Different Types Of Inhibition Research Articles

Association between ADHD symptoms and inhibition-related brain activity using functional near-infrared spectroscopy (fNIRS)

Attention deficit hyperactivity disorder (ADHD) is associated with deficits in inhibitory functions including interference control, inhibition of prepotent/automatic responses and suppression of already initiated responses. This study used functional near-infrared spectroscopy (fNIRS) to investigate the neural basis of these three forms of inhibition assessed by a recently developed behavioral protocol combining the Stroop-matching/stop-signal task in twenty-five young adults with inattention, impulsivity and/or hyperactivity symptoms. The severity of ADHD symptoms was measured using the Adult ADHD Self-Report Scale (ASRS). The concentration of oxygenated hemoglobin (HbO) was assessed in the dorsolateral prefrontal cortex (DLPFC), inferior frontal gyrus (IFG) and temporoparietal regions (TP) during the Stroop-matching/stop-signal task. Correlations yielded significant associations between ASRS scores and HbO concentration in frontal regions during blocks with stop-signal tasks, namely the right IFG, the left DLPFC and the left IFG. This study revealed that different types of inhibition involve unique frontal and temporoparietal activities and linked frontal dysfunction during the suppression of ongoing responses to the severity of ADHD symptoms.

Selective effects of exercise on reactive and proactive inhibition in Parkinson's disease.

ObjectivePatients with Parkinson’s disease (PD) have an obvious motor inhibition disorder, which is closely related to their motor symptoms. Although previous studies have shown that exercise can improve their inhibition deficits, the effect of exercise on different types of inhibition (proactive and reactive inhibition) has not been addressed.MethodsWe used a behavioral paradigm combined with a series of questionnaires to explore the effect of long-term exercise on different types of motor inhibition in 59 patients with PD aged 55–75 years. According to the intensity and frequency of exercise, the participants were divided into regular-exercise and no-exercise groups. To obtain the average reference value for inhibition ability at the same age, we also recruited 30 healthy elderly people as controls.ResultsThe main defect in the motor inhibition of PD is reactive inhibition, while proactive inhibition has no obvious differences compared with healthy controls. Additionally, compared with the non-exercise group, PD in the exercise group showed significantly better reaction speeds and reactive control ability, fewer motor symptoms and negative emotions.ConclusionsTaken together, the motor inhibition defects of patients with PD affect only reactive inhibition. In addition, PD with exercise reported fewer negative emotions than that of the non-exercise group, indicating that exercise can relieve negative emotions and improve behavioral symptoms and quality of life in PD to a certain extent. We demonstrate for the first time that exercise has and can improve reactive inhibition in PD patients and has no effect on proactive inhibition.

The Relationship between the IC50 Values and the Apparent Inhibition Constant in the Study of Inhibitors of Tyrosinase Diphenolase Activity Helps Confirm the Mechanism of Inhibition.

Tyrosinase is the enzyme involved in melanization and is also responsible for the browning of fruits and vegetables. Control of its activity can be carried out using inhibitors, which is interesting in terms of quantitatively understanding the action of these regulators. In the study of the inhibition of the diphenolase activity of tyrosinase, it is intriguing to know the strength and type of inhibition. The strength is indicated by the value of the inhibition constant(s), and the type can be, in a first approximation: competitive, non-competitive, uncompetitive and mixed. In this work, it is proposed to calculate the degree of inhibition (), varying the concentration of inhibitor to a fixed concentration of substrate, L-dopa (D). The non-linear regression adjustment of with respect to the initial inhibitor concentration allows for the calculation of the inhibitor concentration necessary to inhibit the activity by 50%, at a given substrate concentration (IC50), thus avoiding making interpolations between different values of . The analytical expression of the IC50, for the different types of inhibition, are related to the apparent inhibition constant (. Therefore, this parameter can be used: (a) To classify a series of inhibitors of an enzyme by their power. Determining these values at a fixed substrate concentration, the lower IC50, the more potent the inhibitor. (b) Checking an inhibitor for which the type and the inhibition constant have been determined (using the usual methods), must confirm the IC50 value according to the corresponding analytical expression. (c) The type and strength of an inhibitor can be analysed from the study of the variation in and IC50 with substrate concentration. The dependence of IC50 on the substrate concentration allows us to distinguish between non-competitive inhibition ( does not depend on ) and the rest. In the case of competitive inhibition, this dependence of on leads to an ambiguity between competitive inhibition and type 1 mixed inhibition. This is solved by adjusting the data to the possible equations; in the case of a competitive inhibitor, the calculation of is carried out from the IC50 expression. The same occurs with uncompetitive inhibition and type 2 mixed inhibition. The representation of vs. n, with , allows us to distinguish between them. A hyperbolic vs. n representation that passes through the origin of coordinates is a characteristic of uncompetitive inhibition; the calculation of is immediate from the IC50 value. In the case of mixed inhibitors, the values of the apparent inhibition constant of meta-tyrosinase (Em) and oxy-tyrosinase (Eox), and the apparent inhibition constant of metatyrosinase/Dopa complexes (EmD) and oxytyrosinase/Dopa (EoxD), are obtained from the dependence of vs. n, and the results obtained must comply with the IC50 value.

