Cardiac fibroblasts: answering the call.

Cardiac fibroblasts play a pivotal role in maintaining heart homeostasis by depositing extracellular matrix (ECM) to provide structural support for the myocardium, vasculature, and neuronal network and by contributing to essential physiological processes. In response to injury such as myocardial infarction or pressure overload, fibroblasts become activated, leading to increased ECM production that can ultimately drive left ventricular remodeling and progress to heart failure. Recently, the issued a call for papers on cardiac fibroblasts that yielded articles with topics spanning fibroblast physiology, technical considerations, signaling pathways, and interactions with other cell types.

SUMO and the DNA damage response.

The preservation of genome integrity requires specialised DNA damage repair (DDR) signalling pathways to respond to each type of DNA damage. A key feature of DDR is the integration of numerous post-translational modification signals with DNA repair factors. These modifications influence DDR factor recruitment to damaged DNA, activity, protein-protein interactions, and ultimately eviction to enable access for subsequent repair factors or termination of DDR signalling.

USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication.

Mammalian DNA replication employs several RecQ DNA helicases to orchestrate the faithful duplication of genetic information. Helicase function is often coupled to the activity of specific nucleases, but how helicase and nuclease activities are co-directed is unclear. Here we identify the inactive ubiquitin-specific protease, USP50, as a ubiquitin-binding and chromatin-associated protein required for ongoing replication, fork restart, telomere maintenance and cellular survival during replicative stress.

Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting.

A synthetic lethal relationship exists between disruption of polymerase theta (Polθ), and loss of either 53BP1 or homologous recombination (HR) proteins, including BRCA1; however, the mechanistic basis of these observations are unclear. Here we reveal two distinct mechanisms of Polθ synthetic lethality, identifying dual influences of 1) whether Polθ is lost or inhibited, and 2) the underlying susceptible genotype. Firstly, we find that the sensitivity of BRCA1/2- and 53BP1-deficient cells to Polθ loss, and 53BP1-deficient cells to Polθ inhibition (ART558) requires RAD52, and appropriate reduction of RAD52 can ameliorate these phenotypes.

Primary cardiac fibroblast cell culture: methodological considerations for physiologically relevant conditions.

Primary cardiac fibroblast (CF) tissue culture is a necessary tool for interrogating specific signaling mechanisms that dictate the phenotypic heterogeneity observed in vivo in different disease states. Traditional approaches that use tissue culture plastic and nutrient-rich medium have been shown to induce CF activation and, therefore, alter CF subpopulation composition. This shift away from in vivo phenotypes complicate the interpretation of results through the lens of the animal model.

In the Eye of the Cytokine Storm: A Tale of SARS-CoV-2-Induced Acute Macular Neuroretinopathy.

Acute macular neuroretinopathy (AMN) commonly affects young to middle-aged females and is considered a relatively rare retinal disease, and the etiology is complex. Advances in multimodal imaging provide a better characterization of retinal disorders and have helped identify that one of the etiologies of AMN is microvascular in nature. This case is clinically relevant as it adds to the literature that the pathophysiology of AMN is vascular-driven.

Eosinophilic Fasciitis Presenting as an Ichthyosiform Eruption of the Bilateral Ankles.

Eosinophilic fasciitis (EF) is a rare connective tissue disease which closely resembles other scleroderma-like diseases. EF presents with painful swelling and hardening of the distal limbs and is often preceded by a history of strenuous exercise. The marked fascial fibrosis in EF can lead to joint contractures and causes significant morbidity in affected individuals.

SUMO monoclonal antibodies vary in sensitivity, specificity, and ability to detect types of SUMO conjugate.

Monoclonal antibodies (MAb) to members of the Small Ubiquitin-like modifier (SUMO) family are essential tools in the study of cellular SUMOylation. However, many anti-SUMO MAbs are poorly validated, and antibody matching to detection format is without an evidence base. Here we test the specificity and sensitivity of twenty-four anti-SUMO MAbs towards monomeric and polymeric SUMO1-4 in dot-blots, immunoblots, immunofluorescence and immunoprecipitation.

Use of Mental Health Interventions by Physiotherapists to Treat Individuals with Chronic Conditions: A Systematic Scoping Review.

Physiotherapists work with people with chronic conditions and can act as catalysts for behavioural change. Physiotherapy has also seen a shift to a bio-psychosocial model of health management and interdisciplinary care, which is important in the context of chronic conditions. This scoping review addressed the research question "How do physiotherapists use mental health-based interventions in their treatment of individuals with chronic conditions?" The Embase, MEDLINE, PsycINFO, and CINAHL databases were searched, and a variety of study designs were included.

Transient ACE (Angiotensin-Converting Enzyme) Inhibition Suppresses Future Fibrogenic Capacity and Heterogeneity of Cardiac Fibroblast Subpopulations.

Transient ACE (angiotensin-converting enzyme) inhibition in spontaneously hypertensive rats is known to protect against future injury-induced cardiac inflammation, fibrosis, and dysfunction; however, the mechanisms of protection have not been delineated. Here, we used single-cell RNA sequencing to test the hypothesis that transient ACE inhibitor treatment would induce a persistent shift in cardiac fibroblast subpopulations. Adult male spontaneously hypertensive rats (11 weeks old, hypertensive with cardiac hypertrophy) were treated for 2 weeks with an ACE inhibitor, enalapril (30 mg/kg per day, PO), or water (untreated spontaneously hypertensive rats) followed by a 2-week washout period (n=7/group).

