3D-QSAR Study of New Acetyl-COA:Cholesterol O-Acyl Transferase (ACAT) Inhibitors

3D QSAR models using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) were built on a training set of 19 previously described inhibitors of acetyl-CoA:cholesterol O-acyl transferase (ACAT) with a IC50 ranging from 47 nM to 200 µM. The models thus obtained were found to be predictive as shown by correct prediction of the inhibitory activity of a set of recently published compounds

Techno-economic optimisation of a sodium{ extendash}chloride salt heat exchanger for concentrating solar power applications

To enhance the economic viability of Concentrating solar power (CSP) plant, recent efforts have been directed towards employing high-temperature working fluid in the receiver and incorporating higher-efficiency power cycles. This work presents a techno-economic analysis of a sodium–chloride salt heat exchanger included in a sodium-driven CSP system with a supercritical CO2 power block. A quasi-steady state heat exchanger model was developed based on the TEMA guidelines, with the possibility of being customised in terms of media adopted, constraints, boundary conditions, and heat transfer correlations. The sodium–salt heat exchanger has been designed aiming at minimising the Levelized Cost of Electricity (LCOE) of the plant. The performance and the design of the proposed heat exchanger have been evaluated via multi-objective optimisation and sensitivity analyses. Results show that advanced CSP systems employing sodium and an indirect chloride salt storage can represent an economically viable solution and can drive towards the future goal of 5 USD/MWh. For a base-case 100 MWe plant with 12 h of storage, a LCOE of 72.7 USD/MWh and a capacity factor (CF) higher than 60% were reached. The techno-economic investigations showed the potential LCOE reduction of 6% as well as the flexibility and robustness of the heat exchanger model. The developed tool lays the groundwork to explore potential improvements of this new generation of CSP systems

Resolution of enuresis with aripiprazole in children with psychiatric disorders: two case reports

Background: Aripiprazole is a third-generation atypical antipsychotic drug that acts as a stabilizer of the dopaminergic and serotonergic system. As partial agonist of the dopamine (D2) and serotonin (5-HT1A) receptors, it appears to be efective in reducing mania in patients with bipolar disorder, tics in Tourette Syndrome, aggression in schizophrenia and autism spectrum disorder. Enuresis has been reported among its side efects. Only a few studies, with conficting results, have investigated the relationship between aripiprazole and enuresis. Case presentation: We report the disappearance of enuresis in a Caucasian girl with intellectual disability and oppositional defant disorder and in a Caucasian boy with intellectual disability and early-onset psychosis, both following initiation of treatment with aripiprazole. Conclusion: The aim of this study was to contribute to the literature on the use of aripripazole in subjects with enuresis. Our fndings lead us to suggest that aripiprazole is less burdened with side efects, including bedwetting, than other antipsychotic drugs

In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase

Human norovirus causes approximately 219,000 deaths annually, yet there are currently no antivirals available. A virtual screening of commercially available drug-like compounds (~300,000) was performed on the suramin and PPNDS binding-sites of the norovirus RNA-dependent RNA polymerase (RdRp). Selected compounds (n = 62) were examined for inhibition of norovirus RdRp activity using an in vitro transcription assay. Eight candidates demonstrated RdRp inhibition (>25% inhibition at 10 μM), which was confirmed using a gel-shift RdRp assay for two of them. The two molecules were identified as initial hits and selected for structure-activity relationship studies, which resulted in the synthesis of novel compounds that were examined for inhibitory activity. Five compounds inhibited human norovirus RdRp activity (>50% at 10 μM), with the best candidate, 54, demonstrating an IC50 of 5.6 μM against the RdRp and a CC50 of 62.8 μM. Combinational treatment of 54 and the known RdRp site-B inhibitor PPNDS revealed antagonism, indicating that 54 binds in the same binding pocket. Two RdRps with mutations (Q414A and R419A) previously shown to be critical for the binding of site-B compounds had no effect on inhibition, suggesting 54 interacts with distinct site-B residues. This study revealed the novel scaffold 54 for further development as a norovirus antiviral

