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Abstract Background Neural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimer’s disease (AD) pathology. Addressing these impairments by using neurotrophic factors is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations. Methods Here, we use a combination of mouse and human stem cell models for comprehensive in-vitro characterization of a novel neurogenic compound, focusing on the brain-derived neurotrophic factor (BDNF) pathway. The ability of ENT-A011, a steroidal dehydroepiandrosterone derivative, to activate the tyrosine receptor kinase B (TrkB) receptor was tested through western blotting in NIH-3T3 cells and its neurogenic and neuroprotective action were assessed through proliferation, cell death and Amyloid-β (Aβ) toxicity assays in mouse primary adult hippocampal NSCs, mouse embryonic cortical NSCs and neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. RNA-seq profiling was used to assess if the compound acts through the same gene network as BDNF in human NPCs. Results ENT-A011 was able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Aβ-induced cell death, acting selectively through TrkB activation. The compound was able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from Αβ toxicity and prevent synapse loss after Aβ treatment. ENT-A011 successfully induces proliferation and prevents cell death after Aβ toxicity in human NPCs, acting through a core gene network shared with BDNF as shown through RNA-seq. Conclusions Our work characterizes a novel BDNF mimetic with preferable pharmacological properties and neurogenic and neuroprotective actions in Alzheimer’s disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing.

Neurotrophins are growth factors that exert important neuroprotective effects by preventing neuronal death and synaptic loss. Nerve Growth Factor (NGF) acts through the activation of its high-affinity, pro-survival TrkA and low-affinity, pro-apoptotic p75NTR receptors. NGF has been shown to slow or prevent neurodegenerative signals in Alzheimer’s Disease (AD) progression. However, its low bioavailability and its blood–brain-barrier impermeability limit the use of NGF as a potential therapeutic agent against AD. Based on our previous findings on synthetic dehydroepiandrosterone derivatives, we identified a novel NGF mimetic, named ENT-A013, which selectively activates TrkA and exerts neuroprotective, anti-amyloid-β actions. We now report the chemical synthesis, in silico modelling, metabolic stability, CYP-mediated reaction phenotyping and biological characterization of ENT-A013 under physiological and neurodegenerative conditions. We show that ENT-A013 selectively activates the TrkA receptor and its downstream kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death. Moreover, ENT-A013 promotes survival of primary Dorsal Root Ganglion (DRG) neurons upon NGF withdrawal and protects hippocampal neurons against Amyloid β-induced apoptosis and synaptic loss. Furthermore, this neurotrophin mimetic partially restores LTP impairment. In conclusion, ENT-A013 represents a promising new lead molecule for developing therapeutics against neurodegenerative disorders, such as Alzheimer’s Disease, selectively targeting TrkA-mediated pro-survival signals.

Neurotrophins are growth factors that exert important neuroprotective effects by preventing neuronal death and synaptic loss. Nerve Growth Factor (NGF) acts through the activation of its high-affinity, pro-survival TrkA and low-affinity, pro-apoptotic p75NTR receptors. NGF has been shown to slow or prevent neurodegenerative signals in Alzheimer's Disease (AD) progression. However, its low bioavailability and its blood–brain-barrier impermeability limit the use of NGF as a potential therapeutic agent against AD. Based on our previous findings on synthetic dehydroepiandrosterone derivatives, we identified a novel NGF mimetic, named ENT-A013, which selectively activates TrkA and exerts neuroprotective, anti-amyloid-β actions. We now report the chemical synthesis, in silico modelling, metabolic stability, CYP-mediated reaction phenotyping and biological characterization of ENT-A013 under physiological and neurodegenerative conditions. We show that ENT-A013 selectively activates the TrkA receptor and its downstream kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death. Moreover, ENT-A013 promotes survival of primary Dorsal Root Ganglion (DRG) neurons upon NGF withdrawal and protects hippocampal neurons against Amyloid β-induced apoptosis and synaptic loss. Furthermore, this neurotrophin mimetic partially restores LTP impairment. In conclusion, ENT-A013 represents a promising new lead molecule for developing therapeutics against neurodegenerative disorders, such as Alzheimer's Disease, selectively targeting TrkA-mediated pro-survival signals. [ABSTRACT FROM AUTHOR]

Abstract: In this paper the control scheme of a three-level three-phase inverter for grid integration of distributed generation (DG) units is investigated. Furthermore, the inverter compensates the reactive power of the load. The presented control scheme is based on instantaneous power theory in order to generate the appropriate inverter reference currents. In the outer DC bus voltage control loop and in the inner current control loop, the fuzzy logic (FL) control and the Proportional-Resonant (PR) control is applied respectively. The switching pattern generation is achieved using Space Vector Pulse Width Modulation technique. The steady state and dynamic response of the proposed electric power system has been evaluated under various operating conditions. Simulation results verify the effectiveness of the proposed control system. [Copyright &y& Elsevier]

Abstract: This paper presents a novel control scheme for a distribution static compensator (DSTATCOM) aimed at mitigating voltage sag at the Point of Common Coupling (PCC) or eliminating current harmonics of the load. The proposed control scheme uses the d–q reference frame for the decoupling of active and reactive current components. Furthermore a selective algorithm is integrated to the control scheme in order to choose between the voltage support mode or the current harmonics elimination mode. Finally, the DSTATCOM is based on a three phase three level flying capacitor topology. The proposed control scheme outperforms the conventional one due to the ability of the suggested control system to combine multiple functions, allowing DSTATCOM to respond in various power quality issues. The effectiveness of the proposed control scheme to enhance the multifunction ability of the DSTATCOM is verified via Matlab/Simulink© in both steady state and transient response. [Copyright &y& Elsevier]

The control scheme of a three-phase three-level neutral point clamped shunt active power filter (SAPF) is considered in this paper. The control scheme of the SAPF applies the α-β reference frame. The current control and the switching pattern generation are based on the PR current control and on the Space Vector Modulation technique, respectively. However, for the performance improvement of the SAPF, a novel fuzzy PR current controller is proposed and used. The effectiveness of the SAPF both in steady state and transient response is investigated. Moreover, the superiority of the proposed fuzzy PR current controller over the conventional PR controller is established based on test cases where either the electrical components of the electric power system change through time or the current measurements are affected by white noise. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, a photovoltaic (PV) system, with maximum power point tracking (MPPT), connected to a three phase grid is presented. The connection of photovoltaic system on the grid takes place in one stage using voltage source inverter (VSI). For a better utilization of the photovoltaic system, the control strategy applied is based on p–q theory. According to this strategy during sunlight the system sends active power to the grid and at the same time compensates the reactive power of the load. In case there is no sunlight (during the night for instance), the inverter only compensates the reactive power of the load. In this paper the use of p–q theory to supply the grid with active power and compensate the reactive power of the load is investigated. The advantage of this control strategy is that the photovoltaic system is operated the whole day. Furthermore, the p–q theory uses simple algebraic calculations without demanding the use of PLL to synchronize the inverter with the grid. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against COVID-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments., (© 2023 The Authors. Molecular Informatics published by Wiley-VCH GmbH.)