Impact of detergents on the activity of acetylcholinesterase and on the effectiveness of its inhibitors

2009 ◽  
Vol 390 (1) ◽  
Author(s):  
Martina Zimmermann ◽  
Martin S. Westwell ◽  
Susan A. Greenfield
Keyword(s):  
Enzyme Inhibitor ◽  
Biochemical Study ◽  
Tetrabutylammonium Bromide ◽  
Procaine Hydrochloride ◽  
High Cholesterol ◽  
Current Standard ◽  
Ache Inhibitors ◽  
Amphiphilic Molecules ◽  
Detergent Enzyme ◽  
The Impact

Abstract Acetylcholinesterase (AChE) plays a central role in the development of Alzheimer's disease: AChE inhibition for preventing the characteristic dwindling of acetylcholine levels constitutes the current standard treatment for the disorder. Amongst the diverse risk factors contributing to the degenerative process, high cholesterol causes a reduction in the effectiveness of the otherwise therapeutic inhibitors of AChE. Our biochemical study on the activity of AChE elucidates the effect of amphiphilic molecules on the activity and kinetics of AChE, and sheds light onto the nature of the impact of these amphiphilic molecules on enzyme-inhibitor interactions. Using kinetic studies we discovered that detergents alter the enzymatic activity of AChE through an uncompetitive mechanism. Additional experiments using AChE inhibitors (amphiphilic procaine hydrochloride, hydrophobic tetrabutylammonium bromide) in the absence or presence of detergent further illustrate the detergent-enzyme-solvent interactions. The results contribute to the understanding of the importance of hydrophobic-lipophilic interactions for the correct function of AChE and its inhibitors. We present a model system for the study of lipid-related alterations in the activity of isolated AChE in the central nervous system. This model may also be used to assess and predict the effectiveness of AChE inhibitors, which are traditionally used for the treatment of cognitive impairment, under pathological (high-cholesterol) conditions.

Systematic benchmark of ancient DNA read mapping

2021 ◽  
Author(s):  
Adrien Oliva ◽  
Raymond Tobler ◽  
Alan Cooper ◽  
Bastien Llamas ◽  
Yassine Souilmi
Keyword(s):  
Ancient Dna ◽  
Dna Sequences ◽  
Population Genetic ◽  
Reference Genome ◽  
Population Data ◽  
Human Populations ◽  
Current Standard ◽  
Read Mapping ◽  
Reference Bias ◽  
The Impact

Abstract The current standard practice for assembling individual genomes involves mapping millions of short DNA sequences (also known as DNA ‘reads’) against a pre-constructed reference genome. Mapping vast amounts of short reads in a timely manner is a computationally challenging task that inevitably produces artefacts, including biases against alleles not found in the reference genome. This reference bias and other mapping artefacts are expected to be exacerbated in ancient DNA (aDNA) studies, which rely on the analysis of low quantities of damaged and very short DNA fragments (~30–80 bp). Nevertheless, the current gold-standard mapping strategies for aDNA studies have effectively remained unchanged for nearly a decade, during which time new software has emerged. In this study, we used simulated aDNA reads from three different human populations to benchmark the performance of 30 distinct mapping strategies implemented across four different read mapping software—BWA-aln, BWA-mem, NovoAlign and Bowtie2—and quantified the impact of reference bias in downstream population genetic analyses. We show that specific NovoAlign, BWA-aln and BWA-mem parameterizations achieve high mapping precision with low levels of reference bias, particularly after filtering out reads with low mapping qualities. However, unbiased NovoAlign results required the use of an IUPAC reference genome. While relevant only to aDNA projects where reference population data are available, the benefit of using an IUPAC reference demonstrates the value of incorporating population genetic information into the aDNA mapping process, echoing recent results based on graph genome representations.

scholarly journals Mixed NNLO QCD×electroweak corrections of $$ \mathcal{O} $$(Nfαsα) to single-W/Z production at the LHC