A Michaelis-Menten rate model for the electrodialysis of concentrated salts

• A modified Michaelis-Menten model is presented for electrodialysis (ED). • Kinetics with concentrated salts are different than at low salt concentrations. • Electrodialysis of concentrated salts appear to follow saturation kinetics. • A standard electrical resistance model failed to adequately model the process. • The chemistry of the electrode rinse solution impacts the process kinetics. Volt-Amp profiles are used to describe electrodialysis (ED) dynamics when the concentration of the diluate is equal to the concentration of the concentrate and both are at high concentration. A standard electronic model that treats the ED process as a series of resistors failed to describe the performance of a 10-cell pair, 200 cm 2 per membrane pilot electrodialysis unit treating 0.5–6% NaCl. The standard electronic model resulted in a regression coefficient of R 2 < 0.76 and underestimated the observed system resistance by 0.54 to 1.1 Ohms depending on the conductivity of the test water. However, if the overall process was treated as a saturated chemical reaction, such as a modified Michaelis-Menten function, the regression exceeded R 2 > 0.999. The current was plotted as a function of the conductivity of the salt at a constant conductivity of electrode rinse solution. Each curve was a function of the applied voltage. The value of the saturation coefficient for the system plots as {D sat } ∼ 22.1 mS/cm (2.21 S/m). The kinetic coefficient i MAX plotted as a linear function of the effective voltage at 25 °C (298°K). More importantly, a series of tests with a constant feed conductivity and with varied electrode rinse solution conductivity also plotted as Michaelis-Menten type curves. The saturation coefficient for the electrode rinse solution also fitted well to {E sat } ∼ 22.1 mS/cm (2.21 S/m) and the values for i MAX were also linear with respect to applied voltage. Overall, the results from 12 data sets follow the formula i = αβi MAX where α and β are the ratios of the conductivity of the fluid divided by the sum of the conductivity plus the saturation, e.g., for electrode rinse solution α = {E}/({E} + {E sat }) and for the electrode rinse β = {D}/({D} + {D sat }), indicating the co-dependence of the feedstock and electrode rinse in the overall process dynamics. This interpretation is in opposition to the standard modeling of ED where the process is viewed as a series of resistances and the electrode rinse resistance is usually determined to be negligible. These data suggest that the effects of saturated feedstock and saturated rinse solution, measured as current or ion transport, are inextricably co-dependent. Three full-batch test runs of between 7.2 and 9-hr duration using different initial feedstock and electrode rinse water conditions were analyzed to estimate the relative effects of diluate and concentrate concentration on the test results. A third saturation coefficient was introduced, γ = {C}/({C} + {C sat }) where the terms {C} and {C sat } represent the conductivity and the saturation coefficient of the concentrate. The model for long duration batch tests, including the different effects of the concentrate and diluate, is well represented by i = (αβ 0.8 γ 0.2 i MAX ). The empirical power coefficients, β 0.8 and γ 0.2 , indicate that the diluate conductivity carries more influence on the rate of the process than does the conductivity of the concentrate. The model has the potential to allow for the scale-up of the ED process using at most one adjustable parameter (the saturation coefficient of the membrane measured as mS/cm or S/cm). Michaelis-Menten kinetics and the modifications by others represent a rich literature on the modeling of different types of inhibition, topics of concern for membrane transport phenomenon.

