Validation of Horne and Ostberg morningness-eveningness questionnaire in a middle-aged population of French workers

As suggested by the authors, the Horne and Ostberg morning/evening questionnaire (MEQ) has never been adapted to evaluate a nonstudent population. The purpose of this study was to validate this MEQ in a sample of middle-aged workers by modifying only the cutoffs. It was administered in 566 non-shift-workers aged 51.2 to 3.2 years who presented no sleep disorders. According to the Home and Ostberg classification, the sample consisted of 62.1% morning type, 36.6% neither type, and 2.2% evening type. Multiple correspondence analysis, which determines the principal components, was performed on all MEQ items. Then an ascending hierarchical classification was applied to determine 3 clusters from these principal components. On the basis of these 3 clusters, new cutoffs were determined: evening types were considered as scoring under 53 and morning types above 64, thus giving 28.1% morning type, 51.7% neither type, and 20.2% evening type. As an external validation, eveningness was associated with later bedtime and waking-up time (more pronounced at the weekend), greater need for sleep, larger daily sleep debt, greater morning sleepiness, and ease of returning to sleep in the early morning. A positive correlation between age and morningness was again found. This study confirms that "owls" are not rare in a middle-aged sample. We conclude that this adapted MEQ could be useful when investigating age-related changes in sleep.     

MRI-based assessment of hip joint translations

To better understand movement limitations and, to some extent, the pathogenesis of osteoarthritis, it is important to quantitatively measure femoroacetabular translations to assess if any joint subluxation occurs. In this paper, we aim at measuring hip joint displacements from magnetic resonance images (MRI) based on a surface registration technique. Because this measurement is related to the location of the hip joint center (HJC), we investigate and compare different HJC estimation approaches based on patient-specific 3D bone models. We estimate the HJC based on a simulated circumduction while minimizing inter-articular distance changes. Measurements of femoroacetabular translations during low amplitude abductions ($80$ samples) and extreme flexions ($60$ samples) in female professional dancers, which is a population potentially exposed to femoroactebaluar impingements, do not show any significant subluxation.     

Synthesis and properties of new bolaform and macrocyclic galactose-based surfactants obtained by olefin metathesis

A series of galactose-based surfactants with various structures likely to display new interesting properties were synthesized. Four monocatenary surfactants were elaborated by microwave-assisted galactosylation of undecanol or 10-undecenol. These compounds were slightly soluble in water. Their tensioactive properties were determined at 45 degrees C. Olefin metathesis was used to synthesize the two single-chain bolaforms from undec-10-enyl galactopyranosides; two pseudomacrocyclic bolaforms were prepared by grafting two carbamates at O-4 and O-4' sugar positions of the single-chain bolaforms. These four surfactants are insoluble in water and undergo monolayer compression. Cyclization of these bolaforms by olefin metathesis led to macrocyclic surfactant analogues of archaeobacterial membrane components.     

Synthesis and cytotoxic activity of benzo[c][1,7] and [1,8]phenanthrolines analogues of nitidine and fagaronine

Fagaronine and nitidine are natural benzo[c] phenanthridinium alkaloids, which display antileukemic activity. Both act as topoisomerase I and topoisomerase II inhibitors. The objective of the present study was to prepare noncharged isosters of these compounds, with replacement of the aromatic A ring by a pyridine ring, present in other topoisomerase I inhibitors. Various 7,8- and 8,9-dimethoxy and metylenedioxy benzo[c][1,7] and [1,8]phenanthrolines were readily synthesized by benzyne-mediated cyclization of the corresponding substituted N-(2-halobenzyl)-5-quinolinamines or 5-isoquinolinamines. In both series, compounds bearing oxygenated substituents at positions 8 and 9 exhibited cytotoxic properties towards L1210 murine leukemia cells, which may result from their capacities to intercalate into DNA. Topoisomerase I inhibition was observed for all active compounds.     