2020 ◽  
Vol 2020 (12) ◽  
Author(s):  
Stefan Dittmaier ◽  
Timo Schmidt ◽  
Jan Schwarz
Keyword(s):  
Z Bosons ◽  
Leading Order ◽  
Current Standard ◽  
Gauge Invariant ◽  
Mass Distributions ◽  
Self Energy ◽  
Electroweak Gauge Boson ◽  
First Results ◽  
Invariant Part ◽  
The Impact

Abstract First results on the radiative corrections of order $$ \mathcal{O} $$ O (Nfαsα) are presented for the off-shell production of W or Z bosons at the LHC, where Nf is the number of fermion flavours. These corrections comprise all diagrams at $$ \mathcal{O} $$ O (αsα) with closed fermion loops, form a gauge-invariant part of the next-to-next-to-leading-order corrections of mixed QCD×electroweak type, and are the ones that concern the issue of mass renormalization of the W and Z resonances. The occurring irreducible two-loop diagrams, which involve only self-energy insertions, are calculated with current standard techniques, and explicit analytical results on the electroweak gauge-boson self-energies at $$ \mathcal{O} $$ O (αsα) are given. Moreover, the generalization of the complex-mass scheme for a gauge-invariant treatment of the W/Z resonances is described for the order $$ \mathcal{O} $$ O (αsα). While the corrections, which are implemented in the Monte Carlo program Rady, are negligible for observables that are dominated by resonant W/Z bosons, they affect invariant-mass distributions at the level of up to 2% for invariant masses of ≳ 500 GeV and are, thus, phenomenologically relevant. The impact on transverse-momentum distributions is similar, taking into account that leading-order predictions to those distributions underestimate the spectrum.

scholarly journals Determining the Impact of Thickened Liquids on Swallowing in Patients Undergoing Irradiation for Oropharynx Cancer

2021 ◽  
pp. 019459982110104
Author(s):  
Carly E. A. Barbon ◽  
Douglas B. Chepeha ◽  
Andrew J. Hope ◽  
Melanie Peladeau-Pigeon ◽  
Ashley A. Waito ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Head And Neck Cancer ◽  
Clinical Benefit ◽  
Oropharyngeal Cancer ◽  
Thickened Liquids ◽  
Current Standard ◽  
Oropharynx Cancer ◽  
Post Radiation ◽  
Thin Liquids ◽  
The Impact

The current standard for the treatment of oropharynx cancers is radiation therapy. However, patients are frequently left with dysphagia characterized by penetration-aspiration (impaired safety) and residue (impaired efficiency). Although thickened liquids are commonly used to manage dysphagia, we lack evidence to guide the modification of liquids for clinical benefit in the head and neck cancer population. The objective of this study was to assess the impact of slightly and mildly thick liquids on penetration-aspiration and residue in 12 patients with oropharyngeal cancer who displayed penetration-aspiration on thin liquid within 3 to 6 months after completion of radiotherapy. Significantly fewer instances of penetration-aspiration were seen with slightly and mildly thick liquids as compared with thin ( P < .05). No differences were found across stimuli in the frequency of residue. Patients with oropharyngeal cancers who present with post–radiation therapy dysphagia involving penetration-aspiration on thin liquids may benefit from slightly and mildly thick liquids without risk of worse residue.

scholarly journals Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Paulo L. Pfitzinger ◽  
Laura Fangmann ◽  
Kun Wang ◽  
Elke Demir ◽  
Engin Gürlevik ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Tumor Stage ◽  
Ache Inhibitors ◽  
Impact On Survival ◽  
The Impact ◽  
Ache Expression ◽  
Cholinergic Activation

Abstract Background Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. Methods We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/−physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. Results We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. Conclusion For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.

scholarly journals The Impact of Parkinson’s Disease on Social Communication: An Exploratory Questionnaire Study

