scholarly journals PIP2 promotes conformation-specific dimerization of the EphA2 membrane region

2020 ◽  
pp. jbc.RA120.016423
Author(s):  
Katherine M Stefanski ◽  
Charles M Russell ◽  
Justin M Westerfield ◽  
Rajan Lamichhane ◽  
Francisco N Barrera
Keyword(s):  
Single Molecule ◽  
Oncogenic Signaling ◽  
Independent States ◽  
Conformational Coupling ◽  
The Difference ◽  
Tm Domain ◽  
Hydrophobic Matching ◽  
The Impact ◽  
Membrane Region ◽  
Positively Charged

The impact of the EphA2 receptor on cancer malignancy hinges on the two different ways it can be activated. EphA2 induces anti-oncogenic signaling after ligand binding, but ligand-independent activation of EphA2 is pro-oncogenic. It is believed that the transmembrane (TM) domain of EphA2 adopts two alternate conformations in the ligand-dependent and the ligand-independent states. However, it is poorly understood how the difference in TM helical crossing angles found in the two conformations impacts the activity and regulation of EphA2. We devised a method that uses hydrophobic matching to stabilize two conformations of a peptide comprising the EphA2 TM domain and a portion of the intracellular juxtamembrane (JM) segment. The two conformations exhibit different TM crossing angles, resembling the ligand-dependent and ligand-independent states. We developed a single-molecule technique using SMALPs to measure dimerization in membranes. We observed that the signaling lipid PIP2 promotes TM dimerization, but only in the small crossing angle state, which we propose corresponds to the ligand-independent conformation. In this state the two TM are almost parallel, and the positively charged JM segments are expected to be close to each other, causing electrostatic repulsion. The mechanism PIP2 uses to promote dimerization might involve alleviating this repulsion due to its high density of negative charges. Our data reveal a conformational coupling between the TM and JM regions, and suggest that PIP2 might directly exert a regulatory effect on EphA2 activation in cells that is specific to the ligand-independent conformation of the receptor.

scholarly journals PIP2 promotes conformation-specific dimerization of the EphA2 membrane region

2020 ◽  
Author(s):  
Katherine M. Stefanski ◽  
Charles M. Russell ◽  
Justin M. Westerfield ◽  
Rajan Lamichhane ◽  
Francisco N. Barrera
Keyword(s):  
Single Molecule ◽  
Oncogenic Signaling ◽  
Independent States ◽  
Conformational Coupling ◽  
The Difference ◽  
Tm Domain ◽  
Hydrophobic Matching ◽  
The Impact ◽  
Membrane Region ◽  
Positively Charged

AbstractThe impact of the EphA2 receptor on cancer malignancy hinges on the two different ways it can be activated. EphA2 induces anti-oncogenic signaling after ligand binding, but ligand-independent activation of EphA2 is pro-oncogenic. It is believed that the transmembrane (TM) domain of EphA2 adopts two alternate conformations in the ligand-dependent and the ligand-independent states. However, it is poorly understood how the difference in TM helical crossing angles found in the two conformations impacts the activity and regulation of EphA2. We devised a method that uses hydrophobic matching to stabilize two conformations of a peptide comprising the EphA2 TM domain and a portion of the intracellular juxtamembrane (JM) segment. The two conformations exhibit different TM crossing angles, resembling the ligand-dependent and ligand-independent states. We developed a single-molecule technique using SMALPs to measure dimerization in membranes. We observed that the signaling lipid PIP2 promotes TM dimerization, but only in the small crossing angle state, which we propose corresponds to the ligand-independent conformation. In this state the two TM are almost parallel, and the positively charged JM segments are expected to be close to each other, causing electrostatic repulsion. The mechanism PIP2 uses to promote dimerization might involve alleviating this repulsion due to its high density of negative charges. Our data reveal a conformational coupling between the TM and JM regions, and suggest that PIP2 might directly exert a regulatory effect on EphA2 activation in cells that is specific to the ligand-independent conformation of the receptor.

scholarly journals Fluorescence-Labeled Amyloid Beta Monomer: A Molecular Dynamical Study

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3524
Author(s):  
János Gera ◽  
Gábor Paragi
Keyword(s):  
Single Molecule ◽  
Early Stage ◽  
Conformational Space ◽  
Dynamic Simulations ◽  
Dynamical Study ◽  
Fluorescence Dye ◽  
Aβ Aggregation ◽  
The Difference ◽  
Open Question ◽  
The Impact

