Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia

Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing.     

Marked extension of proliferation of rat Sertoli cells in culture using recombinant human FSH

Previous studies indicate that proliferation of rat Sertoli cells in culture can only be maintained until the equivalent of days 10-12 after birth, irrespective of the age of the donor animal. This report describes methods for the isolation and culture of Sertoli cells from day 6 rat testes, which can proliferate in culture for 20-24 days (that is, until the equivalent of days 26-30 after birth). Cells were isolated by enzymatic digestion of seminiferous cords followed by selective depletion of contaminating peritubular cells by adhesion to a polystyrene surface. The purity of the Sertoli cells was assessed using a combination of markers to be > 99.5%. Proliferation was assayed using tritiated thymidine incorporation and further verified by bromodeoxyuridine histochemistry and flow cytometry. Sertoli cells proliferated at basal levels in Dulbecco's modified Eagle's medium (DMEM)-F12 media alone, and proliferation was stimulated further by addition of recombinant human FSH to the culture media. After 20-24 days in culture, proliferation rapidly ceased, and cells assumed abnormal morphology and detached from the culture vessel; these events are consistent with the cells undergoing classic rodent cell senescence. The method described provides a useful tool for investigating the control of Sertoli cell division. Furthermore, these findings indicate that the timely differentiation of Sertoli cells is not dependent solely on an intrinsic timing mechanism, as has been suggested previously.     

Isolation and characterization of antagonists for the biocontrol of the postharvest wound pathogen Botrytis cinerea on strawberry fruits

Antagonistic bacteria and yeasts were isolated from the epiphytic flora of stored strawberry fruits and evaluated for their ability to protect strawberry fruit wounds after harvest against Botrytis cinerea. Among selected potential antagonists, three strains of Candida reukaufii (5L3, 10CL4, 10L2) and one strain of Candida pulcherima (10L8) still protected fruit wounds when applied at 10(3) CFU/wound, reducing lesion or conidiophore development. In the same conditions, two Enterobacteriaceae (10B1, 5B4) highly reduced pathogen development. Strain 5B4 was still highly inhibitory when inoculated at 10(2) CFU/wound. The six strains applied on fruits did not produce any significant change in color, brightness, and firmness of fruits. The two yeasts, 5L3 and 10L8, and particularly the two bacteria, 5B4 and 10B1, were selected for further studies. The four antagonists effectively colonized fruit wounds and strongly inhibited spore germination of B. cinerea in vitro. The bacterial cells surrounded the germinating spores of B. cinerea and attachment of 5L3 cells on germinating spores were additionally observed. Bacterial antagonists, particularly the strain 5B4, multiplied and rapidly used carbohydrates in strawberry fruit juice despite the low pH (pH 3.5). The efficiency of the bacterial antagonists on fruit wounds was related to their growth and nutritional properties.     

Simulation of packaged solar heat-pump water heaters

The performance of heat-pump water heaters with solar boosted evaporators is investigated experimentally, and a simulation model in the TRNSYS package is developed for assessing annual performance. A packaged heat-pump system with a passive evaporator and condenser in the one unit, which eliminates parasitic energy consumption of the usual circulating pump and fan-coil unit, is assessed for a range of climatic conditions.     

Long term performance of thermosyphon solar water heaters

The performance of 6 thermosyphon solar water heaters was measured while the systems were supplying typical domestic hot water loads. The effect of system configuration, daily load draw off times and off-peak vs continuous boosting was studied. In contrast to forced circulation systems the performance of thermosyphon systems was found to be best if a morning peak load pattern was used. Operation with off-peak boosting was found to improve the annual contribution by 14 per cent.     

Controlled trial of the effect of negative dietary cation-anion difference prepartum diets on milk production,reproductive performance,and culling of dairy cows

