Methods for deriving competitive activation mechanisms

1989 ◽  
Author(s):  
Reggia
Keyword(s):  
Activation Mechanisms ◽  
Competitive Activation

Learning Competition and Cooperation

1993 ◽  
Vol 5 (2) ◽  
pp. 242-259 ◽  
Author(s):  
Sungzoon Cho ◽  
James A. Reggia
Keyword(s):  
Learning Rule ◽  
Connection Strength ◽  
Context Sensitive ◽  
Competition And Cooperation ◽  
Activation Mechanisms ◽  
Exclusive Or ◽  
Functional Mechanisms ◽  
Inhibitory Interactions ◽  
Competitive Activation ◽  
Or Task

Competitive activation mechanisms introduce competitive or inhibitory interactions between units through functional mechanisms instead of inhibitory connections. A unit receives input from another unit proportional to its own activation as well as to that of the sending unit and the connection strength between the two. This, plus the finite output from any unit, induces competition among units that receive activation from the same unit. Here we present a backpropagation learning rule for use with competitive activation mechanisms and show empirically how this learning rule successfully trains networks to perform an exclusive-OR task and a diagnosis task. In particular, networks trained by this learning rule are found to outperform standard backpropagation networks with novel patterns in the diagnosis problem. The ability of competitive networks to bring about context-sensitive competition and cooperation among a set of units proved to be crucial in diagnosing multiple disorders.

LEARNING ACTIVATION RULES RATHER THAN CONNECTION WEIGHTS

1996 ◽  
Vol 07 (02) ◽  
pp. 129-147 ◽  
Author(s):  
ERIC L. GRUNDSTROM ◽  
JAMES A. REGGIA
Keyword(s):  
Gradient Descent ◽  
A Priori ◽  
Learning Rule ◽  
Rule Based ◽  
Activation Mechanisms ◽  
Activation Rule ◽  
Associative Recall ◽  
Selection Of ◽  
Competitive Activation ◽  
Standard Learning

In the construction of neural networks involving associative recall, information is sometimes best encoded with a local representation. Moreover, a priori knowledge can lead to a natural selection of connection weights for these networks. With predetermined and fixed weights, standard learning algorithms that work by altering connection strengths are unable to train such networks. To address this problem, this paper derives a supervised learning rule based on gradient descent, where connection weights are fixed and a network is trained by changing the activation rule. It incorporates both traditional and competitive activation mechanisms, the latter being an efficient method for instilling competition in a network. The learning rule has been implemented, and the results from several test networks demonstrate that it works effectively.

scholarly journals Thiol-based switching mechanisms of stress-sensing chaperones

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Kathrin Ulrich ◽  
Blanche Schwappach ◽  
Ursula Jakob
Keyword(s):  
Oxidative Stress ◽  
Environmental Changes ◽  
Stress Conditions ◽  
Stress Exposure ◽  
Atp Levels ◽  
Protein Functions ◽  
Activation Mechanisms ◽  
Client Proteins ◽  
Stress Sensing ◽  
Redox Switches

AbstractThiol-based redox switches evolved as efficient post-translational regulatory mechanisms that enable individual proteins to rapidly respond to sudden environmental changes. While some protein functions need to be switched off to save resources and avoid potentially error-prone processes, protective functions become essential and need to be switched on. In this review, we focus on thiol-based activation mechanisms of stress-sensing chaperones. Upon stress exposure, these chaperones convert into high affinity binding platforms for unfolding proteins and protect cells against the accumulation of potentially toxic protein aggregates. Their chaperone activity is independent of ATP, a feature that becomes especially important under oxidative stress conditions, where cellular ATP levels drop and canonical ATP-dependent chaperones no longer operate. Vice versa, reductive inactivation and substrate release require the restoration of ATP levels, which ensures refolding of client proteins by ATP-dependent foldases. We will give an overview over the different strategies that cells evolved to rapidly increase the pool of ATP-independent chaperones upon oxidative stress and provide mechanistic insights into how stress conditions are used to convert abundant cellular proteins into ATP-independent holding chaperones.

