Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors

2014 ◽  
Vol 87 (6) ◽  
pp. 543-548 ◽  
Author(s):  
M. Pineda ◽  
M. González-Acosta ◽  
B.A. Thompson ◽  
R. Sánchez ◽  
C. Gómez ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Detailed Characterization ◽  
Lynch Syndrome Family

Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family

2020 ◽  
Vol 19 (4) ◽  
pp. 315-322
Author(s):  
Ciyu Yang ◽  
Margaret Sheehan ◽  
Ester Borras ◽  
Karen Cadoo ◽  
Kenneth Offit ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Splice Site ◽  
Lynch Syndrome Family ◽  
Splice Site Variant

Intramolecular Proton Transfer in the Isomerization of Hydroxyacetone: A Detailed Characterization Based on Reaction Force Analysis and the Bond Fragility Spectrum

2020 ◽  
Author(s):  
Wallace Derricotte ◽  
Huiet Joseph
Keyword(s):  
Chemical Potential ◽  
Reaction Force ◽  
Intramolecular Proton Transfer ◽  
Intermediate Energy ◽  
Force Analysis ◽  
Activation Energy Barrier ◽  
Detailed Characterization ◽  
Proton Transfers ◽  
Reaction Force Constant

The mechanism of isomerization of hydroxyacetone to 2-hydroxypropanal is studied within the framework of reaction force analysis at the M06-2X/6-311++G(d,p) level of theory. Three unique pathways are considered: (i) a step-wise mechanism that proceeds through formation of the Z-isomer of their shared enediol intermediate, (ii) a step-wise mechanism that forms the E-isomer of the enediol, and (iii) a concerted pathway that bypasses the enediol intermediate. Energy calculations show that the concerted pathway has the lowest activation energy barrier at 45.7 kcal mol<sup>-1</sup>. The reaction force, chemical potential, and reaction electronic flux are calculated for each reaction to characterize electronic changes throughout the mechanism. The reaction force constant is calculated in order to investigate the synchronous/asynchronous nature of the concerted intramolecular proton transfers involved. Additional characterization of synchronicity is provided by calculating the bond fragility spectrum for each mechanism.

DETAILED CHARACTERIZATION OF EUROPA'S RIDGE MORPHOLOGY

2016 ◽  
Author(s):  
Janelle A.F. Heitmeier ◽  
◽  
Emily S. Martin ◽  
Jordan M. Bretzfelder ◽  
D. Alex Patthoff ◽  
...  
Keyword(s):  
Detailed Characterization

The Problem of Divine Hiddenness

2018 ◽  
Author(s):  
Michael C. Rea
Keyword(s):  
Problem Of Evil ◽  
Philosophical Discussion ◽  
Detailed Characterization ◽  
The Past ◽  
Divine Hiddenness ◽  
The Problem Of Evil ◽  
The Relationship

This chapter provides a detailed characterization of the various meanings of the term “divine hiddenness,” carefully and rigorously articulates the version of the problem of divine hiddenness that has dominated contemporary philosophical discussion for the past twenty-five years, and then explains the relationship between that problem and the problem of evil.

Acid-Sensing Ion Channels

2020 ◽  
Author(s):  
Stefan Gründer
Keyword(s):  
Nervous System ◽  
Ion Channels ◽  
Excitatory Synapses ◽  
Detailed Characterization ◽  
High Affinity ◽  
Acid Sensing Ion Channels ◽  
Long Time ◽  
Pathological Pain

Acid-sensing ion channels (ASICs) are proton-gated Na+ channels. Being almost ubiquitously present in neurons of the vertebrate nervous system, their precise function remained obscure for a long time. Various animal toxins that bind to ASICs with high affinity and specificity have been tremendously helpful in uncovering the role of ASICs. We now know that they contribute to synaptic transmission at excitatory synapses as well as to sensing metabolic acidosis and nociception. Moreover, detailed characterization of mouse models uncovered an unanticipated role of ASICs in disorders of the nervous system like stroke, multiple sclerosis, and pathological pain. This review provides an overview on the expression, structure, and pharmacology of ASICs plus a summary of what is known and what is still unknown about their physiological functions and their roles in diseases.

Impulsivity and Drug Addiction: A Neurobiological Perspective

2012 ◽  
Author(s):  
Trevor Robbins
Keyword(s):  
Drug Addiction ◽  
Conceptual Analysis ◽  
Animal Studies ◽  
Reaction Time Task ◽  
Compulsive Behavior ◽  
Self Administration ◽  
Detailed Characterization ◽  
Cocaine Seeking ◽  
Serial Reaction

A conceptual analysis of the impulsivity construct in behavioral and neurobiological terms is followed by an analysis of its causal role in certain forms of drug addiction in both human and animal studies. The main focus of this chapter is on a rat model of impulsivity based on premature responding in the five-choice serial reaction time task and a more detailed characterization of this phenotype in neurobehavioral, neurochemical, and genetic terms. Evidence is surveyed that high impulsivity on this task is associated with the escalation subsequently of cocaine self-administration behavior and also with a tendency toward compulsive cocaine seeking. Novelty reactivity, by contrast, is associated with the enhanced acquisition of self-administration, but not with the escalation of intravenous self-administration of cocaine or the development of compulsive behavior associated with cocaine seeking. These results indicate that the vulnerability to stimulant addiction may depend on different factors, as expressed through distinct presumed endophenotypes. These observations help us further to dissociate various aspects of the impulsivity construct in neural as well as behavioral terms.

scholarly journals New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 709
Author(s):  
Marta Jorba ◽  
Marina Pedrola ◽  
Ouldouz Ghashghaei ◽  
Rocío Herráez ◽  
Lluis Campos-Vicens ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Efflux Pump ◽  
Synergistic Effects ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Detailed Characterization ◽  
Low Concentrations ◽  
Pump Activity ◽  
Bacteriological Evaluation ◽  
Kinetics Of

This work reports a detailed characterization of the antimicrobial profile of two trimethoprim-like molecules (compounds 1a and 1b) identified in previous studies. Both molecules displayed remarkable antimicrobial activity, particularly when combined with sulfamethoxazole. In disk diffusion assays on Petri dishes, compounds 1a and 1b showed synergistic effects with colistin. Specifically, in combinations with low concentrations of colistin, very large increases in the activities of compounds 1a and 1b were determined, as demonstrated by alterations in the kinetics of bacterial growth despite only slight changes in the fractional inhibitory concentration index. The effect of colistin may be to increase the rate of antibiotic entry while reducing efflux pump activity. Compounds 1a and 1b were susceptible to extrusion by efflux pumps, whereas the inhibitor phenylalanine arginyl β-naphthylamide (PAβN) exerted effects similar to those of colistin. The interactions between the target enzyme (dihydrofolate reductase), the coenzyme nicotinamide adenine dinucleotide phosphate (NADPH), and the studied molecules were explored using enzymology tools and computational chemistry. A model based on docking results is reported.

scholarly journals Leveraging supervised learning for functionally informed fine-mapping of cis-eQTLs identifies an additional 20,913 putative causal eQTLs

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qingbo S. Wang ◽  
David R. Kelley ◽  
Jacob Ulirsch ◽  
Masahiro Kanai ◽  
Shuvom Sadhuka ◽  
...  
Keyword(s):  
Fine Mapping ◽  
Gene Expressions ◽  
Detailed Characterization ◽  
Regulatory Variants ◽  
Functional Variants ◽  
Direct Perturbation ◽  
Localization Analysis ◽  
Coding Variants ◽  
Standard Sets

AbstractThe large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants’ effect on gene expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes.

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