Inbreeding dynamics in reintroduced, age-structured populations of highly fecund species

Reintroduction programs aim at reinstalling a self-sustained population into the wild via a period of supplementation with captive-bred individuals. This procedure can rapidly generate inbreeding among offspring because of the mating scheme and this inbreeding might be further enhanced by the reintroduction scenario. First, we used simulations to assess the consequences of breeding designs on mean inbreeding index F among offspring when the genetic diversity of breeders, the number and sex ratios of breeders, and the proportion of successful crosses vary. A high number of breeders, a balanced sex ratio, a high proportion of effective crosses and a genetically diverse source population generally contribute to lower F values. However, moderately high (≥20) numbers of breeders combined with all but the most biased sex ratios produced mean F values near minimal values. The variability in F was negligible in all parameter combinations except for a very small number of breeders (5) and very biased sex ratios (≤ 1M : 19F). We also simulated the long-term inbreeding dynamics in the introduced population under various demographic scenarios. Our main finding was that the annual number of introduced offspring is a decisive factor in establishing long-term F values in the supplemented population. Low supplementation levels (10²) quickly generated an almost completely inbred population whereas high levels (≥10⁴) produced stable F values close to that of the introduced offspring. Simulations were run based on the life history and specific demographics of the bloater (Coregonus hoyi), whose reintroduction in Lake Ontario is being considered.     

Rapid Species Diagnosis for Invasive Candidiasis Using Mass Spectrometry

Background

Matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI TOF-MS) allows the identification of most bacteria and an increasing number of fungi. The potential for the highest clinical benefit of such methods would be in severe acute infections that require prompt treatment adapted to the infecting species. Our objective was to determine whether yeasts could be identified directly from a positive blood culture, avoiding the 1–3 days subculture step currently required before any therapeutic adjustments can be made.

Methodology/Principal Findings

Using human blood spiked with Candida albicans to simulate blood cultures, we optimized protocols to obtain MALDI TOF-MS fingerprints where signals from blood proteins are reduced. Simulated cultures elaborated using a set of 12 strains belonging to 6 different species were then tested. Quantifiable spectral differences in the 5000–7400 Da mass range allowed to discriminate between these species and to build a reference database. The validation of the method and the statistical approach to spectral analysis were conducted using individual simulated blood cultures of 36 additional strains (six for each species). Correct identification of the species of these strains was obtained.

Conclusions/Significance

Direct MALDI TOF-MS analysis of aliquots from positive blood cultures allowed rapid and accurate identification of the main Candida species, thus obviating the need for sub-culturing on specific media. Subsequent to this proof-of-principle demonstration, the method can be extended to other clinically relevant yeast species, and applied to an adequate number of clinical samples in order to establish its potential to improve antimicrobial management of patients with fungemia.     

Association of Hemolytic Activity of Pseudomonas entomophila,a Versatile Soil Bacterium,with Cyclic Lipopeptide Production

