Long-term Pannexin 1 Ablation Produces an Imbalance Between Small Rho-GTPases Activity and Actin Polymerization Leading to Structural and Functional Modifications in Hippocampal Neurons

Enhanced activity and overexpression of Pannexin 1 (PANX1) channels contribute to neuronal pathologies, such as epilepsy and Alzheimer’s disease (AD). In the hippocampus, the PANX1 channel ablation alters glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, PANX1-knockout (PANX1-KO) mice still preserve the ability to learn, suggesting that compensatory mechanisms work to stabilize neuronal activity. Here, we show that the absence of PANX1 in the adult brain promotes a series of structural and functional modifications in PANX1-KO CA1 hippocampal synapses, preserving spontaneous activity. Adult CA1 neurons of PANX1-KO mice exhibit enhanced excitability, a more complex dendritic branching, enhanced spine maturation, and multiple synaptic contacts compared to the WT condition. These modifications seem to rely on the actin-cytoskeleton dynamics as an increase in actin polymerization and an imbalance between Rac1 and RhoA GTPase activity is observed in the absence of PANX1. Our findings highlight a novel interaction between PANX1, actin, and small Rho GTPases, which appear to be relevant for synapse stability.

Multiple ETS Factors Participate in the Transcriptional Control of TERT Mutant Promoter in Thyroid Cancers

Hotspot mutations in the TERT (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. TERT promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transformation specific”) family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the TERT mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact TERT expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing TERT transcription in the absence of TPMs. Taken together, our results show a more complex scenario of TERT regulation in thyroid cancers compared with other lineages and suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need for a more comprehensive understanding of the mechanisms of TERT deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies.

Physical Fitness Differences, Amenable to Hypoxia-Driven and Sarcopenia Pathophysiology, between Sleep Apnea and COVID-19

Handgrip strength is an indirect indicator of physical fitness that is used in medical rehabilitation for its potential prognostic value. An increasing number of studies indicate that COVID-19 survivors experience impaired physical fitness for months following hospitalization. The aim of our study was to assess physical fitness indicator differences with another prevalent and hypoxia-driven disease, Obstructive Sleep Apnea Syndrome (OSAS). Our findings showed differences between post-COVID-19 and OSAS groups in cardiovascular responses, with post-COVID-19 patients exhibiting higher values for heart rate and in mean arterial blood pressure. Oxygen saturation (SpO2) was lower in post-COVID-19 patients during a six-minute walking test (6MWT), whereas the ΔSpO2 (the difference between the baseline to end of the 6MWT) was higher compared to OSAS patients. In patients of both groups, statistically significant correlations were detected between handgrip strength and distance during the 6MWT, anthropometric characteristics, and body composition parameters. In our study, COVID-19 survivors demonstrated a long-term reduction in muscle strength compared to OSAS patients. Lower handgrip strength has been independently associated with a prior COVID-19 hospitalization. The differences in muscle strength and oxygenation could be attributed to the abrupt onset of the disorder, which does not allow compensatory mechanisms to act effectively. Targeted rehabilitation focusing on such residual impairments may thus be indispensable within the setting of post-COVID-19 syndrome.

Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration

Multidrug-resistant pathogens constitute a serious global issue and, therefore, novel antimicrobials with new modes of action are urgently needed. Here, we investigated the effect of a phenothiazine derivative (JBC 1847) with high antimicrobial activity on Staphylococcus aureus, using a wide range of in vitro assays, flow cytometry, and RNA transcriptomics. The flow cytometry results showed that JBC 1847 rapidly caused depolarization of the cell membrane, while the macromolecule synthesis inhibition assay showed that the synthesis rates of DNA, RNA, cell wall, and proteins, respectively, were strongly decreased. Transcriptome analysis of S. aureus exposed to sub-inhibitory concentrations of JBC 1847 identified a total of 78 downregulated genes, whereas not a single gene was found to be significantly upregulated. Most importantly, there was downregulation of genes involved in adenosintrifosfat (ATP)-dependent pathways, including histidine biosynthesis, which is likely to correlate with the observed lower level of intracellular ATP in JBC 1847–treated cells. Furthermore, we showed that JBC 1847 is bactericidal against both exponentially growing cells and cells in a stationary growth phase. In conclusion, our results showed that the antimicrobial properties of JBC 1847 were primarily caused by depolarization of the cell membrane resulting in dissipation of the proton motive force (PMF), whereby many essential bacterial processes are affected. JBC 1847 resulted in lowered intracellular levels of ATP followed by decreased macromolecule synthesis rate and downregulation of genes essential for the amino acid metabolism in S. aureus. Bacterial compensatory mechanisms for this proposed multi-target activity of JBC 1847 seem to be limited based on the observed very low frequency of resistance toward the compound.

