Synergetic role of TRPV4 inhibitor and mechanical loading on reducing inflammation.

Resolution of inflammation is essential for normal tissue healing and regeneration, with macrophages playing a key role in regulating this process through phenotypic changes from a pro-inflammatory to an anti-inflammatory state. Pharmacological and mechanical (mechanotherapy) techniques can be employed to polarize macrophages toward an anti-inflammatory phenotype, thereby diminishing inflammation. One clinically relevant pharmacological approach is the inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4).

The Scribble-SGEF-Dlg1 complex regulates E-cadherin and ZO-1 stability, turnover and transcription in epithelial cells.

SGEF (also known as ARHGEF26), a RhoG specific GEF, can form a ternary complex with the Scribble polarity complex proteins Scribble and Dlg1, which regulates the formation and maintenance of adherens junctions and barrier function of epithelial cells. Notably, silencing SGEF results in a dramatic downregulation of both E-cadherin and ZO-1 (also known as TJP1) protein levels. However, the molecular mechanisms involved in the regulation of this pathway are not known.

A PACAP-activated network for secretion requires coordination of Ca influx and Ca mobilization.

Chromaffin cells of the adrenal medulla transduce sympathetic nerve activity into stress hormone secretion. The two neurotransmitters principally responsible for coupling cell stimulation to secretion are acetylcholine and pituitary adenylate activating polypeptide (PACAP). In contrast to acetylcholine, PACAP evokes a persistent secretory response from chromaffin cells.

The Scribble/SGEF/Dlg1 complex regulates the stability of apical junctions in epithelial cells.

SGEF, a RhoG specific GEF, can form a ternary complex with the Scribble polarity complex proteins Scribble and Dlg1, which regulates the formation and maintenance of adherens junctions and barrier function of epithelial cells. Notably, silencing SGEF results in a dramatic downregulation of the expression of both E-cadherin and ZO-1. However, the molecular mechanisms involved in the regulation of this pathway are not known.

Modulating TRPV4 Channel Activity in Pro-Inflammatory Macrophages within the 3D Tissue Analog.

Investigating macrophage plasticity emerges as a promising strategy for promoting tissue regeneration and can be exploited by regulating the transient receptor potential vanilloid 4 (TRPV4) channel. The TRPV4 channel responds to various stimuli including mechanical, chemical, and selective pharmacological compounds. It is well documented that treating cells such as epithelial cells and fibroblasts with a TRPV4 agonist enhances the Ca influx to the cells, which leads to secretion of pro-inflammatory cytokines, while a TRPV4 antagonist reduces both Ca influx and pro-inflammatory cytokine secretion.

A PACAP-activated network for secretion requires coordination of Ca influx and Ca mobilization.

Chromaffin cells of the adrenal medulla transduce sympathetic nerve activity into stress hormone secretion. The two neurotransmitters principally responsible for coupling cell stimulation to secretion are acetylcholine and pituitary adenylate activating polypeptide (PACAP). In contrast to acetylcholine, PACAP evokes a persistent secretory response from chromaffin cells.

Performance of the NOSE Questionnaire in Mask Selection for Home CPAP Titration.

 Many patients abandon CPAP treatment because they find the mask uncomfortable. Therefore, specialists may benefit from the predictive value of airway assessment tools.  To identify nasal ventilation failure through the Nasal Obstruction Symptom Evaluation (NOSE) scale in patients with obstructive sleep apnea (OSA) who undergo home-based auto-adjusting CPAP titration and to determine whether there is a correlation between NOSE score and the type of mask selected.

Macrophage Mechano-Responsiveness Within Three-Dimensional Tissue Matrix upon Mechanotherapy-Associated Strains.

Mechano-rehabilitation, also known as mechanotherapy, represents the forefront of noninvasive treatment for musculoskeletal (MSK) tissue disorders, encompassing conditions affecting tendons, cartilage, ligaments, and muscles. Recent emphasis has underscored the significance of macrophage presence in the healing of MSK tissues. However, a considerable gap still exists in comprehending how mechanical strains associated with mechanotherapy impact both the naïve and pro-inflammatory macrophage phenotypes within the three-dimensional (3D) tissue matrix, as well as whether the shift in macrophage phenotype is contingent on the mechanical strains inherent to mechanotherapy.

Deciphering the Cell-Specific Effect of Osteoblast-Macrophage Crosstalk in Periodontitis.

In periodontitis, the bone remodeling process is disrupted by the prevalent involvement of bacteria-induced proinflammatory macrophage cells and their interaction with osteoblast cells residing within the infected bone tissue. The complex interaction between the cells needs to be deciphered to understand the dominant player in tipping the balance from osteogenesis to osteoclastogenesis. Yet, only a few studies have examined the crosstalk interaction between osteoblasts and macrophages using biomimetic three-dimensional (3D) tissue-like matrices.

ARHGAP17 regulates the spatiotemporal activity of Cdc42 at invadopodia.

Invadopodia formation is regulated by Rho GTPases. However, the molecular mechanisms that control Rho GTPase signaling at invadopodia remain poorly understood. Here, we have identified ARHGAP17, a Cdc42-specific RhoGAP, as a key regulator of invadopodia in breast cancer cells and characterized a novel ARHGAP17-mediated signaling pathway that controls the spatiotemporal activity of Cdc42 during invadopodia turnover.

The C-terminal region of phytoene synthase is a key element to control carotenoid biosynthesis in the haloarchaeon Haloferax volcanii.

Phytoene synthase (PSY) converts two molecules of geranyl-geranyl diphosphate to phytoene, the key regulatory step in carotenogenesis. However, post-translational mechanisms that control PSY expression are scarcely understood. Carotenoid biosynthesis (mainly bacterioruberin) is a distinctive feature of haloarchaea thriving in hypersaline environments.

Mechanoresponsive regulation of fibroblast-to-myofibroblast transition in three-dimensional tissue analogues: mechanical strain amplitude dependency of fibrosis.

The spatiotemporal interaction and constant iterative feedback between fibroblasts, extracellular matrix, and environmental cues are central for investigating the fibroblast-induced musculoskeletal tissue regeneration and fibroblast-to-myofibroblast transition (FMT). In this study, we created a fibroblast-laden 3D tissue analogue to study (1) how mechanical loading exerted on three-dimensional (3D) tissues affected the residing fibroblast phenotype and (2) to identify the ideal mechanical strain amplitude for promoting tissue regeneration without initiating myofibroblast differentiation. We applied uniaxial tensile strain (0, 4, 8, and 12%) to the cell-laden 3D tissue analogues to understand the interrelation between the degree of applied mechanical loading amplitudes and FMT.

ARHGEF26 enhances Salmonella invasion and inflammation in cells and mice.

Salmonella hijack host machinery in order to invade cells and establish infection. While considerable work has described the role of host proteins in invasion, much less is known regarding how natural variation in these invasion-associated host proteins affects Salmonella pathogenesis. Here we leveraged a candidate cellular GWAS screen to identify natural genetic variation in the ARHGEF26 (Rho Guanine Nucleotide Exchange Factor 26) gene that renders lymphoblastoid cells susceptible to Salmonella Typhi and Typhimurium invasion.

Treatment of chronic heart failure: an expert system advisor for general practitioners.

Most decision-support systems in medicine have been developed in hospital environments, but only few are designed for being used by general practitioners. The present work aims to design an expert system for practitioners in chronic heart failure (CHF) treatment. It provides assistance in defining the therapy relying on CHF aetiology, gravity, physiopathological conditions, and discriminates if other coexistent diseases and/or drugs taken by the patient could interact with CHF management.