Standardization of Two Checked SARSCoV2 Pseudovirus Neutralization Assays regarding COVID19 Vaccine Examination

The POZ domain Krüppel-like zinc finger transcription repressor (POK family) contains many important molecules, including RP58, Bcl6 and PLZF. They function as transcription repressors via chromatin remodelling and histone deacetylation and are known to be involved in the development and tumourigenesis of various organs. Furthermore, they are important in the formation and function of the nervous system. This review summarizes the role of the POK family transcription repressors in the nervous system. We particularly targeted Rp58 (also known as Znf238, Znp238 and Zbtb18), a sequence-specific transcriptional repressor that is strongly expressed in developing glutamatergic projection neurons in the cerebral cortex. It regulates various physiological processes, including neuronal production, neuronal migration and neuronal maturation. Human studies suggest that reduced RP58 levels are involved in cognitive function impairment and brain tumour formation. This review particularly focuses on the mechanisms underlying RP58-mediated neuronal development and function. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http//onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc.Despite hypoxic respiratory failure representing a large portion of total hospitalizations and healthcare spending worldwide, therapeutic options beyond mechanical ventilation are limited. We demonstrate the technical feasibility of providing oxygen to a bulk medium, such as blood, via diffusion across nonporous hollow fiber membranes (HFMs) using hyperbaric oxygen. The oxygen transfer across Teflon® membranes was characterized at oxygen pressures up to 2 bars in both a stirred tank vessel (CSTR) and a tubular device mimicking intravenous application. Fluxes over 550 ml min-1  m-2 were observed in well-mixed systems, and just over 350 ml min-1  m-2 in flow through tubular systems. Oxygen flux was proportional to the oxygen partial pressure inside the HFM over the tested range and increased with mixing of the bulk liquid. Some bubbles were observed at the higher pressures (1.9 bar) and when bulk liquid dissolved oxygen concentrations were high. High-frequency ultrasound was applied to detect and count individual bubbles, but no increase from background levels was detected during lower pressure operation. A conceptual model of the oxygen transport was developed and validated. Model parametric sensitivity studies demonstrated that diffusion through the thin fiber walls was a significant resistance to mass transfer, and that promoting convection around the fibers should enable physiologically relevant oxygen supply. This study indicates that a device is within reach that is capable of delivering greater than 10% of a patient's basal oxygen needs in a configuration that readily fits intravascularly.
Malaria is one of the deadliest diseases in the world. Novel chemotherapeutic agents are urgently required to combat the widespread Plasmodium resistance to frontline drugs. Here, we report the discovery of a novel benzonaphthyridine antimalarial, methnaridine, which was identified using a structural optimization strategy.
An integrated pharmacological approach was used to evaluate the antimalarial profile of methnaridine. The pharmacokinetic properties of methnaridine were investigated along with the associated safety profile. Host immune response patterns were also analysed.
Methnaridine exhibited potent antimalarial activity against P. falciparum (3D7 IC
= 0.0066 μM; Dd2 IC
= 0.0056 μM). In P. berghei-infected mice, oral administration effectively suppressed parasitemia (ED
= 0.52 mg·kg
·day
) and cured the established infection (CD
= 10.13 mg·kg
·day
). These results are equivalent to or better than those of other antimalarial agents in clinical use. Notably, a four-dose oral regimen at a dosage of 25 mg·kg
achieved a complete cure of P. berghei infection in mice. Methnaridine exhibited a rapid parasiticidal profile (PCT
= 36.0 h) and showed no cross-resistance to chloroquine. Pharmacokinetic studies revealed that methnaridine is readily absorbed, long-lasting and slowly cleared. The safety profile of methnaridine is also satisfactory (maximum tolerated dose = 1,125 mg·kg
). In addition, following methnaridine treatment, infection-induced Th1 immune response was almost fully alleviated in mice.
Methnaridine is an orally bioavailable, fast-acting and long-lasting agent with excellent antimalarial properties. Our study highlights the potential of methnaridine for clinical development as a promising antimalarial candidate.
Methnaridine is an orally bioavailable, fast-acting and long-lasting agent with excellent antimalarial properties. Our study highlights the potential of methnaridine for clinical development as a promising antimalarial candidate.
The lack of selective sodium-calcium exchanger (NCX) inhibitors has hampered the exploration of physiological and pathophysiological roles of cardiac NCX 1.1. We aimed to discover more potent and selective drug like NCX 1.1 inhibitor.
A flavan series-based pharmacophore model was constructed. Virtual screening helped us identify a novel scaffold for NCX inhibition. A distinctively different NCX 1.1 inhibitor, ORM-11372, was discovered after lead optimization. Its potency against human and rat NCX 1.1 and selectivity against other ion channels was assessed. DNA Repair inhibitor The cardiovascular effects of ORM-11372 were studied in normal and infarcted rats and rabbits. Human cardiac safety was studied ex vivo using human ventricular trabeculae.
ORM-11372 inhibited human NCX 1.1 reverse and forward currents; IC
values were 5 and 6 nM respectively. ORM-11372 inhibited human cardiac sodium 1.5 (I
) and hERG K
11.1 currents (I
) in a concentration-dependent manner; IC
values were 23.2 and 10.0 μM. ORM-11372 caused no changes in action potential duration; short-term variability and triangulation were observed for concentrations of up to 10 μM. ORM-11372 induced positive inotropic effects of 18 ± 6% and 35 ± 8% in anaesthetized rats with myocardial infarctions and in healthy rabbits respectively; no other haemodynamic effects were observed, except improved relaxation at the lowest dose.
ORM-11372, a unique, novel, and potent inhibitor of human and rat NCX 1.1, is a positive inotropic compound. NCX inhibition can induce clinically relevant improvements in left ventricular contractions without affecting relaxation, heart rate, or BP, without pro-arrhythmic risk.
ORM-11372, a unique, novel, and potent inhibitor of human and rat NCX 1.1, is a positive inotropic compound. NCX inhibition can induce clinically relevant improvements in left ventricular contractions without affecting relaxation, heart rate, or BP, without pro-arrhythmic risk.