Regulating synchronous oscillations of cerebellar granule cells by different types of inhibition.

Synchronous oscillations in neural populations are considered being controlled by inhibitory neurons. In the granular layer of the cerebellum, two major types of cells are excitatory granular cells (GCs) and inhibitory Golgi cells (GoCs). GC spatiotemporal dynamics, as the output of the granular layer, is highly regulated by GoCs. However, there are various types of inhibition implemented by GoCs. With inputs from mossy fibers, GCs and GoCs are reciprocally connected to exhibit different network motifs of synaptic connections. From the view of GCs, feedforward inhibition is expressed as the direct input from GoCs excited by mossy fibers, whereas feedback inhibition is from GoCs via GCs themselves. In addition, there are abundant gap junctions between GoCs showing another form of inhibition. It remains unclear how these diverse copies of inhibition regulate neural population oscillation changes. Leveraging a computational model of the granular layer network, we addressed this question to examine the emergence and modulation of network oscillation using different types of inhibition. We show that at the network level, feedback inhibition is crucial to generate neural oscillation. When short-term plasticity was equipped on GoC-GC synapses, oscillations were largely diminished. Robust oscillations can only appear with additional gap junctions. Moreover, there was a substantial level of cross-frequency coupling in oscillation dynamics. Such a coupling was adjusted and strengthened by GoCs through feedback inhibition. Taken together, our results suggest that the cooperation of distinct types of GoC inhibition plays an essential role in regulating synchronous oscillations of the GC population. With GCs as the sole output of the granular network, their oscillation dynamics could potentially enhance the computational capability of downstream neurons.

A comparative study on the effects of resveratrol and oxyresveratrol against tyrosinase activity and their inhibitory mechanism

Resveratrol and oxyresveratrol are two natural polyhydroxy trans-stilbene products. Previous studies have shown that both of them can effectively inhibit the activity of tyrosinase. However, little attention has been paid to study the difference of their inhibitory mechanism. To reveal this difference, in this work a comparative study on the inhibitory effects of resveratrol and oxyresveratrol against cellular tyrosinase activity and melanin content were investigated by B16F0 cells, and the inhibitory mechanism of them on tyrosinase was revealed by cell-free tyrosinase inhibition, intrinsic fluorescence spectrum, circular dichroism and molecular docking. The results showed that the inhibitory capacity of oxyresveratrol toward tyrosinase activity and melanin formation was better than that of resveratrol. The difference of their inhibitory mechanism may be closely related to the different types of inhibition, the different strength of their interaction with tyrosinase and the different number of hydrogen bonds between them. The data in this study provide a scientific basis for revealing the inhibitory mechanisms of resveratrol and oxyresveratrol toward tyrosinase, and lay an experimental foundation for further development and utilization of them.

Действие двухвалентных катионов металлов на функционирование НАДФ+-зависимой малатдегидрогеназы из листьев кукурузы

Малатдегидрогеназа (МДГ, НАДФ-зависимая оксидоредуктаза, КФ 1.1.1.82) – НАДФ+-МДГ (КФ 1.1.1.82) является важным ферментом, метаболизирующим органические кислоты растений. Целью данной работы являлось определение таких регуляторных свойств энзима как влияение двухвалентных металлов на его активность. В качестве объекта исследования использовали листья 10-дневных проростков кукурузы. Разделение тканей проводили по методу Клечковского. Очистка фермента была проведена классическим методом. В качестве исследуемых ионов брались хлориды таких двухвалентных катионов металлов как магний, кальций, барий и марганец. Таким образом, четырех стадийная очистка, включающая в себя гомогенизацию, фракционирование сульфатом аммония, гель-фильтрацию на сефадексе G-25 и ионообменную хроматографию на ДЭАЭ-Sephacel, позволила получить высокоочищенные препараты НАДФ+-малатдегидрогеназы из мезофилла листьев кукурузы. При этом степень очистки выросла в 57 раз, а процент выхода исследуемого белка от общего равнялся 6%. Удельная активность очищенной НАДФ+-зависимой малатдегидрогеназы при пересчете на миллиграмм белка составила 91 ферментативную единицу. При универсальном окрашивании нитратом серебра и специфическом окрашивании тетразолиевым методом полиакриламидного геля, полученного после электрофореза очищенной МДГ, была обнаружена только одна белковая полоса, что свидетельствует о гомогенности очищенного препарата малатдегидрогеназы. Исследование влияния катионов различных металлов позволило выявить их действие на функционирование малатдегидрогеназы. Было изучено влияние хлоридов ионов Mg2+, Мn2+, Ва2+, Са2+ на активность очищенного препарата. Показано, что магний в небольших концентрациях (до 3 мМ) активирует НАДФ+-зависимый МДГ. Марганец и барий, напротив, ингибируют фермент. Ионы кальция не оказывали влияния на активность МДГ. Анализ полученных данных, осуществленный с помощью графиков Лайнуивера-Берка, позволил установить наличие разных типов ингибирования. Конкурентный тип ингибирования характерен для действия катионов марганца. Для катионов бария выявлен бесконкурентный тип торможения работы фермента.

