Perception of Probabilities which are Subject to Change

To navigate stochastic and changing environments, people need to keep track of ongoing probabilities as those probabilities are subject to change. Two distinct theories of mental-model updating are compared. In trial-by-trial updating models, every sample is immediately integrated into a working estimate of the probability. In change-point detection, a single estimate of the probability is maintained until evidence accumulates to reject that model to adapt a new model. Disentangling these theories of updating frequencies has been difficult due to a confound found in previous tasks. Participants have been given their last response as their default response, and this has made it easier for them to maintain the same estimate rather than update it. This favours change-point models. To address whether response-maintenance is due to the extra effort it takes to update a response, participants were separated into two groups. In the Automatic condition, participants were given their old response as default. In the Manual condition, participants were given no default and were asked to generate a new estimate of the probability every trial. While offering a default response was found to partially explain response maintenance in previous tasks, it did not fully explain it. Participants in the Manual group showed spontaneous meticulous response maintenance over long series of trials despite being asked to respond anew every trial. This suggests that the hypothesis-testing strategy developed in the change-point detection literature is a fundamental component of probability estimation and is not an artifact of previous task designs

Placebos: Ethical research or unethical deceit

There is an ongoing debate between whether or not it is ethical for researchers to use placebos while studying terminal illnesses. Within this debate there are two parties, the party that believes that it is ethical and the party that believes that it is not. Both parties have many valid points and have very detailed arguments against one another. When determining whether or not the use of placebos is ethical or not, you must first understand what a placebo is, and what the different types are. This paper goes over what a placebo is, what the different types are, and the main points that each party has. This paper also goes over whether or not the use of placebo is ethical. Of course every person has their own ethical opinion

Impact of the Recognition Part of Dipeptidyl Nitroalkene Compounds on the Inhibition Mechanism of Cysteine Proteases Cruzain and Cathepsin L

Cysteine proteases (CPs) are an important class of enzymes, many of which are responsible for several human diseases. For instance, cruzain of protozoan parasite Trypanosoma cruzi is responsible for the Chagas disease, while the role of human cathepsin L is associated with some cancers or is a potential target for the treatment of COVID-19. However, despite paramount work carried out during the past years, the compounds that have been proposed so far show limited inhibitory action against these enzymes. We present a study of proposed covalent inhibitors of these two CPs, cruzain and cathepsin L, based on the design, synthesis, kinetic measurements, and QM/MM computational simulations on dipeptidyl nitroalkene compounds. The experimentally determined inhibition data, together with the analysis and the predicted inhibition constants derived from the free energy landscape of the full inhibition process, allowed describing the impact of the recognition part of these compounds and, in particular, the modifications on the P2 site. The designed compounds and, in particular, the one with a bulky group (Trp) at the P2 site show promising in vitro inhibition activities against cruzain and cathepsin L for use as a starting lead compound in the development of drugs with medical applications for the treatment of human diseases and future designs.This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (Grant PGC2021-23332OB-C21), Generalitat Valenciana and the European Regional Funds (Grant PROMETEO CIPROM/2021/079, IDIFEDER/2021/027), and Universitat Jaume I (UJI-B2020-03 and UJI-2021-71). K.A. thanks Generalitat Valenciana (APOSTD/2020/015) for a postdoctoral contract. The authors thankfully acknowledge the local computational resources of the Servei d’Informàtica and Serveis Centrals d’Instrumentació Científica of Universitat Jaume I

Antioxidant and Anti-Protease Activities of Diazepinomicin from the Sponge-Associated Micromonospora Strain RV115

Diazepinomicin is a dibenzodiazepine alkaloid with an unusual structure among the known microbial metabolites discovered so far. Diazepinomicin was isolated from the marine sponge-associated strain Micromonospora sp. RV115 and was identified by spectroscopic analysis and by comparison to literature data. In addition to its interesting preclinical broad-spectrum antitumor potential, we report here new antioxidant and anti-protease activities for this compound. Using the ferric reducing antioxidant power (FRAP) assay, a strong antioxidant potential of diazepinomicin was demonstrated. Moreover, diazepinomicin showed a significant antioxidant and protective capacity from genomic damage induced by the reactive oxygen species hydrogen peroxide in human kidney (HK-2) and human promyelocytic (HL-60) cell lines. Additionally, diazepinomicin inhibited the proteases rhodesain and cathepsin L at an IC50 of 70–90 µM. It also showed antiparasitic activity against trypomastigote forms of Trypanosoma brucei with an IC50 of 13.5 µM. These results showed unprecedented antioxidant and anti-protease activities of diazepinomicin, thus further highlighting its potential as a future drug candidate

2-Sulfonylpyrimidines as Privileged Warheads for the Development of S. aureus Sortase A Inhibitors

Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against S. aureus sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar K(I) values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the S ( N )Ar reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog