Novel benzothiophene H1-antihistamines for the treatment of insomnia

SAR of lead benzothiophene H₁-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H₁-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.     

Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells

Low and high serum retinol levels are associated with increased fracture risk and poor bone health. We recently showed retinoic acid receptors (RARs) are negative regulators of osteoclastogenesis. Here we show RARs are also negative regulators of osteoblast and adipocyte differentiation. The pan-RAR agonist, all-trans retinoic acid (ATRA), directly inhibited differentiation and mineralisation of early osteoprogenitors and impaired the differentiation of more mature osteoblast populations. In contrast, the pan-RAR antagonist, IRX4310, accelerated differentiation of early osteoprogenitors. These effects predominantly occurred via RARγ and were further enhanced by an RARα agonist or antagonist, respectively. RAR agonists similarly impaired adipogenesis in osteogenic cultures. RAR agonist treatment resulted in significant upregulation of the Wnt antagonist, Sfrp4. This accompanied reduced nuclear and cytosolic β-catenin protein and reduced expression of the Wnt target gene Axin2, suggesting impaired Wnt/β-catenin signalling. To determine the effect of RAR inhibition in post-natal mice, IRX4310 was administered to male mice for 10 days and bones were assessed by µCT. No change to trabecular bone volume was observed, however, radial bone growth was impaired. These studies show RARs directly influence osteoblast and adipocyte formation from mesenchymal cells, and inhibition of RAR signalling in vivo impairs radial bone growth in post-natal mice.     

Hi-Fi transmission of periodic signals amid cell-to-cell variability

Since information in intracellular calcium signaling is often frequency encoded, it is physiologically critical and experimentally useful to have reliable, convenient, and non-invasive methods to entrain it. Because of cell-to-cell variability, synchronization of intracellular signaling across a population of genetically identical cells can still be difficult to achieve. For intrinsically oscillatory signaling pathways, such as calcium, upon continuous stimulation, cell-to-cell variability is manifested as differences in intracellular response frequencies. Even with entrainment using periodic stimulation, cell-to-cell variability is manifested as differences in the fidelity with which extracellular inputs are converted into intracellular signals. Here we present a combined theoretical and experimental analysis that shows how to appropriately balance stimulation strength, duration, and rest intervals to achieve entrainment with high fidelity stimulation-to-response ratios for G-protein-coupled receptor-triggered intracellular calcium oscillations. We further demonstrate that stimulation parameters that give high fidelity entrainment are significantly altered upon changes in intracellular enzyme levels and cell surface receptor levels. Theoretical analysis suggests that, at key threshold values, even small changes in these protein concentrations or activities can result in precipitous changes in entrainment fidelity, with implications for pathophysiology.     

Recruitment of arfaptins to the trans‐Golgi network by PI(4)P and their involvement in cargo export

The BAR (Bin/Amphiphysin/Rvs) domain proteins arfaptin1 and arfaptin2 are localized to the trans‐Golgi network (TGN) and, by virtue of their ability to sense and/or generate membrane curvature, could play an important role in the biogenesis of transport carriers. We report that arfaptins contain an amphipathic helix (AH) preceding the BAR domain, which is essential for their binding to phosphatidylinositol 4‐phosphate (PI(4)P)‐containing liposomes and the TGN of mammalian cells. The binding of arfaptin1, but not arfaptin2, to PI(4)P is regulated by protein kinase D (PKD) mediated phosphorylation at Ser100 within the AH. We also found that only arfaptin1 is required for the PKD‐dependent trafficking of chromogranin A by the regulated secretory pathway. Altogether, these findings reveal the importance of PI(4)P and PKD in the recruitment of arfaptins at the TGN and their requirement in the events leading to the biogenesis of secretory storage granules.     