Organic-Inorganic Composite Nanorods as an Excellent Mimicking Peroxidases for Colorimetric Detection and Evaluation of Antioxidant.

N,N'-Dicarboxy methyl perylene diimide-coated CeO2 nanorods (PDI/CeO2 NR) were synthesized via an ultrasonic-assisted method. PDI/CeO2 exhibits the superb mimic peroxidase functions confirmed by the catalyzed oxidation of TMB by hydrogen peroxide in less than 60 s along with color transformation from colorless to blue. The catalytic mechanism was confirmed to be an electronic transfer mechanism by fluorescence experiment. Thus, a visual colorimetric sensor was constructed for hydrogen peroxide detection with a low detection limit (LOD = 2.23 μM). Comparing the inhibition effects of l-cysteine (Cys), ascorbic acid (AA) and glutathione (GSH) on the catalytic oxidation of TMB, it can be found that they possessed different types of inhibition on the oxidation of TMB by H2O2 using PDI/CeO2, and AA has better antioxidant effect, followed by Cys and GSH. On the basis of the excellent antioxidant effect of AA, a low-cost colorimetric sensor was also used to detect AA, and a lower LOD value (0.68 μM) was obtained in the linear range of 5.0-30 μM.

Interaction of organotin compounds with three major glutathione S-transferases in zebrafish

Glutathione S-transferases (GSTs) play an important role in cellular detoxification as enzymatic mediators of glutathione (GSH) conjugation with a wide range of deleterious compounds, enabling their easier extrusion out of the organism. GSTs are shown to interact with organotin compounds (OTCs), known environmental pollutants, either as substrates, serving as electrophilic targets to the nucleophilic attack of GSH, or as noncompetitive inhibitors by binding to GST active sites and disrupting their enzymatic functions. There is a wide range of deleterious biological effects caused by OTCs in low concentration range. Their environmental concentrations, further potentiated by bioaccumulation in aquatic organisms, correspond with inhibitory constants reported for Gsts in zebrafish, which implies their environmental significance. Therefore, our main goal in this study was to analyze interactions of three major zebrafish Gsts – Gstp1, Gstr1, and Gstt1a – with a series of ten environmentally relevant organotin compounds. Using previously developed Gst inhibition assay with recombinant Gst proteins and fluorescent monochlorobimane as a model substrate, we determined Gst inhibitory constants for all tested OCTs. Furthermore, in order to elucidate nature of Gst interactions with OTCs, we determined type of interactions between tested Gsts and the strongest OTC inhibitors. Our results showed that OTCs can interact with zebrafish Gsts as competitive, noncompetitive, or mixed-type inhibitors. Determined types of interactions were additionally confirmed in silico by molecular docking studies of tested OTCs with newly developed Gst models. In silico models were further used to reveal structures of tested Gsts in more detail and identify crucial amino acid residues which interact with OTCs within Gst active sites. Our results revealed more extensive involvement of Gstr1 and Gstp1 in detoxification of numerous tested OTCs, with low inhibitory constants in nanomolar to low micromolar range and different types of inhibition, whereas Gstt1a noncompetitively interacted with only two tested OTCs with significantly higher inhibitory constants.

