Pathological and immunological evaluation of different regimens of praziquantel treatment in a mouse model of Schistosoma mansoni infection

BackgroundOne of the considerable challenges of schistosomiasis chemotherapy is the inefficacy of praziquantel (PZQ) at the initial phase of the infection. Immature schistosomes are not susceptible to PZQ at the curative dose. Here, we investigated the efficacy of different PZQ regimens administered during the initial stage of Schistosoma mansoni infection in mice.Methodology/Principal findingsTwo months-old mice were individually infected with 80 S. mansoni cercariae and divided into one infected-untreated control group (IC) and four PZQ-treated groups: PZQ at 100 mg/kg/day for five consecutive days (group PZQ1), PZQ at 100 mg/kg/day for 28 days (group PZQ2), PZQ at 18 mg/kg/day for 28 days (group PZQ3) and a single dose of PZQ at 500 mg/kg (group PZQ4). The treatment started on day one post-infection (p.i), and each group of mice was divided into two subgroups euthanized on day 36 or 56 p.i, respectively. We determined the mortality rate, the parasitological burden, the hepatic and intestinal granulomas, the serum levels of Th-1, Th-2, and Th-17 cytokines, and gene expression. The treatment led to a significant (p < 0.001) reduction of worm burden and egg counts in the intestine and liver in groups PZQ2 and PZQ3. On 56^th day p.i, there was a significant reduction (p < 0.001) of the number and volume of the hepatic granulomas in groups PZQ2 and PZQ3 compared to group PZQ1 or PZQ4. Moreover, in group PZQ3, the serum levels of IFN-γ, TNF-α, IL-13, and IL-17 and their liver mRNA expressions were significantly reduced while IL-10 and TGF-β gene expression significantly increased. The highest mortality rate (81.25%) was recorded in group PZQ2.Conclusion/SignificanceThis study revealed that the administration of PZQ at 18 mg/kg/day for 28 consecutive days was the optimal effective posology for treating S. mansoni infection at the initial stage in a murine model.     

Lack of Liver X Receptors Leads to Cell Proliferation in a Model of Mouse Dorsal Prostate Epithelial Cell

Recent studies underline the implication of Liver X Receptors (LXRs) in several prostate diseases such as benign prostatic hyperplasia (BPH) and prostate cancer. In order to understand the molecular mechanisms involved, we derived epithelial cells from dorsal prostate (MPECs) of wild type (WT) or Lxrαβ−/− mice. In the WT MPECs, our results show that LXR activation reduces proliferation and correlates with the modification of the AKT-survival pathway. Moreover, LXRs regulate lipid homeostasis with the regulation of Abca1, Abcg1 and Idol, and, in a lesser extent, Srebp1, Fas and Acc. Conversely cells derived from Lxrαβ−/− mice show a higher basal phosphorylation and consequently activation of the survival/proliferation transduction pathways AKT and MAPK. Altogether, our data point out that the cell model we developed allows deciphering the molecular mechanisms inducing the cell cycle arrest. Besides, we show that activated LXRs regulate AKT and MAPK transduction pathways and demonstrate that LXRs could be good pharmacological targets in prostate disease such as cancer.     

Finite element analysis of active Eustachian tube function.

The inability to open the collapsible Eustachian tube (ET) has been related to the development of chronic otitis media. Although ET dysfunction may be due to anatomic and/or mechanical abnormalities, the precise mechanisms by which these structural properties alter ET opening phenomena have not been investigated. Previous investigations could only speculate on how these structural properties influence the tissue deformation processes responsible for ET opening. We have, therefore, developed a computational technique that can quantify these structure-function relationships. Cross-sectional histological images were obtained from eight normal adult human subjects, who had no history of middle ear disease. A midcartilaginous image from each subject was used to create two-dimensional finite element models of the soft tissue structures of the ET. ET opening phenomena were simulated by applying muscle forces on soft tissue surfaces in the appropriate direction and were quantified by calculating the resistance to flow (R(v)) in the opened lumen. A sensitivity analysis was conducted to determine the relative importance of muscle forces and soft-tissue elastic properties. Muscle contraction resulted in a medial-superior rotation of the medial lamina, stretching deformation in the Ostmann's fatty tissue, and lumen dilation. Variability in baseline R(v) values correlated with tissue size, whereas the functional relationship between R(v) and a given mechanical parameter was consistent in all subjects. ET opening was found to be highly sensitive to the applied muscle forces and relatively insensitive to cartilage elastic properties. These computational models have, therefore, identified how different tissue elements alter ET opening phenomena, which elements should be targeted for treatment, and the optimal mechanical properties of these tissue constructs.     