The aggregation process of the Amyloidβ (Aβ) peptide is one of the central questions in Alzheimers’s research. Fluorescence-labeled single-molecule detection is a novel technique concerning the early stage investigation of Aβ aggregation, where the labeling dyes are covalently bound to the Aβ monomer. As the influence of the dye on the conformational space of the Aβ monomer can be significant, its effect on the seeding process is an open question. The applied fluorescent molecule continuously switches between an active (ON) and an inactive (OFF) state, where the latter supports an extra rotational restriction at many commercially available dyes. However, only a few theoretical studies simulated the Aβ monomer in the presence of a dye and none of them considered the difference between the ON and the OFF states. Therefore, we examined the impact of a selected fluorescence dye (Alexa 568) on the conformational space of the monomeric Aβ(1–42) peptide in its ON and OFF state by replica exchange molecular dynamic simulations. Investigations on secondary structure elements as well as dye-peptide contact analysis for the monomers are presented. Experimental and theoretical NMR shifts were contrasted to qualify the calculation protocol and theoretical values of the labeled and the non-labeled peptide were also compared. We found that the first five residues have higher helical propensity in the presence of the dye, and electrostatic properties could strongly affect the connection between the dye and the peptide parts.

Evaluation of the impact of public investment programs on social and economic performance of territories

2019 ◽  
pp. 109-123
Author(s):  
I. E. Limonov ◽  
M. V. Nesena
Keyword(s):  
Bayesian Modeling ◽  
Positive Impact ◽  
Public Investment ◽  
Difference In Differences ◽  
The Public ◽  
Export Activity ◽  
Regional Investment ◽  
The Difference ◽  
The Impact ◽  
Development Institution

The purpose of this study is to evaluate the impact of public investment programs on the socio-economic development of territories. As a case, the federal target programs for the development of regions and investment programs of the financial development institution — Vnesheconombank, designed to solve the problems of regional development are considered. The impact of the public interventions were evaluated by the “difference in differences” method using Bayesian modeling. The results of the evaluation suggest the positive impact of federal target programs on the total factor productivity of regions and on innovation; and that regional investment programs of Vnesheconombank are improving the export activity. All of the investments considered are likely to have contributed to the reduction of unemployment, but their implementation has been accompanied by an increase in social inequality.

Mechanically-Tunable Quantum Interference in Ferrocene-Based Single-Molecule Junctions

2020 ◽  
Author(s):  
María Camarasa-Gómez ◽  
Daniel Hernangómez-Pérez ◽  
Michael S. Inkpen ◽  
Giacomo Lovat ◽  
E-Dean Fung ◽  
...  
Keyword(s):  
Single Molecule ◽  
Quantum Interference ◽  
Degrees Of Freedom ◽  
Building Blocks ◽  
Ferrocene Derivative ◽  
Single Molecule Junctions ◽  
Molecule Junction ◽  
Single Molecule Junction ◽  
The Impact ◽  
D Orbitals

Ferrocenes are ubiquitous organometallic building blocks that comprise a Fe atom sandwiched between two cyclopentadienyl (Cp) rings that rotate freely at room temperature. Of widespread interest in fundamental studies and real-world applications, they have also attracted<br>some interest as functional elements of molecular-scale devices. Here we investigate the impact of<br>the configurational degrees of freedom of a ferrocene derivative on its single-molecule junction<br>conductance. Measurements indicate that the conductance of the ferrocene derivative, which is<br>suppressed by two orders of magnitude as compared to a fully conjugated analog, can be modulated<br>by altering the junction configuration. Ab initio transport calculations show that the low conductance is a consequence of destructive quantum interference effects that arise from the hybridization of metal-based d-orbitals and the ligand-based π-system. By rotating the Cp rings, the hybridization, and thus the quantum interference, can be mechanically controlled, resulting in a conductance modulation that is seen experimentally.<br>

The Use of Multimedia and its Impact on Bangladeshi EFL Learners at Tertiary Level

2020 ◽  
Vol 4 (2) ◽  
pp. 150
Author(s):  
Farzana Sharmin Pamela Islam
Keyword(s):  
Language Learning ◽  
Academic Writing ◽  
Teaching And Learning ◽  
English Language ◽  
Capital City ◽  
Tertiary Level ◽  
Language Classroom ◽  
The Difference ◽  
The Government ◽  
The Impact

As 21st century is the era of modern technologies with different aspects, it offers us to make the best use of them. After tape recorder and overhead projector (OHP), multimedia has become an important part of language classroom facilities for its unique and effective application in delivering and learning lesson. Although in many parts of Bangladesh, a South Asian developing country, where English enjoys the status of a foreign language, the use of multimedia in teaching and learning is viewed as a matter of luxury. However, nowadays the usefulness and the necessity of it are well recognized by the academics as well as the government. The study aims to focus on the difference between a traditional classroom void of multimedia and multimedia equipped classrooms at university level by explaining how multimedia support the students with enhanced opportunity to interact with diverse texts that give them more in-depth comprehension of the subject. It also focuses on audio-visual advantage of multimedia on the students’ English language learning. The study has followed a qualitative method to get an in-depth understanding of the impact of using multimedia in an English language classroom at tertiary level. For this purpose, the data have been collected from two different sources. Firstly, from students’ written response to  an open ended question as to their comparative experience of learning  lessons with and without multimedia facilities; and secondly, through  observation of English language classes at a private university of Dhaka, the capital city of Bangladesh. The discussion of the study is limited to  the use of multimedia in English language classroom using cartoons, images and music with a view to enhance students’ skills in academic writing, critical analysis of image and critical appreciation of music. For this purpose, cartoons in English language, images from Google and music from You Tube have got focused discussion in this paper.

Monitoring the Structural Dynamics of U2 snRNA Via Single-Molecule Förster Resonance Energy Transfer

2018 ◽  
Author(s):  
Alexander Carl DeHaven
Keyword(s):  
Energy Transfer ◽  
Structural Dynamics ◽  
Single Molecule ◽  
Conformational Dynamics ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Förster Resonance Energy Transfer ◽  
U2 Snrna ◽  
Folding Dynamics ◽  
The Impact

This thesis contains four topic areas: a review of single-molecule microscropy methods and splicing, conformational dynamics of stem II of the U2 snRNA, the impact of post-transcriptional modifications on U2 snRNA folding dynamics, and preliminary findings on Mango aptamer folding dynamics.

Case study: Prediction and field tests of railway noise and effects of a low-height noise barrier

2020 ◽  
Vol 68 (4) ◽  
pp. 303-314
Author(s):  
Yuna Park ◽  
Hyo-In Koh ◽  
University of Science and Technology, Transpo ◽  
University of Science and Technology, Transpo ◽  
University of Science and Technology, Transpo ◽  
...  
Keyword(s):  
High Speed ◽  
Field Tests ◽  
Residential Areas ◽  
Railway Systems ◽  
Railway Noise ◽  
Sound Levels ◽  
Noise Barrier ◽  
The Difference ◽  
Reduction Effect ◽  
The Impact

Railway noise is calculated to predict the impact of new or reconstructed railway tracks on nearby residential areas. The results are used to prepare adequate counter- measures, and the calculation results are directly related to the cost of the action plans. The calculated values were used to produce noise maps for each area of inter- est. The Schall 03 2012 is one of the most frequently used methods for the production of noise maps. The latest version was released in 2012 and uses various input para- meters associated with the latest rail vehicles and track systems in Germany. This version has not been sufficiently used in South Korea, and there is a lack of standard guidelines and a precise manual for Korean railway systems. Thus, it is not clear what input parameters will match specific local cases. This study investigates the modeling procedure for Korean railway systems and the differences between calcu- lated railway sound levels and measured values obtained using the Schall 03 2012 model. Depending on the location of sound receivers, the difference between the cal- culated and measured values was within approximately 4 dB for various train types. In the case of high-speed trains, the value was approximately 7 dB. A noise-reducing measure was also modeled. The noise reduction effect of a low-height noise barrier system was predicted and evaluated for operating railway sites within the frame- work of a national research project in Korea. The comparison of calculated and measured values showed differences within 2.5 dB.

scholarly journals Soil Moisture Dynamics in Response to Precipitation and Thinning in a Semi-Dry Forest in Northern Mexico

Water ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 105
Author(s):  
Argelia E. Rascón-Ramos ◽  
Martín Martínez-Salvador ◽  
Gabriel Sosa-Pérez ◽  
Federico Villarreal-Guerrero ◽  
Alfredo Pinedo-Alvarez ◽  
...  
Keyword(s):  
Soil Moisture ◽  
Forest Management ◽  
Water Availability ◽  
Dry Forest ◽  
Rainfall Events ◽  
Rainfall Characteristics ◽  
Northern Mexico ◽  
The Difference ◽  
The Impact ◽  
Moisture Dynamics

Understanding soil moisture behavior in semi-dry forests is essential for evaluating the impact of forest management on water availability. The objective of the study was to analyze soil moisture based in storm observations in three micro-catchments (0.19, 0.20, and 0.27 ha) with similar tree densities, and subject to different thinning intensities in a semi-dry forest in Chihuahua, Mexico. Vegetation, soil characteristics, precipitation, and volumetric water content were measured before thinning (2018), and after 0%, 40%, and 80% thinning for each micro-catchment (2019). Soil moisture was low and relatively similar among the three micro-catchments in 2018 (mean = 8.5%), and only large rainfall events (>30 mm) increased soil moisture significantly (29–52%). After thinning, soil moisture was higher and significantly different among the micro-catchments only during small rainfall events (<10 mm), while a difference was not noted during large events. The difference before–after during small rainfall events was not significant for the control (0% thinning); whereas 40% and 80% thinning increased soil moisture significantly by 40% and 53%, respectively. Knowledge of the response of soil moisture as a result of thinning and rainfall characteristics has important implications, especially for evaluating the impact of forest management on water availability.

scholarly journals 216. Are Automatic Antimicrobial Stop Orders an Effective Stewardship Tool for Urinary Tract and Intra-Abdominal Infections?

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S110-S110
Author(s):  
Christina Maguire ◽  
Dusten T Rose ◽  
Theresa Jaso
Keyword(s):  
Urinary Tract ◽  
Antimicrobial Therapy ◽  
Source Control ◽  
Clostridioides Difficile ◽  
Days Of Therapy ◽  
Before And After ◽  
The Difference ◽  
Tract Infections ◽  
Length Of Therapy ◽  
The Impact

Abstract Background Automatic antimicrobial stop orders (ASOs) are a stewardship initiative used to decrease days of therapy, prevent resistance, and reduce drug costs. Limited evidence outside of the perioperative setting exists on the effects of ASOs on broad spectrum antimicrobial use, discharge prescription duration, and effects of missed doses. This study aims to evaluate the impact of an ASO policy across a health system of adult academic and community hospitals for treatment of intra-abdominal (IAI) and urinary tract infections (UTI). ASO Outcome Definitions ASO Outcomes Methods This multicenter retrospective cohort study compared patients with IAI and UTI treated before and after implementation of an ASO. Patients over the age of 18 with a diagnosis of UTI or IAI and 48 hours of intravenous (IV) antimicrobial administration were included. Patients unable to achieve IAI source control within 48 hours or those with a concomitant infection were excluded. The primary outcome was the difference in sum length of antimicrobial therapy (LOT). Secondary endpoints include length and days of antimicrobial therapy (DOT) at multiple timepoints, all cause in hospital mortality and readmission, and adverse events such as rates of Clostridioides difficile infection. Outcomes were also evaluated by type of infection, hospital site, and presence of infectious diseases (ID) pharmacist on site. Results This study included 119 patients in the pre-ASO group and 121 patients in the post-ASO group. ASO shortened sum length of therapy (LOT) (12 days vs 11 days respectively; p=0.0364) and sum DOT (15 days vs 12 days respectively; p=0.022). This finding appears to be driven by a decrease in outpatient LOT (p=0.0017) and outpatient DOT (p=0.0034). Conversely, ASO extended empiric IV LOT (p=0.005). All other secondary outcomes were not significant. Ten patients missed doses of antimicrobials due to ASO. Subgroup analyses suggested that one hospital may have influenced outcomes and reduction in LOT was observed primarily in sites without an ID pharmacist on site (p=0.018). Conclusion While implementation of ASO decreases sum length of inpatient and outpatient therapy, it may not influence inpatient length of therapy alone. Moreover, ASOs prolong use of empiric intravenous therapy. Hospitals without an ID pharmacist may benefit most from ASO protocols. Disclosures All Authors: No reported disclosures

Arterial Stiffness Assessed by Cardio-Ankle Vascular Index in Patients With Abdominal Aortic Aneurysm and Its Alterations After Treatment

2021 ◽  
pp. 153857442110232
Author(s):  
Spyridon N. Mylonas ◽  
Konstantinos G. Moulakakis ◽  
Nikolaos Kadoglou ◽  
Constantinos Antonopoulos ◽  
Thomas E. Kotsis ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Surgical Repair ◽  
Open Repair ◽  
Abdominal Aortic ◽  
Gender And Age ◽  
Baseline Values ◽  
The Difference ◽  
The Impact ◽  
Repair Group

Purpose: The aim of the present study was to investigate a potential difference on the arterial stiffness among aneurysm patients and non-aneurysm controls, as well as to explore potential changes between patients treated either with endovascular or open repair. Materials and Methods: A 110 patients with an infrarenal AAA were prospectively enrolled in this study. Fifty-six patients received an EVAR, whereas 54 patients received an open surgical repair. Moreover, 103 gender and age-matched subjects without AAA served as controls. The cardio-ankle vascular index (CAVI) was applied for measurement of the arterial stiffness. Results: CAVI values were statistically higher in the AAA patients when compared with control subjects. Although at 48 hours postoperatively the CAVI values were increased in both groups when compared to baseline values, the difference in CAVI had a tendency to be higher in the open group compared to the endovascular group. At 6 months of follow up the CAVI values returned to the baseline for the patients of the open repair group. However, in the endovascular group CAVI values remained higher when compared with the baseline values. Conclusion: Patients with AAAs demonstrated a higher value of CAVI compared to healthy controls. A significant increase of arterial stiffness in both groups during the immediate postoperative period was documented. The increase in arterial stiffness remained significant at 6 months in EVAR patients. Further studies are needed to elucidate the impact of a decreased aortic compliance after stentgraft implantation on the cardiac function of patients with AAA.

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