Phosphonic and Phosphinic Acid Derivatives as Novel Tyrosinase Inhibitors: Kinetic Studies and Molecular Docking.

A dozen of phosphonic and phosphinic acid derivatives containing pyridine moiety were synthesized and its inhibitory activity toward mushroom tyrosinase was investigated. Moreover, molecular docking of these compounds to the active site of the enzyme was performed. All the compounds (1-10) demonstrated the inhibitory effect with the IC50 and inhibition constants ranging millimolar concentrations. The obtained results indicate that the compounds show different types of inhibition (competitive, noncompetitive, mixed), but all of them are reversible inhibitors. The obtained outcomes allowed to make the structure-activity relationship (SAR) analysis. Compound 4 ([(benzylamino)(pyridin-2-yl)methyl]phenylphosphinic acid) revealed the lowest IC50 value of 0.3 mm and inhibitory constant of Ki 0.076 mm, with noncompetitive type and reversible mechanism of inhibition. According to SAR analysis, introducing bulky phenyl moieties to phosphonic and amino groups plays an important role in the inhibitory potency on activity of mushroom tyrosinase and could be useful in design and development of a new class of potent organophosphorus inhibitors of tyrosinase. Combined results of molecular docking and SAR analysis can be helpful in designing novel tyrosinase inhibitors of desired properties. They may have broad application in food industry and cosmetology.

Exploring Different Types of Inhibition During Bilingual Language Production.

Multilinguals have to control their languages constantly to produce accurate verbal output. They have to inhibit possible lexical competitors not only from the target language, but also from non-target languages. Bilinguals’ training in inhibiting incongruent or irrelevant information has been used to endorse the so-called bilingual advantage in executive functions, assuming a transfer effect from language inhibition to domain-general inhibitory skills. Recent studies have suggested that language control may rely on language-specific inhibitory control mechanisms. In the present study, unbalanced highly proficient bilinguals completed a rapid naming multi-inhibitory task in two languages. The task assessed three types of inhibitory processes: inhibition of the non-target language, inhibition of lexical competitors, and inhibition of erroneous auditory feedback. The results showed an interaction between lexical competition and erroneous auditory feedback, but no interactions with the inhibition of the non-target language. The results suggested that different subcomponents of language inhibition are involved during bilingual language production.

Specific features of l-histidine production by Escherichia coli concerned with feedback control of AICAR formation and inorganic phosphate/metal transport

BackgroundIn the l-histidine (His) biosynthetic pathway of Escherichia coli, the first key enzyme, ATP-phosphoribosyltransferase (ATP-PRT, HisG), is subject to different types of inhibition. Eliminating the feedback inhibition of HisG by the His end product is an important step that enables the oversynthesis of His in breeding strains. However, the previously reported feedback inhibition-resistant mutant enzyme from E. coli, HisGE271K, is inhibited by purine nucleotides, particularly ADP and AMP, via competitive inhibition with its ATP substrate. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), which is formed not only during His biosynthesis but also during de novo purine biosynthesis, acts as a natural analog of AMP and substitutes for it in some enzymatic reactions. We hypothesized that AICAR could control its own formation, particularly through the His biosynthetic pathway, by negatively influencing HisG enzymatic activity, which would make preventing ATP-PRT transferase inhibition by AICAR crucial for His overproduction.ResultsFor the first time, both the native E. coli HisG and the previously described feedback-resistant mutant HisGE271K enzymes were shown to be sensitive to inhibition by AICAR, a structural analog of AMP. To circumvent the negative effect that AICAR has on His synthesis, we constructed the new His-producing strain EA83 and demonstrated its improved histidine production. This increased production was particularly associated with the improved conversion of AICAR to ATP due to purH and purA gene overexpression; additionally, the PitA-dependent phosphate/metal (Me2+-Pi) transport system was modified by a pitA gene deletion. This His-producing strain unexpectedly exhibited decreased alkaline phosphatase activity at low Pi concentrations. AICAR was consequently hypothesized inhibit the two-component PhoBR system, which controls Pho regulon gene expression.ConclusionsInhibition of a key enzyme in the His biosynthetic pathway, HisG, by AICAR, which is formed in this pathway, generates a serious bottleneck during His production. The constructed His-producing strain demonstrated the enhanced expression of genes that encode enzymes involved in the metabolism of AICAR to ATP, which is a substrate of HisG, and thus led to improved His accumulation.