Hot spots and functional organization of human chromosomes

Summary Our working hypothesis is that the Q-darker human chromosome segments have higher gene densities than the bright regions. Especially prominent in this respect are six hot spots, the short Q-dark regions in 3p, 6p, 11q, 12q, 17q, and 19 (p or q), which have been chosen because their density of mitotic chiasmata is above 5. Chromosomes with gene-rich segments would act as trisomy lethals in very early embryos, whose spontaneous abortions would not be recognized. Containing active genes, the regions would be looped out in interphase and thus be more easily available for mitotic pairing and crossing-over.To test this hypothesis, correlations and partial correlations of the following parameters have been determined: the density of mitotic chiasmata, the number and density of localized genes, the incidence of trisomic abortions, the length of chromosomes, and their Q-brightness. Overall, the correlations and partial correlations agree with, but do not prove, the working hypothesis. Far stronger evidence for our hypothesis comes from the highly significant negative effect of hot spots on trisomic abortions which would act as a kind of trisomy lethal. The gene numbers on the hot-spot chromosomes as compared with the controls, on the other hand, are in the right direction, but the difference is not significant.This is paper No. 2161 from the Genetics Laboratory, University of Wisconsin. It was supported by National Institutes of Health (Washington) grants GM 22881, GM 15422-09, and, to Dr. Hans Ris, GM 04738; by grant IN-35P from the American Cancer Society, and by the U. W. Graduate Research Committee (Grant 101-4403). The photography was done by Mr. Walter Kugler, Jr.     

PFIESTERIA PISCICIDA GEN. ET SP. NOV. (PFIESTERIACEAE FAM. NOV.), A NEW TOXIC DINOFLAGELLATE WITH A COMPLEX LIFE CYCLE AND BEHAVIOR1

The newly described toxic dinoflagellate Pfiesteria piscicida is a polymorphic and multiphasic species with flagellated, amoeboid, and cyst stages. The species is structurally a heterotroph; however, the flagellated stages can have cleptochloroplasts in large food vacuoles and can temporarily function as mixotrophs. The flagellated stage has a typical mesokaryotic nucleus, and the theca is composed of four membranes, two of which are vesicular and contain thin plates arranged in a Kofoidian series of Po, cp, X, 4′, 1a, 5″, 6c, 4s, 5″′, and 2″″. The plate tabulation is unlike that of any other armored dinoflagellate. Nodules often demark the suture lines underneath the outer membrane, but fixation protocols can influence the detection of plates. Amoeboid benthic stages can be filose to lobose, are thecate, and have a reticulate or spiculate appearance. Amoeboid stages have a eukaryotic nuclear profile and are phagocytic. Cyst stages include a small spherical stage with a honeycomb, reticulate surface and possibly another stage that is elongate and oval to spherical with chrysophyte-like scales that can have long bracts. The species is placed in a new family, Pfiesteriaceae, and the order Dinamoebales is emended.     

Co-culture of human fibroblasts,smooth muscle and endothelial cells promotes osteopontin induction in hypoxia

Arteriovenous fistulas (AVFs) are the preferred vascular access for haemodialysis of patients suffering from end-stage renal disease, a worldwide public health problem. However, they are prone to a high rate of failure due to neointimal hyperplasia and stenosis. This study aimed to determine if osteopontin (OPN) was induced in hypoxia and if OPN could be responsible for driving AVF failure. Identification of new factors that participate in remodelling of AVFs is a challenge. Three cell lines representing the cells of the three layers of the walls of arteries and veins, fibroblasts, smooth muscle cells and endothelial cells, were tested in mono- and co-culture in vitro for OPN expression and secretion in normoxia compared to hypoxia after silencing the hypoxia-inducible factors (HIF-1α, HIF-2α and HIF-1/2α) with siRNA or after treatment with an inhibitor of NF-kB. None of the cells in mono-culture showed OPN induction in hypoxia, whereas cells in co-culture secreted OPN in hypoxia. The changes in oxygenation that occur during AVF maturation up-regulate secretion of OPN through cell-cell interactions between the different cell layers that form AVF, and in turn, these promote endothelial cell proliferation and could participate in neointimal hyperplasia.     

Forecasting intensifying disturbance effects on coral reefs

Anticipating future changes of an ecosystem's dynamics requires knowledge of how its key communities respond to current environmental regimes. The Great Barrier Reef (GBR) is under threat, with rapid changes of its reef‐building hard coral (HC) community structure already evident across broad spatial scales. While several underlying relationships between HC and multiple disturbances have been documented, responses of other benthic communities to disturbances are not well understood. Here we used statistical modelling to explore the effects of broad‐scale climate‐related disturbances on benthic communities to predict their structure under scenarios of increasing disturbance frequency. We parameterized a multivariate model using the composition of benthic communities estimated by 145,000 observations from the northern GBR between 2012 and 2017. During this time, surveyed reefs were variously impacted by two tropical cyclones and two heat stress events that resulted in extensive HC mortality. This unprecedented sequence of disturbances was used to estimate the effects of discrete versus interacting disturbances on the compositional structure of HC, soft corals (SC) and algae. Discrete disturbances increased the prevalence of algae relative to HC while the interaction between cyclones and heat stress was the main driver of the increase in SC relative to algae and HC. Predictions from disturbance scenarios included relative increases in algae versus SC that varied by the frequency and types of disturbance interactions. However, high uncertainty of compositional changes in the presence of several disturbances shows that responses of algae and SC to the decline in HC needs further research. Better understanding of the effects of multiple disturbances on benthic communities as a whole is essential for predicting the future status of coral reefs and managing them in the light of new environmental regimes. The approach we develop here opens new opportunities for reaching this goal.