Novel tricyclic antagonists of the prostaglandin D2 receptor DP2 with efficacy in a murine model of allergic rhinitis

The synthesis of a series of tricyclic antagonists for the prostaglandin D₂ receptor DP2 (CRTH2) is disclosed. The activities of the compounds were evaluated in a human DP2 binding assay and a human whole blood eosinophil shape change assay. Potential metabolic liabilities of the compounds were addressed through in vitro CYP studies. The lead compound was demonstrated to have efficacy in a mouse model of allergic rhinitis following oral dosing.     

Biceps brachii myoelectric and oxygenation changes during static and sinusoidal isometric exercises

Surface myoelectric signal changes occurring during sustained isometric contractions have been extensively studied with quantitative surface electromyography (sEMG) and are described by means of some sEMG global variables in time and frequency domain (such as the median power spectral frequency). Recently, the possibility of studying local muscle O₂ saturation during exercise using non-invasive methods has been enhanced thanks to the use of near-infrared spectroscopy (NIRS). The purpose of this work was to combine NIRS and sEMG techniques to analyze the relationship between modifications of sEMG parameters and the underlying metabolic status of the exercising biceps brachii muscle. This relationship was tested under different isometric contraction modalities, namely static (ST) at 20, 40, 60 and 80%MVC and sinusoidal (SIN) at 40 ± 20 and 60 ± 20%MVC. Results clearly indicated the presence of an initial fast phase of muscle O₂ desaturation followed by a slow phase, regardless of the contraction modality. Moreover, the initial rate of muscle O₂ desaturation was related to the level of force output (R = 0.92), but it was independent on the contraction modality (p < 0.05). Similarly, changes in sEMG parameters were related to force level (Conduction Velocity-CV vs. Force: R = 0.87; sEMG Median Frequency-MDF vs. Force: R = 0.86). The high correlation found between CV-MDF and Tissue Oxygenation Index (TOI) slope (R = 0.73 and 0.72, respectively) suggests a strong relationship between NIRS and sEMG data. This study indicates that muscle O₂ demand during isometric contractions from low to high force levels is influenced by the type of active motor units and not from the type of isometric exercise modality.     

Involvement of thiol-disulfide groups in the sensitivity of fully grown mouse oocytes to calcium-free medium

The lethality caused by calcium-free medium (CFM) to fully grown mouse oocytes significantly decreases if a disulfide reducing agent (dithiothreitol, reduced glutathione, or L-cysteine) is added to the medium. In this condition, most of the surviving oocytes do not spontaneously resume meiosis. We also show that the sulfhydryl content of fully grown oocytes, estimated by monobromobimane labeling, rapidly decreases during culture in CFM. The hypothesis is discussed that lethality of oocytes cultured in CFM may be a consequence of an alteration of thiol-disulfide balance.     

In vitro differentiation of germ cells from stem cells: a comparison between primordial germ cells and in vitro derived primordial germ cell-like cells

Stem cells are unique cell types capable to proliferate, some of them indefinitely, while maintaining the ability to differentiate into a few or any cell lineages. In 2003, a group headed by Hans R. Schöler reported that oocyte-like cells could be produced from mouse embryonic stem (ES) cells in vitro. After more than 10 years, where have these researches reached? Which are the major successes achieved and the problems still remaining to be solved? Although during the last years, many reviews have been published about these topics, in the present work, we will focus on an aspect that has been little considered so far, namely a strict comparison between the in vitro and in vivo developmental capabilities of the primordial germ cells (PGCs) isolated from the embryo and the PGC-like cells (PGC-LCs) produced in vitro from different types of stem cells in the mouse, the species in which most investigation has been carried out. Actually, the formation and differentiation of PGCs are crucial for both male and female gametogenesis, and the faithful production of PGCs in vitro represents the basis for obtaining functional germ cells.     

Unravelling physiological signatures of tomato bacterial wilt and xylem metabolites exploited by Ralstonia solanacearum

The plant pathogen Ralstonia solanacearum uses plant resources to intensely proliferate in xylem vessels and provoke plant wilting. We combined automatic phenotyping and tissue/xylem quantitative metabolomics of infected tomato plants to decipher the dynamics of bacterial wilt. Daily acquisition of physiological parameters such as transpiration and growth were performed. Measurements allowed us to identify a tipping point in bacterial wilt dynamics. At this tipping point, the reached bacterial density brutally disrupts plant physiology and rapidly induces its death. We compared the metabolic and physiological signatures of the infection with drought stress, and found that similar changes occur. Quantitative dynamics of xylem content enabled us to identify glutamine (and asparagine) as primary resources R. solanacearum consumed during its colonization phase. An abundant production of putrescine was also observed during the infection process and was strongly correlated with in planta bacterial growth. Dynamic profiling of xylem metabolites confirmed that glutamine is the favoured substrate of R. solanacearum. On the other hand, a triple mutant strain unable to metabolize glucose, sucrose and fructose appears to be only weakly reduced for in planta growth and pathogenicity.     

Polygenic score for neuroticism is related to sleep difficulties

Neuroticism, a broad trait measure of the tendency to experience negative emotions and vulnerability to stress, is consistently related to poor sleep quality. Less is known about potential pleiotropy in the genetic risk for high neuroticism and poor sleep. Therefore, the present study examined whether polygenic score (PGS) for neuroticism is related to sleep quality in two large samples of adults. In addition, depressive symptoms, anxiety and phenotypical neuroticism were tested as mediators in both samples. Participants were 8316 individuals aged from 50 to 101 years (mean age = 68.29, SD = 9.83) from the Health and Retirement Study, and 4973 individuals aged from 63 to 67 years (mean age = 64.30, SD = 0.68) from the Wisconsin Longitudinal Study. Participants from both samples were genotyped and answered questions on sleep quality. A higher PGS for neuroticism was related to lower sleep quality concurrently and over time in both samples. Anxiety, depressive symptoms and neuroticism mediated these relationships in the two samples. Although effect sizes were small, the present study provides replicable evidence that individuals with a higher genetic predisposition to experience negative emotions and distress are at risk of sleep difficulties.     

A new genus and two new species of dactylogyrid monogeneans from gills of Neotropical catfishes (Siluriformes: Doradidae and Loricariidae)

A new genus of dactylogyrid monogeneans (Ancyrocephalinae), Paracosmetocleithrum n. gen., is erected to accommodate P. trachydorasi n. sp. from Trachydoras paraguayensis (Siluriformes: Doradidae) in the Upper Paraná River basin, Brazil. The new genus differs from Neotropical dactylogyrids in the presence of a well-developed ornamentation in the middle portion of the ventral bar, and a sclerotized patch on the surface of the dorsal bar with an inconspicuous medial process that possesses two submedial projections arising from the tapered ends of this patch. In addition, Demidospermus rhinelepisi n. sp. is described from Rhinelepis aspera (Siluriformes: Loricariidae). The new species, which is the fifth species of the genus described from loricariids, can be differentiated from congeners by the possession of a sclerotized patch attached to the middle portion of the ventral bar, and by morphology of the accessory piece, which presents broad ends, tapering in the centre, rounded proximal end, distal end folding on both sides with folds extending to approximately ¾ of the accessory piece length. Molecular data on both new species are also provided and species composition of Demidospermus, recently revealed as polyphyletic by molecular studies including the present one, is discussed.