scholarly journals Structure–function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhenfang Du ◽  
Benjamin P. Brown ◽  
Soyeon Kim ◽  
Donna Ferguson ◽  
Dean C. Pavlick ◽  
...  
Keyword(s):  
Tandem Duplication ◽  
Function Analysis ◽  
Treatment Strategies ◽  
Kinase Domain ◽  
Time Resolved ◽  
Egfr Activation ◽  
Domain Duplication ◽  
Activation Mechanisms ◽  
Potential Therapeutic Intervention ◽  
Egfr Kinase

AbstractMechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. We recently identified in-frame, tandem duplication of EGFR exons 18 - 25, which causes EGFR Kinase Domain Duplication (EGFR-KDD). Here, we characterize the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention. We provide computational and experimental evidence that EGFR-KDD functions by forming asymmetric EGF-independent intra-molecular and EGF-dependent inter-molecular dimers. Time-resolved fluorescence microscopy and co-immunoprecipitation reveals EGFR-KDD can form ligand-dependent inter-molecular homo- and hetero-dimers/multimers. Furthermore, we show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra- and inter-molecular dimerization. Collectively, our findings define a previously unrecognized model of EGFR dimerization, providing important insights for the understanding of EGFR activation mechanisms and informing personalized treatment of patients with tumors harboring EGFR-KDD. Finally, we establish ERBB KDDs as recurrent oncogenic events in multiple cancers.

scholarly journals Species-Specific Regulation of TRPM2 by PI(4,5)P2 via the Membrane Interfacial Cavity

2021 ◽  
Vol 22 (9) ◽  
pp. 4637
Author(s):  
Daniel Barth ◽  
Andreas Lückhoff ◽  
Frank J. P. Kühn
Keyword(s):  
Amino Acid Residues ◽  
Hek 293 ◽  
Complete Inactivation ◽  
293 Cells ◽  
Activation Mechanisms ◽  
Specific Regulation ◽  
Species Specific ◽  
Inside Out ◽  
Positively Charged

The human apoptosis channel TRPM2 is stimulated by intracellular ADR-ribose and calcium. Recent studies show pronounced species-specific activation mechanisms. Our aim was to analyse the functional effect of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), commonly referred to as PIP2, on different TRPM2 orthologues. Moreover, we wished to identify the interaction site between TRPM2 and PIP2. We demonstrate a crucial role of PIP2, in the activation of TRPM2 orthologues of man, zebrafish, and sea anemone. Utilizing inside-out patch clamp recordings of HEK-293 cells transfected with TRPM2, differential effects of PIP2 that were dependent on the species variant became apparent. While depletion of PIP2 via polylysine uniformly caused complete inactivation of TRPM2, restoration of channel activity by artificial PIP2 differed widely. Human TRPM2 was the least sensitive species variant, making it the most susceptible one for regulation by changes in intramembranous PIP2 content. Furthermore, mutations of highly conserved positively charged amino acid residues in the membrane interfacial cavity reduced the PIP2 sensitivity in all three TRPM2 orthologues to varying degrees. We conclude that the membrane interfacial cavity acts as a uniform PIP2 binding site of TRPM2, facilitating channel activation in the presence of ADPR and Ca2+ in a species-specific manner.

scholarly journals Anti-NLRP3 Inflammasome Natural Compounds: An Update

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 136
Author(s):  
Baolong Liu ◽  
Jiujiu Yu
Keyword(s):  
Nlrp3 Inflammasome ◽  
Protein Complex ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Natural Compounds ◽  
Pyrin Domain ◽  
Inflammatory Protein ◽  
Wide Range ◽  
Activation Mechanisms ◽  
Stress Signals

The nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex that recognizes various danger or stress signals from pathogens, the host, and the environment, leading to activation of caspase-1 and inducing inflammatory responses. This pro-inflammatory protein complex plays critical roles in pathogenesis of a wide range of diseases including neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Therefore, intensive efforts have been devoted to understanding its activation mechanisms and to searching for its specific inhibitors. Approximately forty natural compounds with anti-NLRP3 inflammasome properties have been identified. Here, we provide an update about new natural compounds that have been identified within the last three years to inhibit the NLRP3 inflammasome and offer an overview of the underlying molecular mechanisms of their anti-NLRP3 inflammasome activities.

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