Impact of High-Dose Irradiation on Human iPSC-Derived Cardiomyocytes Using Multi-Electrode Arrays: Implications for the Antiarrhythmic Effects of Cardiac Radioablation

Cardiac radioablation is emerging as an alternative option for refractory ventricular arrhythmias. However, the immediate acute effect of high-dose irradiation on human cardiomyocytes remains poorly known. We measured the electrical activities of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) upon irradiation with 0, 20, 25, 30, 40, and 50 Gy using a multi-electrode array, and cardiomyocyte function gene levels were evaluated. iPSC-CMs showed to recover their electrophysiological activities (total active electrode, spike amplitude and slope, and corrected field potential duration) within 3–6 h from the acute effects of high-dose irradiation. The beat rate immediately increased until 3 h after irradiation, but it steadily decreased afterward. Conduction velocity slowed in cells irradiated with ≥25 Gy until 6–12 h and recovered within 24 h; notably, 20 and 25 Gy-treated groups showed subsequent continuous increase. At day 7 post-irradiation, except for cTnT, cardiomyocyte function gene levels increased with increasing irradiation dose, but uniquely peaked at 25–30 Gy. Altogether, high-dose irradiation immediately and reversibly modifies the electrical conduction of cardiomyocytes. Thus, compensatory mechanisms at the cellular level may be activated after the high-dose irradiation acute effects, thereby, contributing to the immediate antiarrhythmic outcome of cardiac radioablation for refractory ventricular arrhythmias.

Peculiarities of the relationship between aggressive and protective factors of the gastric mucosa in patients with esophagogastroduodenal pathology with impaired adaptive potential and autonomic homeostasis (according to PRECISE-diagnostics)

Background. An imbalance of interaction between the sympathetic and parasympathetic links of the autonomic nervous system leads to autonomic dysregulation of the heart rate resulting in insufficient stress resistance, impaired adaptation and depletion of the protective mechanisms of the gastric mucosa. Therefore, the purpose of our research was to study adaptive potential of the body depending on the aggressive and protective factors of the gastric juice. Materials and methods. Seventy-one patients with esophagogastroduodenal pathology were examined using the method of PRECISE-diagnostics. The level of pH, pepsin, glycoproteins, fucose and sialic acids in the gastric contents was determined. The patients were divided into 3 representative groups: I — 30 individuals with hiatal hernia; II — 20 patients with achalasia cardia; III — 21 people with duodenal ulcer disease complicated by stenosis. Results. An imbalance of sympathetic and parasympathetic links of autonomic system was detected in 85.2 % of patients. The sympathetic mechanisms dominated in 71.3 % of cases. At the same time, most patients with achalasia cardia had vagotonia. The adaptive and compensatory mechanisms were identified after studying the relationship between the aggressive and protective factors of the gastric mucosa. When analyzing the correlation of aggressive and protective factors of gastric juice, the following adaptive and compensatory options were revealed: 1) hyperreactive, with simultaneous increase in the factors of both aggression and protection; 2) compensatory (an increase in the level of aggressive factors against the background of normal protective indicators); 3) decompensatory (an increase in the level of aggressive factors simultaneously with a decrease in protective factors). Conclusions. The adaptive potential of the body in 85.2 % of surgical patients, mostly those with hiatal hernia and achalasia cardia, according to PRECISE-diagnostics was defined as reduced, in the form of impaired adaptation in decompensatory type of the relationship between aggressive and protective factors of gastric juice.

Blink rate study in patients with Alzheimer's disease, Mild Cognitive Impairment and Subjective Cognitive Decline

Background: Blink rate (BR) is considered a marker of dopaminergic activity in humans. BR is increased in patients with Mild Cognitive Impairment (MCI), but no study has yet investigated whether BR changes with the progression of cognitive decline from MCI to Alzheimer’s disease (AD) and whether BR abnormalities are present in subjects with Subjective Cognitive Decline (SCD). Objective: The aim of our study was to assess BR in patients with AD, MCI, and SCD and to correlate BR with demographic and clinical features of cognitive decline. Methods: We enrolled 22 subjects with SCD, 23 with MCI, and 18 with AD and a group of 20 age-matched healthy controls (HCs). Cognitive function was assessed by testing global cognitive status and frontal, attentional, memory, verbal, and visuospatial functions. BR was measured by counting the number of blinks per minute. Results: MCI subjects had an increased BR (p<0.001), whereas AD subjects had a lower BR than HCs (p<0.05). Conversely, SCD subjects had a BR similar to HCs. No significant correlations emerged between neuropsychological scores and BR in SCD, MCI, and AD subjects. Conclusion: Increased BR in MCI likely reflects early compensatory mechanisms occurring before AD, whereas decreased BR in AD suggests dopaminergic system involvement in this condition.

A Window in the Heart Is Sometimes a Good Start: It’s Not Always Sepsis

Cardiac tamponade is a life-threatening compression of the heart caused by abnormal accumulation of pericardial fluid. Important elements affecting its disposition and treatment are the rate of fluid accumulation relative to pericardial stretch and the effectiveness of compensatory mechanisms before critical hemodynamic compromise occurs. It is a clinical diagnosis and waiting for the threshold of steep rise in cardiac transmural pressure to critical levels may lead to catastrophic outcomes which is why early drainage has to be strongly considered in suspected cases.

The Roles of Neurotrophins in Traumatic Brain Injury

Neurotrophins are a collection of structurally and functionally related proteins. They play important roles in many aspects of neural development, survival, and plasticity. Traumatic brain injury (TBI) leads to different levels of central nervous tissue destruction and cellular repair through various compensatory mechanisms promoted by the injured brain. Many studies have shown that neurotrophins are key modulators of neuroinflammation, apoptosis, blood–brain barrier permeability, memory capacity, and neurite regeneration. The expression of neurotrophins following TBI is affected by the severity of injury, genetic polymorphism, and different post-traumatic time points. Emerging research is focused on the potential therapeutic applications of neurotrophins in managing TBI. We conducted a comprehensive review by organizing the studies that demonstrate the role of neurotrophins in the management of TBI.