2-Aminoethyl Diphenylborinate Blocks G A B A A -Receptor- Mediated Currents in Rat Medial Preoptic Neurons

Abstract. The effect of 2-aminoethyl diphenylborinate (2-APB), a commonly used drug to modulate inositol-1,4,5-triphosphate (IP3) receptors and transient receptor potential (TRP) channels, on GABAA receptor-mediated currents was studied in neurons from the medial preoptic nucleus (MPN) of rat. 2-APB gradually and reversibly reduced the currents evoked by GABA but had no effect on the currents evoked by glycine. The blocking effect was not mediated by alterations in intracellular calcium concentration and showed a concentration dependence with half maximal effect at ~50 µM 2-APB, for currents evoked by 100 µM, as well as by 1.0 mM GABA, suggesting that 2-APB is not competing with GABA for its binding site at the GABAA receptor. Thus, the present study describes a novel pharmacological property of 2-APB as a non-competitive blocker of GABAA receptors and calls for caution in the interpretation of the results where 2-APB is used to affect IP3 receptors or TRP channels

Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy.

MotivationMultiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.ResultsWe performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.Availability and implementationDatasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.Supplementary informationSupplementary data are available at Bioinformatics online

2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154675/1/art41191.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154675/2/art41191_am.pd

Multiomics Characterization of Preterm Birth in Low- and Middle-Income Countries.

Importance: Worldwide, preterm birth (PTB) is the single largest cause of deaths in the perinatal and neonatal period and is associated with increased morbidity in young children. The cause of PTB is multifactorial, and the development of generalizable biological models may enable early detection and guide therapeutic studies. Objective: To investigate the ability of transcriptomics and proteomics profiling of plasma and metabolomics analysis of urine to identify early biological measurements associated with PTB. Design, Setting, and Participants: This diagnostic/prognostic study analyzed plasma and urine samples collected from May 2014 to June 2017 from pregnant women in 5 biorepository cohorts in low- and middle-income countries (LMICs; ie, Matlab, Bangladesh; Lusaka, Zambia; Sylhet, Bangladesh; Karachi, Pakistan; and Pemba, Tanzania). These cohorts were established to study maternal and fetal outcomes and were supported by the Alliance for Maternal and Newborn Health Improvement and the Global Alliance to Prevent Prematurity and Stillbirth biorepositories. Data were analyzed from December 2018 to July 2019. Exposures: Blood and urine specimens that were collected early during pregnancy (median sampling time of 13.6 weeks of gestation, according to ultrasonography) were processed, stored, and shipped to the laboratories under uniform protocols. Plasma samples were assayed for targeted measurement of proteins and untargeted cell-free ribonucleic acid profiling; urine samples were assayed for metabolites. Main Outcomes and Measures: The PTB phenotype was defined as the delivery of a live infant before completing 37 weeks of gestation. Results: Of the 81 pregnant women included in this study, 39 had PTBs (48.1%) and 42 had term pregnancies (51.9%) (mean [SD] age of 24.8 [5.3] years). Univariate analysis demonstrated functional biological differences across the 5 cohorts. A cohort-adjusted machine learning algorithm was applied to each biological data set, and then a higher-level machine learning modeling combined the results into a final integrative model. The integrated model was more accurate, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% CI, 0.72-0.91) compared with the models derived for each independent biological modality (transcriptomics AUROC, 0.73 [95% CI, 0.61-0.83]; metabolomics AUROC, 0.59 [95% CI, 0.47-0.72]; and proteomics AUROC, 0.75 [95% CI, 0.64-0.85]). Primary features associated with PTB included an inflammatory module as well as a metabolomic module measured in urine associated with the glutamine and glutamate metabolism and valine, leucine, and isoleucine biosynthesis pathways. Conclusions and Relevance: This study found that, in LMICs and high PTB settings, major biological adaptations during term pregnancy follow a generalizable model and the predictive accuracy for PTB was augmented by combining various omics data sets, suggesting that PTB is a condition that manifests within multiple biological systems. These data sets, with machine learning partnerships, may be a key step in developing valuable predictive tests and intervention candidates for preventing PTB

2-aminoethyl diphenylborinate blocks GABAA-receptor-mediated currents in rat medial preoptic neurons

The effect of 2-aminoethyl diphenylborinate (2-APB), a commonly used drug to modulate inositol-1,4,5-triphosphate (IP3) receptors and transient receptor potential (TRP) channels, on GABAA receptor-mediatedcurrents was studied in neurons from the medial preoptic nucleus (MPN) of rat. 2-APB gradually and reversibly reducedthe currents evoked by GABA but had no effect on the currents evoked by glycine. The blocking effect was not mediatedby alterations in intracellular calcium concentration and showed a concentration dependence with half maximal effect at~50 μM 2-APB, for currents evoked by 100 μM, as well as by 1.0 mM GABA, suggesting that 2-APB is not competing withGABA for its binding site at the GABAA receptor. Thus, the present study describes a novel pharmacological property of2-APB as a non-competitive blocker of GABAA receptors and calls for caution in the interpretation of the results where2-APB is used to affect IP3 receptors or TRP channels

Choosing the optimal rat stock as a model for research into pharmacological correction of male sexual dysfunction

The aim of the study is to identify the mechanisms mediating differences in sexual behavior between Sprague Dawley and Wistar rats, in order to choose the optimal stock for research into pharmacological correction of male sexual dysfunction. Materials and Methods. The experiments were carried out on sexually mature male rats of two stocks (Sprague Dawley and Wistar) weighing 350–450 g and aged 3 to 6 months. The comparative study of animal behavior was performed using standard tests for social interaction, locomotor activity, and anxiety level, as well as male mating behavior patterns. In order to determine the role of hypothalamic glycine receptors in the male sexual behavior, pharmacological manipulations of glycine receptor activity during mating with receptive females were conducted via bilateral intracerebral microcannulas implanted in the medial preoptic area (mPOA) of the male rat anterior hypothalamus. Results. The obtained results revealed statistically significant inter-stock differences in sexual behavior at the final consummatory stage of both intact animals and those after pharmacological activation of glycine receptors in the mPOA. The number of anxiety-related grooming patterns in the Open Field test significantly differed between the stocks for both intact animals and those after pharmacological activation of glycine receptors; the observed differences disappeared after the mPOA glycine receptors were blocked. In the Crowley test of social interaction, no significant difference was found between the stocks. Thus, the revealed difference in sexual behavior between Sprague Dawley and Wistar male rats is likely due to the difference in the level of anxiety, which, in turn, may be associated with difference in the mechanisms of glycinergic neurotransmission in the hypothalamic mPOAs of these rats. Conclusion. To study the relationship between the level of anxiety and sexual behavior, the choice of the Wistar rat stock is optimal since the male sexual behavior in this stock is more sensitive to stress than that in Sprague Dawley rats. However, to model male sexual dysfunction not associated with anxiety, the use of Sprague Dawley male rats should be preferred as these animals show more stable sexual behavior, which is less dependent on the level of anxiety