Design,Synthesis, and in vitro Evaluation of P2X7 Antagonists

The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan-1-yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand-based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two-electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl-cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2-chloro-N-[1-(3-(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide ( 56 ) exhibiting the best potency with an IC₅₀ value of 0.39 μM.     

Direct Observation at Room Temperature of the Orthorhombic Weyl Semimetal Phase in Thin Epitaxial MoTe2

The direct observation at room temperature (RT) of the noncentrosymmetric orthorhombic topological Weyl semimetal phase in epitaxial thin films of MoTe₂ grown on InAs(111)/Si(111) substrates by molecular beam epitaxy (MBE) is reported. The orthorhombic phase is typically found at lower temperatures but its observation at RT in this work is attributed to the enlarged lattice parameters, influenced by the substrate, which stabilize an interlayer antibonding state compatible with the orthorhombic stacking. First‐principles calculations predict eight type II Weyl nodes which are located below (but near) the Fermi energy making them accessible to charge transport and creating the prospect for practical applications exploiting the nontrivial topological properties. The orthorhombic phase coexists with an unconventional triclinic layer stacking which is different than the monoclinic or orthorhombic structures but it is centrosymmetric and topologically trivial.     

A kinetic study of oil deterioration during frying and a comparison with heating

The thermooxidative alterations of cottonseed oil during frying of potato chips without oil turnover, in a temperature range of 155–195°C, were studied. The results showed that the content of polar compounds, conjugated dienes, conjugated trienes, and p-anisidine value (p-AV) increased linearly with the time of frying at a rate depending on temperature. The rate constants showed a significant but low increase with temperature, except for the rate constant of conjugated trienes that was not correlated to frying temperature. The alterations induced by heating the oil were also measured and compared with those observed in frying at the same temperature. The major difference observed between frying and heating was related to the p-AV increase, which presented a considerably higher rate during heating. The FA content, as a function of process time during frying at 185°C, showed a significant increase in palmitic acid (C16∶0) and a significant decrease in linoleic acid (C18∶2). Oleic acid (C18∶1) also showed a small but significant decrease. The same results were obtained for the oil heated at 185°C. Examination of p-AV or conjugated dienes with polar compounds showed that both p-AV and conjugated dienes had a linear relationship with total polar compounds, with correlation coefficients of 0.946 and 0.862, respectively.     

Performance evaluation of the Cognitive Packet Network in the presence of network worms

Reliable networks that provide good service quality are expected to become more crucial in every aspect of communication, especially as the information transferred between network users gets more complex and demanding and as malicious users try to deliberately degrade or altogether deny legitimate network service. The Cognitive Packet Network (CPN) routing protocol provides Quality of Service (QoS) driven routing and performs self-improvement in a distributed manner, by learning from the experience of special packets, which gather on-line QoS measurements and discover new routes. Although CPN is generally very resilient to network changes, it may suffer worse performance during node failures caused by network threats, such as network worms. Here we evaluate the performance of CPN in such crises and compare it with the Open Shortest Path First (OSPF) routing protocol, an industry standard and widely used in Internet Protocol networks. We also improve it by introducing a failure detection element that reduces packet loss and delay during failures. Our experiments were performed in a real networking testbed.     

Technological properties and non-enzymatic browning of white lupin protein enriched spaghetti

Spaghetti was prepared by replacing semolina with different amounts of lupin protein, in order to increase the protein content. A detailed investigation of the rheological properties of the dough and the cooking quality of pasta was performed in comparison to standard semolina spaghetti. Moreover, the effect of the addition of lupin protein on non-enzymatic browning was evaluated by measuring ε-furoylmethyllysine (furosine) and 5-hydroxymethyl-2-furancarboxaldehyde (HMF), which are considered useful indices of semolina quality and pasta processing conditions. Dried spaghetti fortified with 5% of lupin protein isolate has a colour and rheological features comparable with the semolina sample and also the behaviour during cooking results to be satisfactory. As far as the thermal damage is concerned, the furosine values of fortified spaghetti differ only marginally from standard pasta and the percentage lysine loss is quite small (ranging from 12.1% to 15.7%).     

Pituitary–Adrenal Responses and Glucocorticoid Receptor Expression in Critically Ill Patients with COVID-19

The hypothalamus–pituitary–adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR).     

Using Computational Drug-Gene Analysis to Identify Novel Therapeutic Candidates for Retinal Neuroprotection

Retinal cell death is responsible for irreversible vision loss in many retinal disorders. No commercially approved treatments are currently available to attenuate retinal cell loss and preserve vision. We seek to identify chemicals/drugs with thoroughly-studied biological functions that possess neuroprotective effects in the retina using a computational bioinformatics approach. We queried the National Center for Biotechnology Information (NCBI) to identify genes associated with retinal neuroprotection. Enrichment analysis was performed using ToppGene to identify compounds related to the identified genes. This analysis constructs a Pharmacome from multiple drug-gene interaction databases to predict compounds with statistically significant associations to genes involved in retinal neuroprotection. Compounds with known deleterious effects (e.g., asbestos, ethanol) or with no clinical indications (e.g., paraquat, ozone) were manually filtered. We identified numerous drug/chemical classes associated to multiple genes implicated in retinal neuroprotection using a systematic computational approach. Anti-diabetics, lipid-lowering medicines, and antioxidants are among the treatments anticipated by this analysis, and many of these drugs could be readily repurposed for retinal neuroprotection. Our technique serves as an unbiased tool that can be utilized in the future to lead focused preclinical and clinical investigations for complex processes such as neuroprotection, as well as a wide range of other ocular pathologies.