Mechanisms after the end of New Mechanism.

Mougenot and Matheson provide an interesting analysis on how some core ideas of the 'New Mechanists' - the proponents of a normative framework for scientific explanations based on the identification and description of mechanisms - might be relevant for the development of an embodied approach to cognitive neuroscience. Although we are highly sympathetic to such an approach, we struggle to identify the benefits of adopting the notion of mechanism for such enterprise.

Electrochemical Urea Production over Diatomic Fe-Ni Catalyst: a Mechanism for C-N Coupling.

Co-electrocatalytic reduction of CO2 and nitrate/nitrite as carbon and nitrogen sources to synthesize urea is an effective strategy to solve the energy problem and alleviate environmental pollution. In this work, combined density functional theory calculations with a constant-potential implicit solvent model, we proposed a strategy for the determination of the preferred reaction pathway and the potential window that is guided by the potential-dependent free energy change. It was found that on the FeNi-N6-C surface, the C-N coupling occurs between *NHO and the protonated CO2 in the potential window of -2.43 to -1.34 V for the urea electrochemical production, where the predicted onset potential accords well with the experimental results. The activity originates from the less weak bonding strength of N-O and the negatively charged N atom in *NHO. This study offers a general approach to determining the optimal reaction pathway in electrochemistry and insights into the mechanism of electrochemical synthesis of urea.

Turing and von Neumann machines: Completing the new mechanism.

Turing (1937) introduces a model of code that is followed by other pioneers of computing machines (such as Flowers 1983, Eckert, Mauchly, Brainerd 1945 and others). One of them is John von Neumann, who defines the concept of optimal code in the context of the conception of EDVAC. He later uses it to build on in his theoretical considerations of the universal constructor (von Neumann 1966). Von Neumann (1963) further presents one of the first neural network models, in relation to the work of McCulloch and Pitts (1943), for both theoretical purposes (von Neumann probe) and practical applications (computer architecture of EDVAC). The aim of this paper is (1) to describe the differences between Turing's and von Neumann's conceptualizations of code and the mechanical computing model. Between von Neumann's abstract technical conception (von Neumann 1963 and 1966) and Turing's more concrete biochemical conception (Turing 1952). Furthermore, (2) we want to answer the question why these influential models of mechanisms (predominantly in computer science) have so far been ignored by philosophers of the new mechanism (Machamer, Darden, Craver 2000, Glennan 2017). We will show that these classical models of machines are not only compatible with the new mechanism, but moreover complement it, since they represent a completely separate type of model of mechanism, alongside producing, maintaining and underlying (Zámecník 2021). The final (3) and main goal of our paper will be an attempt to relate von Neumann's and Turing's notion of mechanism to Barbieri's notion of extended mechanism (Barbieri 2015).

Targeted microbiome-sparing antibiotics.

A factor in our inability to meet the challenge of clinical antibiotic resistance has been the low productivity of research and development (R&D) efforts, with only incremental improvements on existing broad-spectrum classes coming into clinical use recently. The disappointing returns from this approach have focussed attention on narrower-spectrum antibiotics; such new agents are directed against the pathogen of relevance with the additional benefit of preserving the human microbiome(s). Our knowledge of the gut microbiome and its contribution to health homeostasis increases yearly and suggests that broad-spectrum treatments incur health costs beyond the initial infection. Improved diagnostics, antibiotic stewardship, and the crucial role of the gut microbiome in health indicate targeted agents as a more viable approach for future antibiotic R&D.

Finding of Remarkable Synergistic Effect on the Aroxyl-Radical-Scavenging Rates (ks) under the Coexistence of Vitamin E Homologues (or Vegetable Oils) and Ubiquinol-10: Proposal of A New Mechanism to Explain An Increase of ks Value.

Measurements of aroxyl (ArO · )-radical-scavenging rate constants (ksAOH) of antioxidants (AOHs) (i.e., α-, ß-, γ-, δ-Tocopherol (TocH) and ubiquinol-10 (UQ10H2)) were performed in ethanol/chloroform/H2O (50/50/1, v/v) solution, using stopped-flow spectrophotometry. ksAOH values were measured not only for each AOH, but also for the mixtures of two AOHs (i.e., TocH and UQ10H2). ksTocH values for α-, ß-, γ-, δ-TocH increased 1.21, 1.28, 1.55, and 1.19 times, respectively, under the coexistence of constant concentrations of UQ10H2. Similar measurements were performed for eight vegetable oils 1 - 8, containing different concentrations of α-, ß-, γ-, δ-tocopherol (TocH) and -tocotrienol (Toc-3H). ksOil values of all eight vegetable oils 1 - 8 also increased 1.24 - 1.54 times under the coexistence of constant concentrations of UQ10H2. A new mechanism to explain the notable increase of ksAOH values under the coexistence of two kinds of phenolic AOHs was proposed. UV-vis absorption of α-, ß-, γ-Toc · radicals, produced by reaction of α-, ß-, γ-TocHs (or vegetable oils 1 - 8) with ArO · , disappeared under the coexistence of TocHs (or oils) and UQ10H2, suggesting that the prooxidant reaction resulting from the presence of Toc · radicals is suppressed in the presence of UQ10H2.

A ratiometric fluorescence probe based on a novel recognition mechanism for monitoring endogenous hypochlorite in living cells.

A ratiometric fluorescence probe (named ZOC) for the fast detection of HClO/ClO- was constructed by coumarin (donor) and pyridinium (acceptor) based on Forster resonance energy transfer (FRET) and intramolecular charge transfer (ICT) platform. ZOC possessed red emission signal (610 nm), large Stocks shift (190 nm), high energy transfer efficiency (95.3%), high selectivity and sensitivity, low detection limit (25 nM), wider detection range (from 25 nM to 30 µM), rapid response (within 13 S), and good biocompatibility. It was very interesting that the recognition mechanism involved a new organic reaction in which olefin double bond reacted first with HClO/ClO- regioselectively, followed by cyclization. ZOC was successfully used to the real time detection of endogenous HClO/ClO- in RAW 264.7 cells.

Novel Classes of Antibacterial Drugs in Clinical Development, a Hope in a Post-antibiotic Era.

Bacterial resistance is a growing problem worldwide and is estimated that deaths by infectious diseases associated with resistant pathogens will generate 10 million deaths per year in 2050. This problem becomes more serious due to the low level of research and development of new drugs, which has fallen drastically in the last 40 years. For example, in the last decade of a total of 293 new drugs approved by the FDA, only 9 corresponded to antimicrobial drugs and none constituted a new structural class. The majority of the molecules in the clinical phase II or III, coming from modifications of drugs in clinical use, this strategy makes easier the bacterial susceptibility to generate resistance through the mechanisms expressed for their drug predecessors. Under this scenario, it is urgent to generate the most novel strategies for the development of antibacterial compounds with new targets or mechanism of action, without a structural relationship with the antibiotic drugs predecessors. Under this look, the present review addresses the development of the latest antibacterial drugs in clinical phases II and III, analyzing the design strategies by which these new molecules were obtained and the structure-activity relationship of these new families of antibiotics, in order to define the state of the vanguard antibacterial drugs in the post-antibiotic era.

Mutant p53 promotes cell spreading and migration via ARHGAP44.

The tumor suppressor p53 protein is either lost or mutated in about half of all human cancers. Loss of p53 function is well known to influence cell spreading, migration and invasion. While expression of mutant p53 is not equivalent to p53 loss, mutant p53 can acquire new functions to drive cell spreading and migration via different mechanisms. In our study, we found that mutant p53 significantly increased cell spreading and migration when comparing with p53-null cells. RNA-Seq analysis suggested that Rho GTPase activating protein 44 (ARHGAP44) is a new target of mutant p53, which suppressed ARHGAP44 transcription. ARHGAP44 has GAP activity and catalyze GTP hydrolysis on Cdc42. Higher level of GTP-Cdc42 was correlated with increase expression of mutant p53 and reduced ARHGAP44. Importantly, wt-ARHGAP44 but not mutant ARHGAP44 (R291A) suppressed mutant p53 mediated cell spreading and migration. Bioinformatics analysis indicated lower expression of ARHGAP44 in lung carcinoma compared with normal tissues, which was verified by RT-qPCR using specimens from patients. More interestingly, ARHGAP44 mRNA level was lower in tumors with mutant p53 than those with normal p53. Collectively, our results disclose a new mechanism by which mutant p53 stimulates cell spreading and migration.

Exploration of Novel Botanical Insecticide Leads: Synthesis and Insecticidal Activity of ß-Dihydroagarofuran Derivatives.

The discovery of novel leads and new mechanisms of action is of vital significance to the development of pesticides. To explore lead compounds for botanical insecticides, 77 ß-dihydroagarofuran derivatives were designed and synthesized. Their structures were mainly confirmed by (1)H NMR, (13)C NMR, DEPT-135°, IR, MS, and HRMS. Their insecticidal activity was evaluated against the third-instar larvae of Mythimna separata Walker, and the results indicated that, of these derivatives, eight exhibited more promising insecticidal activity than the positive control, celangulin-V. Particularly, compounds 5.7, 6.6, and 6.7 showed LD50 values of 37.9, 85.1, and 21.1 µg/g, respectively, which were much lower than that of celangulin-V (327.6 µg/g). These results illustrated that ß-dihydroagarofuran ketal derivatives can be promising lead compounds for developing novel mechanism-based and highly effective botanical insecticides. Moreover, some newly discovered structure-activity relationships are discussed, which may provide some important guidance for insecticide development.

Role of surfactant derived intermediates in the efficacy and mechanism for radiation chemical degradation of a hydrophobic azo dye, 1-phenylazo-2-naphthol.

A combined methodology involving gamma and pulse radiolysis, product analysis and toxicity studies has been adopted to comprehend the degradation process of a model hydrophobic azo dye, 1-phenylazo-2-naphthol, emphasizing the role of the surfactant, which is an integral part of textile waste. Two new and important findings are underlined in this article. The first is the direct attestation of the hydrazyl radical-parent adduct, formed in the reaction of the dye with e(-)aq followed by protonation and subsequent addition to the unreacted dye molecule. This has been confirmed from concentration dependent studies. Secondly, we have clearly shown that in the reaction of hydroxyl radical with the dye in Triton X-100 media, the initially produced TX radicals cause reductive degradation of the dye. Identification and detailed analysis of HPLC and GCMS data reveals that similar products are formed in both the reactions of e(-)aq and OH radicals. Moreover, the cytotoxicity of 10(-4)moldm(-3) dye was found to be reduced significantly after irradiation. Thus, the present study not only depicts new pathways for the degradation of hydrophobic azo dye, but also demonstrates the role of a surfactant in the entire process.

Oral iodinated activated charcoal improves lung function in patients with COPD.

The effect of 8 weeks treatment with oral iodinated activated charcoal (IAC) on lung function of patients with moderate chronic obstructive pulmonary disease (COPD) was examined in a double blind randomized placebo controlled parallel group study with 40 patients. In the IAC group, patients showed a statistically significant improvement of FEV1 baseline by 130 ml compared to placebo, corresponding to 8.2% improvement (p = 0.031*). Correlation statistics revealed that the improvement of FEV1 baseline was significantly correlated both to FEV1 post-bronchodilator (p = 0.0020**) and FEV1 post-exercise (0.033*) values. This demonstrates that the improved baseline lung function by IAC did not inhibit a further beta2-adrenoceptor relaxation, and thus that patients did not reach a limit for maximal improvement of the lung function after IAC treatment. Eight patients in the IAC group developed abnormal thyroid hormone levels transiently during the treatment. This side effect was not correlated to improvement of lung function (p = 0.82). No serious adverse effects directly related to the treatment were recorded. In summary, this study demonstrates that iodinated activated charcoal surprisingly and significantly improved lung function of patients with moderate COPD. The underlying mechanism of action is unclear, but is likely to be different from the drugs used today. The immediate conclusion is that further studies are now justified in order to determine clinical efficacy of IAC in COPD and explore possible mechanisms of action.