2021 ◽  
Author(s):  
Saryu Sharma ◽  
Kimberly Fleck ◽  
Sherri Winslow ◽  
Kathrin Rothermich
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Emotional Expression ◽  
Social Communication ◽  
Standard Of Care ◽  
Pragmatic Language ◽  
Current Standard ◽  
Comprehensive Management ◽  
Pragmatic Skills ◽  
The Impact

Individuals with Parkinson’s Disease (PD) often show breakdown in the interpretation of pragmatic language meaning. However, there is no current standard of care for evaluating social communication dysfunction in PD which affects the persons with PD and their caregivers. Thus, we developed a questionnaire for individuals with PD to evaluate social communication difficulties. Objective: The aim of this study was to develop a questionnaire to demonstrate a need for comprehensive management guidelines for individuals with PD regarding social communication skills. This questionnaire will highlight the areas of deficit for the individuals with PD. Methods: Fifty-one people with self-reported Parkinson’s Disease answered 28 survey questions. These questions pertained to emotional expression and perception, social communication, sarcasm/humor, and pragmatic skills. Exploratory factor analysis and reliability analysis were performed to identify which items loaded onto the desired factor and to check the internal consistency of the items. Results: Persons with PD reported changes in emotional expression and perception, social communication, sarcasm and humor, and pragmatic skills domains post PD diagnosis. No correlations were found between age/time since diagnosis and emotional expression, social communication, sarcasm, and humor.Conclusion: The current study provides evidence that persons with PD experience social communication challenges. Therefore, it is crucial to increase awareness of these deficits in PD to recognize the impact of the disease on social communication.

scholarly journals Influence of combined antihypertensive therapy on plasmatic,vascular-thrombocytic hemostasis and lipid peroxidation in patientswith metabolic syndrome and arterial hypertension

2007 ◽  
Vol 6 (4) ◽  
pp. 58-63
Author(s):  
N. M. Krasnova ◽  
E. A. Bushkova
Keyword(s):  
Metabolic Syndrome ◽  
Lipid Peroxidation ◽  
Arterial Hypertension ◽  
Antihypertensive Therapy ◽  
Enzyme Inhibitor ◽  
Combined Therapy ◽  
Density Lipoprotein ◽  
Aggregation Activity ◽  
Long Acting ◽  
The Impact

The impact of antihypertensive therapy with the angiotensin-converting enzyme inhibitor enalapril (enap) and with enalapril in combination with the long-acting calcium channel blocker verapamil SR (isoptin SR) on changes of plasmatic, vascular-thrombocytic hemostasis and lipid peroxidation in patients with metabolic syndrome and arterial hypertension was studied. Combined therapy with enalapril and verapamil significantly reduces the fasting glucose and glycated hemoglobin concentrations, the aggregation activity of thrombocytes in the patient's blood, inhibits the lipid peroxidation, increases the level of high-density lipoprotein cholesterol, and decreases the coefficient of atherogenecity. Combined therapy with enalapril and verapamil SR can be recommended for treatment of arterial hypertension in patients with metabolic syndrome.

scholarly journals Update on the drug-food interactions

2014 ◽  
Vol 1 (2) ◽  
pp. 100-106
Author(s):  
Hafid Bahri ◽  
◽  
Abdelkader Douaoui ◽  
Moufida Gharbi ◽  
Djamila Amroun
Keyword(s):  
Drug Interactions ◽  
Renal Clearance ◽  
Enzyme Inhibitor ◽  
Plasma Concentrations ◽  
Public Health Problem ◽  
Therapeutic Index ◽  
Major Public Health Problem ◽  
Urine Ph ◽  
Pharmacodynamic Interaction ◽  
The Impact