Distinct brain responses to different inhibitions: Evidence from a modified Flanker Task

Whether inhibition is a unitary or multifaceted construct is still an open question. To clarify the electrophysiological distinction among the different types of inhibition, we used a modified flanker paradigm, in which interference inhibition, rule inhibition, and response inhibition were compared to non-inhibition condition. The results indicated that, compared to the non-inhibition condition (1) the interference inhibition condition induced larger negativities during N2 epoch at the frontal region, (2) the rule inhibition condition elicited a larger N1 at the posterior region, followed by a larger P3a at the frontal region, reflecting the function of proactive cognitive control in the new stimulus-reaction (S-R) association, and (3) the response inhibition condition evoked a larger P3b at the posterior region, reflecting the process of suppressing the old response and reprogramming the new action. These findings provide new evidence that distinct neural mechanisms underlie different types of inhibition.

Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death.

Malaria is a life-threatening disease caused by different species of the protozoan parasite Plasmodium, with P. falciparum being the deadliest. Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes responsible for the synthesis of phosphatidylcholine and phosphatidylethanolamine are attractive drug targets to treat malaria as their selective inhibition leads to an arrest of the parasite’s growth and cures malaria in a mouse model. We present here a detailed study that reveals a mode of action for two P. falciparum choline kinase inhibitors both in vitro and in vivo. The compounds present distinct binding modes to the choline/ethanolamine-binding site of P. falciparum choline kinase, reflecting different types of inhibition. Strikingly, these compounds primarily inhibit the ethanolamine kinase activity of the P. falciparum choline kinase, leading to a severe decrease in the phosphatidylethanolamine levels within P. falciparum, which explains the resulting growth phenotype and the parasites death. These studies provide an understanding of the mode of action, and act as a springboard for continued antimalarial development efforts selectively targeting P. falciparum choline kinase.

Mathematica program: Its use to simulate metabolic irreversible pathways and inhibition of the first enzyme of a pathway by its end product as visualized with the reservoir model

The main objective of this report is to show the usefulness and versatility of the Mathematica program to simulate enzyme linear pathways and to depict the effect of changing the Vmax and/or Km values of one or more enzymes on the course of the reaction. In addition, analysis of the different types of inhibition of the first enzyme of the pathway by its end product is viewed with the reservoir model for enzyme kinetics. All the data shown here are quantitatively related to the kinetic constants of the implicated enzymes. Particular attention has been paid to calculate the time needed to achieve half of the possible total synthesis of the final product of a metabolic pathway.

THE IMPORTANCE OF INHIBITORS FOR THE SIMULATION OF METABOLIC PROCESSES: IN SILICOZn2+ INHIBITION OF m-ACONITASE FROM ANALYSIS OF GLYCOLYSIS AND KREBS CYCLE KINETIC MODELS

Metal ions have a major effect on the metabolic processes in cells either as inhibitors or as integral components of enzymes. The inhibition of enzymes can take place either through the inhibition of gene expression or through inhibition of protein function. A particularly interesting example of the effect of a metal ion on metabolism is the observed inhibition of Krebs cycle and alteration of energy metabolism by zinc (II) cations. In this particular case metal ion inhibition of enzyme is linked to one of the major functions of prostate cells of accumulation and excretion of citrate. Experimental results have shown that increase in concentration of zinc (II) in prostate cells effectively blocks progression of a part of the Krebs cycle leading to change in the concentration of several metabolites with largest effect in the accumulation of citrate. Based on previously reported experimental results, several distinct mechanisms for zinc (II) inhibition of Krebs cycle were proposed. In order to determine the precise mechanism of inhibition in this system, a mathematical model of glycolysis and Krebs cycle was constructed. Three different types of inhibition were analyzed, including competitive and uncompetitive inhibition as well as inhibition through the alteration of the expression level of m-aconitase. The effects of different inhibition models on metabolite concentrations were investigated as a time course simulation of the system of reactions. Several kinetic parameters in the model were optimized in order to best resemble experimental measurements. The simulation shows that only competitive inhibition leads to an agreement with experimental data.

Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for Down’s syndrome

Down's syndrome (DS), with an incidence of one in 800 live births, is the most common genetic disorder associated with mental retardation. This trisomy on chromosome 21 induces a variable phenotype in which the only common feature is the presence of mental retardation. The neural mechanisms underlying mental retardation might include defects in the formation of neuronal networks and neural plasticity. DS patients have alterations in the morphology, the density and the distribution of dendritic spines in the pyramidal neurons of the cortex. Our hypothesis is that the deficits in dendritic arborization observed in the principal neurons of DS patients and Ts65Dn mice (a model for DS that mimics most of the structural alterations observed in humans) may be mediated to some extent by changes in their inhibitory inputs. Different types of interneurons control different types of inhibition. Therefore, to understand well the changes in inhibition in DS, it is necessary to study the different types of interneurons separately. We have studied the expression of synaptophysin, Glutamic acid decarboxylase-67 (GAD-67) and calcium-binding protein-expressing cells in the primary somatosensory cortex of 4-5 month old Ts65Dn mice. We have observed an increment of GAD67 immunoreactivity that is related mainly to an increment of calretinin-immunoreactive cells and among them the ones with bipolar morphology. Since there is a propensity for epilepsy in DS patients, this increase in interneurons might reflect an attempt by the system to block overexcitation rather than an increment in total inhibition and could explain the deficit in interneurons and principal cells observed in elderly DS patients.

Inhibition Kinetics and the Aggregation of α-Glucosidase by Different Denaturants

Kinetic changes of alpha-glucosidase from Saccharomyces cerevisiae in guanidinium chloride (GdmCl) and SDS solutions were investigated. The results showed both denaturants can lead conformational changes and loss of enzymatic activities. However, the concentrations of denaturants causing loss of activities were much lower than that of conformational changes, which suggested that the conformation of active site of alpha-glucosidase was more fragile than the whole molecular conformation in response to the two denaturants. According to the different kinetic process of the enzyme in the GdmCl and SDS solutions, the further investigation on the process of denaturation were made, it showed GdmCl and SDS had different types of inhibition and different types of interaction with the enzyme. Furthermore, the mechanisms of the two denaturants were discussed.

Mechanism-Based Inhibition: Deriving KI and kinact Directly from Time-Dependent IC50 Values

The potential of enzyme inhibition of a drug is frequently quantified in terms of IC(50) values. Although this is a suitable quantity for reversible inhibitors, concerns arise when dealing with irreversible or mechanism-based inhibitors (MBIs). IC(50) values of MBIs are time dependent, causing serious problems when aiming at ranking different compounds with respect to their inhibitory potential. As a consequence, most studies and ranking schemes related to MBIs rely on the inhibition constant (K(I)) and the rate of enzyme inactivation (k(inact)) rather than on IC(50) values. In this article, the authors derive a novel relation between potentially time-dependent IC(50) values and K(I), k(inact) parameters for different types of inhibition. This allows for direct estimation of K(I) and k(inact) values from time-dependent IC(50) values, even without the need of additional preincubation experiments. The application of this approach is illustrated using a fluorimetric assay to access the drug-drug interaction potential associated with new chemical entities. The approach can easily be implemented using standard software tools (e.g., XLfit) and may also be suitable for applications where mechanism-based inhibition is a desired mode of action (e.g., at particular pharmacological drug targets).

Individual differences in experiencing intrusive memories: The role of the ability to resist proactive interference

This study explored whether a relatively poor ability to resist or inhibit interference from irrelevant information in working memory is associated with experiencing undesirable intrusive memories. Non-selected participants ( N = 91) completed a self-report measure of intrusive memories, and carried out experimental tasks intended to measure two different types of inhibition: resistance to proactive interference and response inhibition (i.e., the ability to prevent automatically triggered responses). The results showed a significant relationship between inhibition at the cognitive level (i.e., resistance to proactive interference) and the frequency of intrusive memories (especially in the group of female participants) whereas no such relationship with measures of response inhibition emerged. These findings are consistent with the idea that deficient inhibitory control reflects a vulnerability factor for experiencing intrusive memories. Implications for research investigating risk factors for the development of posttraumatic stress disorder (PTSD) are discussed.