the human, rabbit and calf liver MT-1 and MT-2 are observed, especially for cluster A. Small variations in chemical shifts are explained in terms of differences in the primary structure between the two human isoproteins.     

Modulation of β-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family

Selenium is an essential micronutrient that function through selenoproteins. Selenium deficiency results in lower concentrations of selenium and selenoproteins. The brain maintains it's selenium better than other tissues under low-selenium conditions. Recently, the selenium-containing protein selenoprotein P (Sepp) has been identified as a possible transporter of selenium. The targeted disruption of the selenoprotein P gene (Sepp1) results in decreased brain selenium concentration and neurological dysfunction, unless selenium intake is excessive However, the effect of selenoprotein P deficiency on the processes of memory formation and synaptic plasticity is unknown. In the present studies Sepp1(-/-) mice and wild type littermate controls (Sepp1(+/+)) fed a high-selenium diet (1 mg Se/kg) were used to characterize activity, motor coordination, and anxiety as well as hippocampus-dependent learning and memory. Normal associative learning, but disrupted spatial learning was observed in Sepp1(-/-) mice. In addition, severe alterations were observed in synaptic transmission, short-term plasticity and long-term potentiation in hippocampus area CA1 synapses of Sepp1(-/-) mice on a 1 mg Se/kg diet and Sepp1(+/+) mice fed a selenium-deficient (0 mg Se/kg) diet. Taken together, these data suggest that selenoprotein P is required for normal synaptic function, either through presence of the protein or delivery of required selenium to the CNS.     

Hypoxic alterations of cortisol circadian rhythm in man after simulation of a long duration flight

Fatigue is often reported after long duration flights. Mild hypobaric hypoxia caused by pressurisation may be involved in this effect through disruption of circadian rhythms, independently of the number of time zones crossed. In this controlled crossover study, we assessed the effects of two levels of hypoxia equivalent to 8000 and 12,000 ft on the circadian rhythm of plasma cortisol, a marker of the circadian time structure. Sixteen healthy young male volunteers (23-39 years) were exposed in a hypobaric chamber for 8 h (08:00-16:00 h) to 8000 ft, followed 4 weeks later to 12,000 ft. Plasma cortisol was assayed during two 24-h cycles (control and hypoxic exposure) every 2h in all subjects. We found a significant change in the pattern of cortisol secretion during both hypoxic exposures, with an initial fall in cortisol followed by a transient rebound, whereas the phase and the 24-h mean level remained unchanged. The change in cortisol pattern followed the alterations in autonomic balance assessed by heart rate variability (HRV) spectral analysis. The normalised high frequencies and the low-to-high frequencies ratio showed a significant shift toward sympathetic dominance with some differences in time course for both altitudes studied. HRV analysis improved the interpretation of cortisol 24-h profiles. Our data, which strongly suggest that prolonged mild hypoxia alters the expression of cortisol circadian rhythm, should be taken into account to interpret secretory rhythm changes after transmeridian flights.     

Efficient production of Clostridium botulinum exotoxin C3 in bacteria: a screening method to optimize production yields

Clostridium botulinum exoenzyme C3 is responsible for the inactivation of members of the Rho GTPase family that are implicated in actin-cytoskeleton reorganization. This property has been extensively used in the field to investigate the functionality of the Rho GTPases. However, systematic analysis of Rho GTPase functions requires large amounts of such inhibitors and consequently an optimization of the production yield of these proteins. Bacterial production of soluble proteins often requires a refolding step that noticeably affects the production yields and necessitates additional experiments to verify functional activity. This is particularly true for TAT-C3, the production yields of which are generally low. In this report, we describe a rapid and efficient method for the production of soluble C3 exoenzyme developed by screening a collection of bacterial strains. The recombinant C3 protein was fused to the TAT protein-transduction domain from HIV, to allow protein delivery into cells, and to a hexahistidine tag, that permitted purification by Nickel affinity chromatography. We have demonstrated the production of large amounts of soluble and functional protein using the bacterial strain AD494 (DE3)pLysS. This rapid and efficient method for the production of soluble C3 exoenzyme could also be useful for the production of other proteins with solubility problems.