Drug interactions are a major public health problem, which partly attributed to some 10,000 deaths/year in Canada. Besides the interactions between two drugs, drug interactions are also due to the effect of other substances such as foods or nutrients. The drug-food interaction will be pharmacokinetic (affecting the absorption, distribution, metabolism, and elimination) or pharmacodynamic interaction. It is in the intestine that food may have the greatest impact with mainly a change in the amount of drugs absorbed that may be clinically significant for some drugs with narrow therapeutic index (cyclosporine, phenytoin, theophylline, etc.). The absorption of the drug in the presence of food will be determined by the particular physicochemical properties of the drug but also by the impact of food on one of the parameters determining the absorption such as: modified gastric acidity and emptying, the fat content of the food, the use of common transport between the drug and nutrients, chemical reactions between elements and drugs. Fasting situations or malnutrition can affect the distribution of drugs by increasing the free drug fraction, involving sometimes the risk of overdose. Diet affects drug metabolism by changing the activity of cytochrome P450. Most often is described the increase by grapefruit juice (enzyme inhibitor) of plasma concentrations of some drugs (cyclosporine, some statins, and calcium antagonists). Other foods (garlic, smoked meats and fish, caffeine) may increase metabolism. Diet can influence two stages of renal clearance (glomerular filtration - tubular reabsorption) by modifying urine pH or renal clearance. Pharmacodynamic interactions are also monitored, especially foods rich in vitamin k or tyramine with antivitamins K or MAOIs. Finally, health professionals must mobilize against these interactions, including through patient information.

Household finances and social comparison: Determinants of financial well-being in Indonesia

2021 ◽  
Vol 4 (1) ◽  
pp. 81
Author(s):  
Aisyah Amatul Ghina ◽  
Subiakto Sukarno
Keyword(s):  
Social Comparison ◽  
Financial Education ◽  
Well Being ◽  
Standard Of Living ◽  
Current Standard ◽  
Financial Position ◽  
Negative Effect ◽  
Socioeconomic And Demographic Factors ◽  
The Impact ◽  
Positive Effect

To achieve a vision of sustainable financial well-being (FWB) in Indonesia, generating more knowledge in household behavior and FWB is pivotal. This study assesses the impact of household financial position and social comparison on individual FWB in Indonesia. Using the latest wave of Indonesia Family Life Survey (IFLS) dataset, subjective FWB assessed by questions on subjective prosperity, perceived current standard of living adequacy and perceived future standard of living. The empirical analysis shows that net wealth and total assets are also essential determinants and positively related to FWB along with income. On the contrary, though it is only found significant on the perceived current standard of living adequacy, the total debt level has a negative effect on FWB. The findings also confirm that socioeconomic and demographic factors also significantly affect FWB (e.g., being female and more educated has a positive effect on FWB). Furthermore, it also found that relative financial position (i.e., social comparison) has important roles in determining individuals' FWB level. Being above the reference group's average for a particular financial measure (i.e., income and total assets) has a positive effect on an individual's FWB. The findings of this study suggest for promoting financial education in the national school system starting senior high school to increase the level of financial well-being among young adult and people with lower educational attainment.JEL Classification C31; D14; I31

Measuring the Impact of Social Media use in the Public Sector

2012 ◽  
pp. 48-64 ◽  
Author(s):  
Inez Mergel
Keyword(s):  
Social Media ◽  
Public Sector ◽  
Measurement Techniques ◽  
Current Standard ◽  
The Public ◽  
Use Of Technology ◽  
Standard Practices ◽  
Media Applications ◽  
The Impact ◽  
Current Practices

Existing research on eGovernment performance has provided limited proof for the impact the use of technology has on citizen participation, engagement or generally satisfaction with government activities. Social media applications have the potential to improve responsiveness, reach, and efficiency, and even cost savings in government. The current Government 2.0 initiatives launched by all executive departments and agencies of the U.S. Federal Government as a response to President Obama’s Transparency and Open Government memo show that government agencies are implementing social media applications as additional information and communication channels. This chapter provides a comparison between traditional eGovernment measurement techniques and the current practices, highlighting the current practices of measuring social media impact in the public sector. The insights are based on data collected in 2010 from interviews with social media directors in the most innovative executive departments and agencies. The results show that the current standard practices mostly include quantitative impact measures instead of the qualitative measures needed to better understand the sentiments of citizens.

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