Our objective was to assess the effects of feeding negative dietary cation-anion difference (DCAD) prepartum diets on milk production, reproductive performance, and culling. Cows from 4 commercial farms in Ontario, Canada were enrolled in a pen-level controlled trial from November 2017 to April 2019. Close-up pens (1 per farm) with cows 3 wk before calving were randomly assigned to a negative DCAD (TRT; ?108 mEq/kg of dry matter; target urine pH 6.0–6.5) or a control diet (CON; +105 mEq/kg of dry matter with a placebo supplement). Each pen was fed TRT or CON for 3 mo (1 period), and then switched to the other treatment for the next period (4 periods per farm). Data from 15 experimental units (8 pen treatments in TRT and 7 in CON), with a total of 1,086 observational units (cows), were included. The effect of treatment on milk yield at the first 3 milk recording tests of lactation was assessed with linear regression models accounting for repeated measures. The risk of pregnancy at first artificial insemination and culling by 30, 60, and 305 d in milk (DIM) were analyzed with logistic regression models, and effects on time to first AI, pregnancy, and culling were assessed with Cox proportional hazards models. All models included treatment, parity, and their interactions, accounting for pen-level randomization and clustering of animals within farm with random effects, giving 10 degrees of freedom for treatment effects. Multiparous cows fed TRT produced more milk at the first (42.0 vs. 38.8 ± 1.2 kg/d) and second (44.2 vs. 41.7 ± 1.3 kg/d) milk tests. However, multiparous cows fed TRT tended to have 0.2 percentage units less milk fat content at these tests. Although multiparous cows fed TRT tended to have greater energy-corrected milk at the first test (least squares means ± standard error: TRT = 46.1 ± 0.9 vs. CON = 43.8 ± 1 kg/d), there were no differences observed in energy-corrected milk at the second or third tests. In primiparous cows, there was no effect of treatment on milk production. Multiparous cows fed TRT had greater pregnancy to first insemination (TRT = 42 ± 3 vs. CON = 32 ± 4%) and tended to have shorter time to pregnancy [hazard ratio (HR) = 1.20; 95% CI: 0.96–1.49]. In primiparous cows fed TRT, time to pregnancy was increased (HR = 0.76; 95% CI: 0.59–0.99). Culling by 30 DIM tended to be less in TRT (3.3 ± 1.1%) than CON (5.5 ± 1.8%). No effect of treatment on culling by 305 DIM was detected in primiparous cows, but in multiparous cows, the TRT diets decreased the odds of culling (21.3 ± 1.9 vs. 31.7 ± 2.8%) and daily risk of culling to 305 DIM (HR = 0.64; 95% CI: 0.46 to 0.89). Under commercial herd conditions, prepartum negative DCAD diets improved milk production and reproductive performance, and reduced culling risk in multiparous cows. In primiparous cows, TRT diets had no effect on milk yield or culling, but increased the time to pregnancy. Our results suggest that negative DCAD diets should be targeted to multiparous cows.     

Effect of multipurpose solutions for contact lens care on the in vitro drug-induced spoliation of poly(2-hydroxyethyl methacrylate) in simulated aqueous humour.

Drug-induced spoliation of hydrogels as contact lenses or as implants in the anterior eye is a frequent occurrence in clinical practice. This study explores the capacity of three commercial multipurpose solutions for contact lens care to reduce the spoliation of poly(2-hydroxyethyl methacrylate) (PHEMA) specimens exposed to a simulated aqueous humour formulation and to three topical drugs commonly administered after insertion of artificial corneas (Predsol, Optimol and Depo-Ralovera). ReNu MultiPlus (Bausch & Lomb), Complete Blink-N-Cleantrade mark Lens Drops (Allergan) and Complete Protein Remover Tablets dissolved in Complete ComfortPLUS (both from Allergan) were evaluated. All multipurpose solutions were able to dislodge passively the deposits formed on hydrogels in the simulated aqueous and in the presence of Predsol and Optimol, but none were effective against the deposits induced by Depo-Ralovera. A reduction of the calcium content in deposits caused by Predsol and Optimol was confirmed after treatment with the protein remover preparation, while the other multipurpose solutions caused the complete removal of the deposits. In experiments designed to evaluate the preventive action of the multipurpose solutions, no such effects were observed regardless of the drug involved. The prospect of using multipurpose solutions as eye drops following implantation of a hydrogel artificial cornea is a valid alternative for reducing device spoliation, however it appears to depend on the nature of the postoperative medication.     

Inside the rings of Saturn

Kress’ multimodality and design approaches are applied in a rhetorical play on the online mediation of the recent space mission to Saturn. Activity theory provides an educational framing for Kress’ multimodal semiosis. Links are made to mythical texts on Saturn and to blogs. Social network software is now seen as central to performative, multilogical web discourse.