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  • Klitgaard Dalgaard posted an update 1 week, 2 days ago

    The Coronavirus disease-2019 (COVID-19) presents a variability of clinical symptoms, ranging from asymptomatic to severe respiratory and systemic conditions. In a cohort of patients, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), beyond the classical respiratory manifestations, induces anosmia. Evidence has suggested SARS-CoV-2-induced anosmia can be the result of neurodegeneration of the olfactory pathway. Neurologic symptoms associated with COVID-19 have been reported; however, the precise mechanism and possible long-lasting effects remain poorly investigated. Preclinical models are valuable tools for describing and testing new possible treatments for neurologic disorders. In this way, the zebrafish (Danio rerio) organism model represents an attractive tool in the field of neuroscience, showing economic and logistic advantages besides genetic and physiologic similarities with mammalian, including the brain structure and functions. Besides, its external embryonic development, high availability of eggs, and fast development allows easy genetic manipulation and fast replications. In the present review, we suggest that the zebrafish model can be advantageous to investigate the neurologic features of COVID-19.When animals repeatedly receive a combination of neutral conditional stimulus (CS) and aversive unconditional stimulus (US), they learn the relationship between CS and US, and show conditioned fear responses after CS. They show passive responses such as freezing or panic movements (classical or Pavlovian fear conditioning), or active behavioral responses to avoid aversive stimuli (active avoidance). Previous studies suggested the roles of the cerebellum in classical fear conditioning but it remains elusive whether the cerebellum is involved in active avoidance conditioning. In this study, we analyzed the roles of cerebellar neural circuits during active avoidance in adult zebrafish. When pairs of CS (light) and US (electric shock) were administered to wild-type zebrafish, about half of them displayed active avoidance. The expression of botulinum toxin, which inhibits the release of neurotransmitters, in cerebellar granule cells (GCs) or Purkinje cells (PCs) did not affect conditioning-independent swimming behaviors, but did inhibit active avoidance conditioning. Nitroreductase (NTR)-mediated ablation of PCs in adult zebrafish also impaired active avoidance. Furthermore, the inhibited transmission of GCs or PCs resulted in reduced fear-conditioned Pavlovian fear responses. Our findings suggest that the zebrafish cerebellum plays an active role in active avoidance conditioning.Growing evidence suggests an important role of the inflammatory component in heart failure (HF). Recent developments in this field indicate an ambiguous role that innate immunity plays in immune-driven HF. Damaged or stressed cells, cardiomyocytes, in particular, emit damage-associated molecular patterns (DAMPs) including HMGB1, S100 A8/A9, HSP70, and other molecules, unfolding paracrine mechanisms that induce an innate immune response. Designed as an adaptive, regenerative reaction, innate immunity may nevertheless become overactivated and thus contribute to the development of HF by altering the pacemaker rhythm, contraction, and electromechanical coupling, presumably by impairing the calcium homeostasis. The current review will explore a hypothesis of the involvement of the calcium-regulating hormones such as parathyroid hormone and parathyroid hormone-related protein in counteracting the detrimental impact of the excess of DAMPs and therefore improving the functional cardiac characteristics especially in the acute phase of the disease.Overview of Black DM, Geiger EJ, Eastell MD, et al Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. New Engl J Med 2020;383743-753.Tropifexor (NVP-LJN452) is a highly potent, selective, nonsteroidal, non-bile acid farnesoid X receptor agonist for the treatment of nonalcoholic steatohepatitis. Its absorption, metabolism, and excretion were studied after a 1-mg oral dose of [14C]tropifexor was given to four healthy male subjects. Mass balance was achieved with ∼94% of the administered dose recovered in excreta through a 312-hour collection period. Enfortumab vedotin-ejfv Fecal excretion of tropifexor-related radioactivity played a major role (∼65% of the total dose). Tropifexor reached a maximum blood concentration (Cmax) of 33.5 ng/ml with a median time to reach Cmax of 4 hours and was eliminated with a plasma elimination half-life of 13.5 hours. Unchanged tropifexor was the principal drug-related component found in plasma (∼92% of total radioactivity). Two minor oxidative metabolites, M11.6 and M22.4, were observed in circulation. Tropifexor was eliminated predominantly via metabolism with >68% of the dose recovered as metabolites in excreta. Oxidative metaboliative process becoming more important at lower concentrations near clinical exposure range. The body of work demonstrated the importance of carefully designed in vivo and in vitro experiments for better understanding of disposition processes during drug development.The increasing incidence of ocular diseases has accelerated research into therapeutic interventions needed for the eye. Ocular enzymes play important roles in the metabolism of drugs and endobiotics. Various ocular drugs are designed as prodrugs that are activated by ocular enzymes. Moreover, ocular enzymes have been implicated in the bioactivation of drugs to their toxic metabolites. The key purpose of this study was to compare global proteomes of the pooled samples of the eye (n=11) and the liver (n=50), with a detailed analysis of the abundance of enzymes involved in the metabolism of xenobiotics and endobiotics. We used the post-mitochondrial supernatant fraction (S9 fraction) of the lens-free whole eye homogenate as a model to allow accurate comparison with the liver S9 fraction. A total of 269 proteins (including 23 metabolic enzymes) were detected exclusively in the pooled eye S9, against 648 proteins in the liver S9 (including 174 metabolic enzymes), whereas 424 proteins (including 94 metabolic enzymes) were detected in both the organs.