Pseudomonas entomophila is an entomopathogenic bacterium that is able to infect and kill Drosophila melanogaster upon ingestion. Its genome sequence suggests that it is a versatile soil bacterium closely related to Pseudomonas putida. The GacS/GacA two-component system plays a key role in P. entomophila pathogenicity, controlling many putative virulence factors and AprA, a secreted protease important to escape the fly immune response. P. entomophila secretes a strong diffusible hemolytic activity. Here, we showed that this activity is linked to the production of a new cyclic lipopeptide containing 14 amino acids and a 3-C₁₀OH fatty acid that we called entolysin. Three nonribosomal peptide synthetases (EtlA, EtlB, EtlC) were identified as responsible for entolysin biosynthesis. Two additional components (EtlR, MacAB) are necessary for its production and secretion. The P. entomophila GacS/GacA two-component system regulates entolysin production, and we demonstrated that its functioning requires two small RNAs and two RsmA-like proteins. Finally, entolysin is required for swarming motility, as described for other lipopeptides, but it does not participate in the virulence of P. entomophila for Drosophila. While investigating the physiological role of entolysin, we also uncovered new phenotypes associated with P. entomophila, including strong biocontrol abilities.Pseudomonas entomophila is a recently isolated Pseudomonas species that is closely related to the saprophytic soil bacterium Pseudomonas putida. It was initially characterized as a natural pathogen of Drosophila (63). Indeed, P. entomophila was first isolated from flies sampled in Guadeloupe, and it is highly pathogenic for Drosophila larvae and adults. P. entomophila can also effectively kill members of other insect orders (e.g., Bombyx mori, Anopheles gambiae), which makes it a new entomopathogenic bacterium. Its ability to infect and kill Drosophila melanogaster very efficiently after ingestion makes it an appropriate model for the study of host-pathogen interactions (38, 62, 63).In order to unravel features contributing to the entomopathogenic properties of P. entomophila, its genome was sequenced. The results suggest that this strain is a ubiquitous, metabolically versatile bacterium that may colonize diverse habitats, including soil, rhizosphere, and aquatic systems, as shown for P. putida KT2440 (62). However, in contrast to the P. putida genome, the P. entomophila genome contains many genes that are predicted to be important for virulence toward insects. Notably, P. entomophila could secrete many degradative enzymes (proteases and lipases), putative toxins, and secondary metabolites (62). Similar factors have been shown to play a key role in the virulence of other entomopathogenic bacteria like Photorhabdus and Xenorhabdus sp. (27, 29).Insertional mutagenesis allowed the identification of several P. entomophila genes required to infect and/or kill Drosophila. This analysis demonstrated that P. entomophila virulence is under the control of the GacS/GacA two-component system (62, 63), a global regulatory system which is known to control secondary metabolite production, protein secretion, and pathogenic abilities in gammaproteobacteria (37, 65). Another study indicates that P. entomophila can counteract the Drosophila gut immune response as a result of the secretion of an abundant protease, AprA, which degrades antimicrobial peptides produced by gut epithelia and thereby promotes bacterial persistence (38). However, an AprA-deficient mutant remains virulent to some extent, indicating that P. entomophila virulence is multifactorial, AprA being one virulence factor among others.The secretion of virulence factors is a common mechanism employed by pathogens to compromise host defenses. Several entomopathogenic bacteria (e.g., Photorhabdus luminescens) secrete toxins that allow them to impair host function (8). The starting point of this study was the observation that, in contrast to several other Pseudomonas strains, P. entomophila secretes a strong diffusible hemolytic activity (which is also controlled by the Gac system). This raises the possibility of a link between this hemolytic activity and the pathogenicity of P. entomophila for Drosophila. Indeed, bacterial hemolysins are exotoxins that attack blood cell membranes and cause cell rupture by poorly defined mechanisms. It was conceivable that this hemolytic activity could be a readout for the ability of P. entomophila to damage the epithelial cells of the Drosophila gut, which plays a crucial role in its virulence (10, 33, 63).In this study, the P. entomophila hemolytic factor was identified as a cyclic lipopeptide (CLP) whose structure was elucidated. CLPs are versatile molecules with antimicrobial, cytotoxic, and surfactant properties that are produced by members of the genera Bacillus, Serratia, Burkholderia, and Pseudomonas (31, 41, 43, 50). They are produced by a ribosome-independent mechanism that utilizes multifunctional enzymes called nonribosomal peptide synthetases (NRPSs) (42, 59). These NRPSs are composed of repeated amino acid activation modules containing domains for condensation, aminoacyl adenylation, and thiolation. Modules are responsible for activation and incorporation of amino acids into the growing peptide. A large number of prokaryotic and some eukaryotic organisms synthesize peptide metabolites via this nonribosomal mechanism of biosynthesis (42, 47).Several genes involved in P. entomophila lipopeptide production were identified, three of them encoding NRPSs. The physiological role of this lipopeptide was also investigated, and it does not seem to play a role in the process of virulence towards Drosophila and Dictyostelium or in the P. entomophila biocontrol activity that was uncovered by this study. This suggests that the lifestyle of this newly identified bacterium is probably quite versatile and that lipopeptide production could be required only under specific circumstances.     

Design and synthesis of indole and tetrahydroisoquinoline hydantoin derivatives as human chymase inhibitors

The synthesis of new potential inhibitors of human chymase is described. Treatment of dihydroimidazo[1,5-a]indole and [1,5-b]isoquinoline-dione with thioaryl followed by oxidation gave the N-arylsulfonylmethyl of polycyclic hydantoin derivatives 3, 5 and 6.     

Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation

The energy requirements of the brain are very high, and tight regulatory mechanisms operate to ensure adequate spatial and temporal delivery of energy substrates in register with neuronal activity. Astrocytes-a type of glial cell-have emerged as active players in brain energy delivery, production, utilization, and storage. Our understanding of neuroenergetics is rapidly evolving from a "neurocentric" view to a more integrated picture involving an intense cooperativity between astrocytes and neurons. This review focuses on the cellular aspects of brain energy metabolism, with a particular emphasis on the metabolic interactions between neurons and astrocytes.     

ER–mitochondria contacts control surface glycan expression and sensitivity to killer lymphocytes in glioma stem‐like cells

Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem‐like cells (GSC) being more sensitive to cytotoxic lymphocyte‐mediated killing than glioma differentiated cells (GDC). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSCs modulates the ER–mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSCs displayed diminished ER–mitochondria contacts compared to GDCs. Forced ER–mitochondria contacts in GSCs increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. Therefore, mitochondrial morphology and dynamism dictate the ER–mitochondria contacts in order to regulate the surface expression of certain glycans and thus play a role in GSC recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma.