Time-dependent inhibition of covert shifts of attention

Buonocore A, Dietze N, McIntosh RD. Time-dependent inhibition of covert shifts of attention. Experimental brain research. 2021.Visual transients can interrupt overt orienting by abolishing the execution of a planned eye movement due about 90ms later, a phenomenon known as saccadic inhibition (SI). It is not known if the same inhibitory process might influence covert orienting in the absence of saccades, and consequently alter visual perception. In Experiment 1 (n=14), we measured orientation discrimination during a covert orienting task in which an uninformative exogenous visual cue preceded the onset of an oriented probe by 140-290ms. In half of the trials, the onset of the probe was accompanied by a brief irrelevant flash, a visual transient that would normally induce SI. We report a time-dependent inhibition of covert orienting in which the irrelevant flash impaired orientation discrimination accuracy when the probe followed the cue by 190 and 240ms. The interference was more pronounced when the cue was incongruent with the probe location, suggesting an impact on the reorienting component of the attentional shift. In Experiment 2 (n=12), we tested whether the inhibitory effect of the flash could occur within an earlier time range, or only within the later, reorienting range. We presented probes at congruent cue locations in a time window between 50 and 200ms. Similar to Experiment 1, discrimination performance was altered at 200ms after the cue. We suggest that covert attention may be susceptible to similar inhibitory mechanisms that generate SI, especially in later stages of attentional shifting (>200ms after a cue), typically associated with reorienting

Time – dependent inhibition of electric eel ache induced by chlorpyrifos

The aim of the work was to investigate the influence of contact time between acetylcholinesterase (AChE) and chlorpyrifos, on the sensitivity of earlier developed AChE based bioanalytical method for detection and determination of organophosphates in water samples. The IC50 values were obtained from the concentration- dependent responses of AChE activity to chlorpyrifos and they decreased with the increasing the contact time. The results indicated that the sensitivity of AChE based bioassay can be improved by increasing the time of incubation, but this comes at the expense of additional analysis time. In addition, the inhibition parameters of chlorpyrifos induced inhibition of AChE were determined.Physical chemistry 2008 : 9th international conference on fundamental and applied aspects of physical chemistry; Belgrade (Serbia); 24-28 September 200

New N,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

A series of N,N-dimethylcarbamates containing a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compounds 4 and 8, showed 85 and 69% of inhibition at 50 mM, respectively. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aromatics rings of the dibenzylamino group reduce the inhibitory power. Compound 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compound 4 and by MALDI-TOF MS analysis of trypsinized AChE inhibited by compound 4. Instead, compound 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain

α-VINYLLYSINE AND α-VINYLARGININE ARE TIME-DEPENDENT INHIBITORS OF THEIR COGNATE DECARBOXYLASES

(±)-α-Vinyllysine and (±)-α-vinylarginine display time-dependent inhibition of L-lysine decarboxylase from B. cadaveris, and L-arginine decarboxylase from E. coli, respectively. A complete Kitz-Wilson analysis has been performed using a modification of the Palcic continuous UV assay for decarboxylase activity

Time-dependent inhibition of oxygen radical induced lung injury

Experimental acute lung injury mediated by reactive metabolites of oxygen can be inhibited by the antioxidant enzymes catalase and Superoxide dismutase (SOD). However, the specific time interval during which these enzymes must be present in order to cause protection is not well defined. Using two experimental models of oxidant-dependent acute lung injury, one involving the intratracheal injection of glucose, glucose oxidase, and lactoperoxidase and the other involving the intravenous injection of cobra venom factor (CVF), we investigated the effects of delaying antioxidant administration on the outcome of the inflammatory response. In both cases, the protective effects of catalase and SOD were rapidly attenuated when their administration was delayed for a short period of time. For example, intratracheal catalase resulted in 98% protection when given simultaneously with the glucose oxidase and lactoperoxidase, but only 13% protection when the catalase was delayed 4 min. Likewise, in the CVF-induced lung injury model, intravenous catalase resulted in 40% protection when given simultaneously with the CVF, but only 2% protection when the catalase was delayed 20 min, even though the peak of the injury occurred hours after the initiation of the injury. A similar time dependence was seen with SOD. These results indicate that antioxidant therapy is required early in the course of oxygen radical-mediated acute lung injury for effective protection.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44504/1/10753_2004_Article_BF00914272.pd

Time-Dependent Inhibition by Naloxone, an Opiate Receptor Antagonist, of the Sensitization to Morphine-Induced Ambulatory Stimulation

Abstract:A significant sensitization to the ambulation-stimulating effect of morphine (10 mg/kg s.c.), a narcotic analgesic drug with agonistic action on opiate receptors, was produced when mice were repeatedly administered morphine at intervals of 3 days, and their ambulation was measured for 3 hr in an activity cage of 20 cm in diameter after each administration. Naloxone (0.01-1 mg/kg s.c.), an opiate receptor antagonist, blocked the morphine-induced ambulation in a dose-dependent manner. The mice treated with naloxone at post-morphine period of 3/4 hr and later showed a strong ambulatory sensitization as high as that in the mice repeatedly given morphine alone. The treatment with naloxone at post-morphine period of 1/2 hr caused a partial sensitization, and at 0-1/3 hr no significant sensitization. The repeated administrations of naloxone alone or saline caused no significant change in the sensitivity to morphine. These results suggest that experience of morphine effect and the resultant ambulation for 1/2 hr prior to the peak effect is important for induction of the sensitization to the ambulation-increasing effect of morphine in mice. This finding also indicates that the reward effect of morphine appears in the early post-morphine period prior to the peak effect, which is the essential factor for induction and maintenance of the abuse and dependence of narcotic analgesic drugs such as morphine and heroin

Inhibition of monocyte complement receptor enhancement by low molecular weight material from human lung cancers

We have studied the effect of dialysates from lung cancer homogenates to alter both the expression of complement (C3b) receptors per se and also to inhibit leucoattractant-induced enhancement of complement rosettes on monocytes from healthy individuals. Enhancement and enhancement-inhibition by tumour extracts were compared with material derived from normal lung excised from distance from the tumour. There was no significant difference between tumour homogenate (TH) and normal lung homogenate (NLH) in terms of enhancement of complement rosettes per se. In contrast, TH produced a dose- and time-dependent inhibition of leucoattractant-induced enhancement of C3b rosettes which was significantly different from that obtained with NLH. This enhancement-inhibition was observed with four undifferentiated, four squamous and three adenocarcinomas of lung. The degree of enhancement-inhibition was not related to the type of tumour or varying accompanying histological features such as necrosis and the degree of infiltration with inflammatory cells. Following gel filtration on Sephadex G-50 each type of cancer gave a major peak of inhibitory activity which eluted with molecules having an apparent molecular size of approximately 3,000 daltons. A second larger peak (8,000-10,000 daltons) was also detected with extracts from the undifferentiated and adenocarcinomas. These results support previous findings, mainly from experimental animals, indicating that 'anti-macrophage/monocyte principles' are elaborated from certain tumour types

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum-infected mice

Inactivation of Mandelate Racemase by 3-Hydroxypyruvate Reveals a Potential Mechanistic Link between Enzyme Superfamilies

Mandelate racemase (MR), a member of the enolase superfamily, catalyzes the Mg2+-dependent interconversion of the enantiomers of mandelate. Several α-keto acids are modest competitive inhibitors of MR [e.g., mesoxalate (Ki = 1.8 ± 0.3 mM) and 3-fluoropyruvate (Ki = 1.3 ± 0.1 mM)], but, surprisingly, 3-hydroxypyruvate (3-HP) is an irreversible, time-dependent inhibitor (kinact/KI = 83 ± 8 M–1 s–1). Protection from inactivation by the competitive inhibitor benzohydroxamate, trypsinolysis and electrospray ionization tandem mass spectrometry analyses, and X-ray crystallographic studies reveal that 3-HP undergoes Schiff-base formation with Lys 166 at the active site, followed by formation of an aldehyde/enol(ate) adduct. Such a reaction is unprecedented in the enolase superfamily and may be a relic of an activity possessed by a promiscuous progenitor enzyme. The ability of MR to form and deprotonate a Schiff-base intermediate furnishes a previously unrecognized mechanistic link to other α/β-barrel enzymes utilizing Schiff-base chemistry and is in accord with the sequence- and structure-based hypothesis that members of the metal-dependent enolase superfamily and the Schiff-base-forming N-acetylneuraminate lyase superfamily and aldolases share a common ancestor

New Tetromycin Derivatives with Anti-Trypanosomal and Protease Inhibitory Activities †

Four new tetromycin derivatives, tetromycins 1–4 and a previously known one, tetromycin B (5) were isolated from Streptomyces axinellae Pol001T cultivated from the Mediterranean sponge Axinella polypoides. Structures were assigned using extensive 1D and 2D NMR spectroscopy as well as HRESIMS analysis. The compounds were tested for antiparasitic activities against Leishmania major and Trypanosoma brucei, and for protease inhibition against several cysteine proteases such as falcipain, rhodesain, cathepsin L, cathepsin B, and viral proteases SARS-CoV Mpro, and PLpro. The compounds showed antiparasitic activities against T. brucei and time-dependent inhibition of cathepsin L-like proteases with Ki values in the low micromolar range