RAS inhibition in resident fibroblast biology.

Angiotensin II (Ang II) is a primary mediator of profibrotic signaling in the heart and more specifically, the cardiac fibroblast. Ang II-mediated cardiomyocyte hypertrophy in combination with cardiac fibroblast proliferation, activation, and extracellular matrix production compromise cardiac function and increase mortality in humans. Profibrotic actions of Ang II are mediated by increasing production of fibrogenic mediators (e.

Beyond reversal: ubiquitin and ubiquitin-like proteases and the orchestration of the DNA double strand break repair response.

The cellular response to genotoxic DNA double strand breaks (DSBs) uses a multitude of post-translational modifications to localise, modulate and ultimately clear DNA repair factors in a timely and accurate manner. Ubiquitination is well established as vital to the DSB response, with a carefully co-ordinated pathway of histone ubiquitination events being a central component of DSB signalling. Other ubiquitin-like modifiers (Ubl) including SUMO and NEDD8 have since been identified as playing important roles in DSB repair.

Isomerization of BRCA1-BARD1 promotes replication fork protection.

The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear.

Ascorbic acid degradation in aqueous solution during UV-Vis irradiation.

This work studied the effect of multi-wavelength UV processing on the ascorbic acid content of aqueous solutions, at different pH values (3, 4, and 5). The source of radiation was a mid-pressure mercury lamp (460 W), emitting between 250 and 740 nm. The samples were treated for 60 min, at 25 °C and 45 °C, with the lamp on and with the lamp off.

Kinetic and thermodynamic compensation study of the hydration of faba beans (Vicia faba L.).

This work applies kinetic and thermodynamic compensation to evaluate the kinetics of hydration of faba beans. A mechanism was proposed, consisting of a zero-order adsorption step followed by a first-order desorption step, with both reactions going through a transition state with a previous equilibrium stage. The kinetic constants were obtained from a previous study for pHs 3, 6, 9 and 12 and at temperatures of 20, 35, 50 and 65 °C.

GSK3β-SCFFBXW7α mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover.

IRF1 (Interferon Regulatory Factor-1) is the prototype of the IRF family of DNA binding transcription factors. IRF1 protein expression is regulated by transient up-regulation in response to external stimuli followed by rapid degradation via the ubiquitin-proteasome system. Here we report that DNA bound IRF1 turnover is promoted by GSK3β (Glycogen Synthase Kinase 3β) via phosphorylation of the T181 residue which generates a phosphodegron for the SCF (Skp-Cul-Fbox) ubiquitin E3-ligase receptor protein Fbxw7α (F-box/WD40 7).

The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms.

SUMOylation (small ubiquitin-like modifier) in the DNA double-strand break (DSB) response regulates recruitment, activity, and clearance of repair factors. However, our understanding of a role for deSUMOylation in this process is limited. Here we identify different mechanistic roles for deSUMOylation in homologous recombination (HR) and nonhomologous end joining (NHEJ) through the investigation of the deSUMOylase SENP2.

Inhibition of programmed necrosis limits infarct size through altered mitochondrial and immune responses in the aged female rat heart.

Both advancing age and estrogen loss exacerbate acute myocardial infarction in the female heart. However, the mechanistic underpinnings of age-related differences in cell death after ischemia-reperfusion (I/R) injury in female subjects and reductions in cardioprotective reserve capacity remain largely unexplored. The aim of the present study was to determine the efficacy of programmed necrosis inhibition on infarct size reduction and preservation of left ventricular (LV) function after I/R injury with female aging.

SUMO, a small, but powerful, regulator of double-strand break repair.

The response to a DNA double-stranded break in mammalian cells is a process of sensing and signalling the lesion. It results in halting the cell cycle and local transcription and in the mediation of the DNA repair process itself. The response is launched through a series of post-translational modification signalling events coordinated by phosphorylation and ubiquitination.

Kinetic and thermodynamic study of the photochemical degradation of patulin.

In a previous work, the UV photodegradation of patulin was concluded to follow a first-order kinetic and to be faster at acidic pH. In this case, the UV photodegradation of aqueous patulin solutions was studied at acidic pH values (3-6) similar to the values of apple juices where patulin has been found, obtaining that the first-order kinetic constant increased when the acidity of the reaction media was also increased (pH decreased). From the parameters obtained by fitting the experimental data to both the Arrhenius and Van't Hoff equations, the existence of kinetic and thermodynamic compensations was studied.

Age and ischemia differentially impact mitochondrial ultrastructure and function in a novel model of age-associated estrogen deficiency in the female rat heart.

Altered mitochondrial respiration, morphology, and quality control collectively contribute to mitochondrial dysfunction in the aged heart. Because myocardial infarction remains the leading cause of death in aged women, the present study utilized a novel rodent model to recapitulate human menopause to interrogate the combination of age and estrogen deficiency on mitochondrial ultrastructure and function with cardiac ischemia/reperfusion (I/R) injury. Female F344 rats were ovariectomized (OVX) at 15 months and studied at 24 months (MO OVX; n = 40) vs adult ovary intact (6 months; n = 41).