The crystal structure of the phosphatidylinositol 4‐kinase IIα

Phosphoinositides are a class of phospholipids generated by the action of phosphoinositide kinases with key regulatory functions in eukaryotic cells. Here, we present the atomic structure of phosphatidylinositol 4‐kinase type IIα (PI4K IIα), in complex with ATP solved by X‐ray crystallography at 2.8 Å resolution. The structure revealed a non‐typical kinase fold that could be divided into N‐ and C‐lobes with the ATP binding groove located in between. Surprisingly, a second ATP was found in a lateral hydrophobic pocket of the C‐lobe. Molecular simulations and mutagenesis analysis revealed the membrane binding mode and the putative function of the hydrophobic pocket. Taken together, our results suggest a mechanism of PI4K IIα recruitment, regulation, and function at the membrane.     

Evaluating and comparing performance of feature combinations of heart rate variability measures for cardiac rhythm classification

Automatic classification of cardiac arrhythmias using heart rate variability (HRV) analysis has been an important research topic in recent years. Explorations reveal that various HRV feature combinations can provide highly accurate models for some rhythm disorders. However, the proposed feature combinations lack a direct and carefully designed comparison. The goal of this work is to assess the various HRV feature combinations in classification of cardiac arrhythmias. In this setting, a total of 56 known HRV features are grouped in eight feature combinations. We evaluate and compare the combinations on a difficult problem of automatic classification between nine types of cardiac rhythms using three classification algorithms: support vector machines, AdaBoosted C4.5, and random forest. The effect of analyzed segment length on classification accuracy is also examined. The results demonstrate that there are three combinations that stand out the most, with total classification accuracy of roughly 85% on time segments of 20 s duration. A simple combination of time domain features is shown to be comparable to the more informed combinations, with only 1–4% worse results on average than the three best ones. Random forest and AdaBoosted C4.5 are shown to be comparably accurate, while support vector machines was less accurate (4–5%) on this problem. We conclude that the nonlinear features exhibit only a minor influence on the overall accuracy in discerning different arrhythmias. The analysis also shows that reasonably accurate arrhythmia classification lies in the range of 10–40 s, with a peak at 20 s, and a significant drop after 40 s.     

Studies on the structure-activity relationship of bicifadine analogs as monoamine transporter inhibitors

Compounds with various activities and selectivities were discovered through structure-activity relationship studies of bicifadine analogs as monoamine transporter inhibitors. The norepinephrine-selective 2-thienyl compound S-6j was efficacious in a rodent pain model.     

Prevalence and Patterns of Multi-Morbidity in Serbian Adults: A Cross-Sectional Study

Introduction

Like many developing countries, Serbia is facing a growing burden of chronic diseases. Within such public health issue, multi-morbidity requires a special attention.

Aims

This study investigated the prevalence of multi-morbidity in the Serbia population and assessed the co-occurrence of chronic diseases by age and gender.

Methods

We analyzed data from the 2013 National Health Survey, which included 13,103 individuals ≥ 20 years old. Multi-morbidity patterns were identified by exploratory factor analysis of data on self-reported chronic diseases, as well as data on measured body weight and height. The analysis was stratified by age and gender.

Results

Multi-morbidity was present in nearly one-third of respondents (26.9%) and existed in all age groups, with the highest prevalence among individuals aged 65 years and older (47.2% of men and 65.0% of women). Six patterns of multi-morbidity were identified: non-communicable, cardio-metabolic, respiratory, cardiovascular, aggregate, and mechanical/mental/metabolic. The non-communicable pattern was observed in both genders but only in the 20–44 years age group, while the aggregate pattern occurred only in middle-aged men. Cardio-metabolic and respiratory patterns were present in all age groups. Cardiovascular and mechanical/mental/metabolic patterns showed similar presentation in both men and women.

Conclusions

Multi-morbidity is a common occurrence among adults in Serbia, especially in the elderly. While several patterns may be explained by underlying pathophysiologies, some require further investigation and follow-up. Recognizing the complexity of multi-morbidity in Serbia is of great importance from both clinical and preventive perspectives given that it affects one-third of the population and may require adjustment of the healthcare system to address the needs of affected individuals.