Biology subjects

Segales, J.

Publications and source records attributed to Segales, J..

3 recordsLinked to original sources

bioRxiv2020

Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to successive stimulus.

The transcriptional profile of immediate early genes (IEGs) is indicative of the duration of neuronal activity, but it is unknown whether it affected by the strength of depolarization. Also unknown is whether an activity history of graded potential changes influences further neuronal activity. In this work with dissociated rat cortical neurons, we found mild depolarization - mediated by elevated extracellular KCl - not only induces a wide array of rapid IEGs, but also transiently depresses transcriptional and signaling responses to a successive stimulus. This latter effect was independent of de novo transcription, translation, calcineurin (CaN) signaling, and MAPK signaling downstream of PKC. Furthermore, as measured by multiple electrode arrays, mild depolarization acutely subdues subsequent spontaneous and bicuculline-evoked activity. Collectively, this work suggests that a recent history of graded potential changes acutely depresses neuronal intrinsic properties and subsequent responses. Such effects may have several potential downstream implications, including reducing signal-to-noise ratio during Hebbian plasticity processes.

neuroscience↗

bioRxiv2020

Cross-neutralization activity against SARS-CoV-2 is present in currently available intravenous immunoglobulins

BackgroundThere is a crucial need for effective therapies that are immediately available to counteract COVID-19 disease. Recently, ELISA binding cross-reactivity against components of human epidemic coronaviruses with currently available intravenous immunoglobulins (IVIG) Gamunex-C and Flebogamma DIF (5% and 10%) have been reported. In this study, the same products were tested for neutralization activity against SARS-CoV-2, SARS-CoV and MERS-CoV and their potential as an antiviral therapy. MethodsThe neutralization capacity of six selected lots of IVIG was assessed against SARS-CoV-2 (two different isolates), SARS-CoV and MERS-CoV in cell cultures. Infectivity neutralization was measured by determining the percent reduction in plaque-forming units (PFU) and by cytopathic effects for two IVIG lots in one of the SARS-CoV-2 isolates. Neutralization was quantified using the plaque reduction neutralization test 50 (PRNT50) in the PFU assay and the half maximal inhibitory concentration (IC50) in the cytopathic/cytotoxic method (calculated as the minus log10 dilution which reduced the viral titer by 50%). ResultsAll IVIG preparations showed neutralization of both SARS-CoV-2 isolates, ranging from 79 to 89.5% with PRNT50 titers from 4.5 to >5 for the PFU method and ranging from 47.0%-64.7% with an IC50 ~1 for the cytopathic method. All IVIG lots produced neutralization of SARS-CoV ranging from 39.5 to 55.1 % and PRNT50 values ranging from 2.0 to 3.3. No IVIG preparation showed significant neutralizing activity against MERS-CoV. ConclusionIn cell culture neutralization assays, the tested IVIG products contain antibodies with significant cross-neutralization capacity against SARS-CoV-2 and SARS-CoV. However, no neutralization capacity was demonstrated against MERS-CoV. These preparations are currently available and may be immediately useful for COVID-19 management.

immunology↗

bioRxiv2020

Search for SARS-CoV-2 inhibitors in currently approved drugs to tackle COVID-19 pandemia

There is an urgent need to identify therapeutics for the treatment of Coronavirus diseases 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication in vitro. Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18% had an IC50 below 25 M or 102 IU/mL. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell-type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.

microbiology↗