Third Case of Visceral Leishmaniasis in COVID-19: Mini Review Article

Background: In the currently ongoing coronavirus pandemic, coinfections with unrelated life-threatening febrile conditions may pose a particular challenge to clinicians. Leishmaniasis is a zoonosis that may present general symptoms, including fever, malaise, and arthralgia, rendering it indistinguishable from COVID-19. Methods: In this paper, we aim to draw attention to this issue and analyze the clinical characteristics of the coinfection SARS-CoV-2/Leishmania through a systematic review of the literature. We were motivated by the observation of the first case of visceral leishmaniasis and COVID-19 in a paediatric patient. Conclusion: Our case is a reminder for healthcare providers to consider the diagnosis of visceral leishmaniasis in patients presenting with febrile syndrome in endemic regions during the COVID-19 pandemic

Parameters for irreversible inactivation of monoamine oxidase

Funding:RRR, AA, SH and SB are grateful to COST Action CA13153 for facilitating their collaboration and funding short-term visits. AA acknowledges funding under P1-0005 (Slovenian Research Agency). The APC was funded by MDPI.The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO, hydrazines, cyclopropylamines and propargylamines form a covalent adduct with the flavin cofactor. To assist the design of new compounds to combat neurodegeneration, we have updated the kinetic parameters defining the interaction of these established drugs with human MAO-A and MAO-B and analyzed the required features. The Ki values for binding to MAO-A and molecular models show that selectivity is determined by the initial reversible binding. Common to all the irreversible inhibitor classes, the non-covalent 3D-chemical interactions depend on a H-bond donor and hydrophobic-aromatic features within 5.7 angstroms apart and an ionizable amine. Increasing hydrophobic interactions with the aromatic cage through aryl halogenation is important for stabilizing ligands in the binding site for transformation. Good and poor inactivators were investigated using visible spectroscopy and molecular dynamics. The initial binding, close and correctly oriented to the FAD, is important for the oxidation, specifically at the carbon adjacent to the propargyl group. The molecular dynamics study also provides evidence that retention of the allenyl imine product oriented towards FADH− influences the formation of the covalent adduct essential for effective inactivation of MAO.Publisher PDFPeer reviewe

In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase

Human norovirus causes approximately 219,000 deaths annually, yet there are currently no antivirals available. A virtual screening of commercially available drug-like compounds (~300,000) was performed on the suramin and PPNDS binding-sites of the norovirus RNA-dependent RNA polymerase (RdRp). Selected compounds (n = 62) were examined for inhibition of norovirus RdRp activity using an in vitro transcription assay. Eight candidates demonstrated RdRp inhibition (>25% inhibition at 10 μM), which was confirmed using a gel-shift RdRp assay for two of them. The two molecules were identified as initial hits and selected for structure-activity relationship studies, which resulted in the synthesis of novel compounds that were examined for inhibitory activity. Five compounds inhibited human norovirus RdRp activity (>50% at 10 μM), with the best candidate, 54, demonstrating an IC50 of 5.6 μM against the RdRp and a CC50 of 62.8 μM. Combinational treatment of 54 and the known RdRp site-B inhibitor PPNDS revealed antagonism, indicating that 54 binds in the same binding pocket. Two RdRps with mutations (Q414A and R419A) previously shown to be critical for the binding of site-B compounds had no effect on inhibition, suggesting 54 interacts with distinct site-B residues. This study revealed the novel scaffold 54 for further development as a norovirus antiviral

Fishers’ Perception on the Interaction between Dolphins and Fishing Activities in Italian and Croatian Waters

Interactions between fishing and dolphins can be detrimental, since on one hand dolphins can be lethally entangled by nets and trawls, and on the other dolphins can predate fish caught by nets. For dolphins, this interaction can be dangerous as they can be wounded or accidentally killed; for fishers, the predation of their catch results in economic losses due to reduced quantity and/or quality of catches and damage to fishing gear. During July and November 2020, we surveyed the “dolphin–fisheries conflict” through compiling 209 fisher interviews from nine locations in Italy and Croatia. Fishers mentioned the common bottlenose dolphin (Tursiops truncatus) as the species primarily interacting with fishing, with the major issue being catch damage by predation. The interaction probability varied among gears and seasons, with some fishing activities (e.g., passive nets) more affected than others (e.g., bottom trawls), especially in terms of economic loss (1000–10,000 €/year on average). More than 70% of the fishers claimed that dolphin populations have increased over the last 10 years, in different degrees and based on different areas. Dolphin bycatch rates are generally low; however, 34.6% of respondents reported having captured at least one dolphin during their career. The fishers’ attitude towards acoustic deterrents (“pingers”) as a mitigation measure revealed that few of them were aware of these devices or were using them