scholarly journals Reshaping cAMP nanodomains through targeted disruption of compartmentalised phosphodiesterase signalosomes

2019 ◽  
Vol 47 (5) ◽  
pp. 1405-1414 ◽  
Author(s):  
Connor M. Blair ◽  
George S. Baillie
Keyword(s):  
Protein Complexes ◽  
Short Review ◽  
Effector Protein ◽  
Protein Activity ◽  
Targeted Disruption ◽  
Temporal Regulation ◽  
Wide Range ◽  
Signalling Cascades ◽  
Cell Permeable Peptide ◽  
Spatio Temporal

Abstract Spatio-temporal regulation of localised cAMP nanodomains is highly dependent upon the compartmentalised activity of phosphodiesterase (PDE) cyclic nucleotide degrading enzymes. Strategically positioned PDE–protein complexes are pivotal to the homeostatic control of cAMP-effector protein activity that in turn orchestrate a wide range of cellular signalling cascades in a variety of cells and tissue types. Unsurprisingly, dysregulated PDE activity is central to the pathophysiology of many diseases warranting the need for effective therapies that target PDEs selectively. This short review focuses on the importance of activating compartmentalised cAMP signalling by displacing the PDE component of signalling complexes using cell-permeable peptide disrupters

scholarly journals Organellar protein multi-functionality and phenotypic plasticity in plants

2019 ◽  
Vol 375 (1790) ◽  
pp. 20190182 ◽  
Author(s):  
Sally A. Mackenzie ◽  
Hardik Kundariya
Keyword(s):  
Phenotypic Plasticity ◽  
Protein Targeting ◽  
Ecological Systems ◽  
Temporal Regulation ◽  
Adaptation Mechanisms ◽  
Retrograde Signalling ◽  
Wide Range ◽  
Mitochondrial Genotype ◽  
Spatio Temporal ◽  
Ample Reason

With the increasing impact of climate instability on agricultural and ecological systems has come a heightened sense of urgency to understand plant adaptation mechanisms in more detail. Plant species have a remarkable ability to disperse their progeny to a wide range of environments, demonstrating extraordinary resiliency mechanisms that incorporate epigenetics and transgenerational stability. Surprisingly, some of the underlying versatility of plants to adapt to abiotic and biotic stress emerges from the neofunctionalization of organelles and organellar proteins. We describe evidence of possible plastid specialization and multi-functional organellar protein features that serve to enhance plant phenotypic plasticity. These features appear to rely on, for example, spatio-temporal regulation of plastid composition, and unusual interorganellar protein targeting and retrograde signalling features that facilitate multi-functionalization. Although we report in detail on three such specializations, involving MSH1, WHIRLY1 and CUE1 proteins in Arabidopsis , there is ample reason to believe that these represent only a fraction of what is yet to be discovered as we begin to elaborate cross-species diversity. Recent observations suggest that plant proteins previously defined in one context may soon be rediscovered in new roles and that much more detailed investigation of proteins that show subcellular multi-targeting may be warranted. This article is part of the theme issue ‘Linking the mitochondrial genotype to phenotype: a complex endeavour’.

E3 ubiquitin ligases

2005 ◽  
Vol 41 ◽  
pp. 15-30 ◽  
Author(s):  
Helen C. Ardley ◽  
Philip A. Robinson
Keyword(s):  
Protein Complexes ◽  
Loss Of Function ◽  
Direct Role ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Protein Ubiquitination ◽  
C Terminus ◽  
Full Complement ◽  
Spatio Temporal ◽  
Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

Chaperonin as the normal controls and pathological anti-stress response in the human reproductive system

2016 ◽  
pp. 126-129
Author(s):  
M. Makarenko ◽  
◽  
D. Hovsyeyev ◽  
L. Sydoryk ◽  
◽  
...  
Keyword(s):  
Reproductive System ◽  
Stress Proteins ◽  
Physiological Stress ◽  
Protein Complexes ◽  
Reproductive Function ◽  
Intercellular Signaling ◽  
Toll Like Receptors ◽  
Wide Range ◽  
Protein Functions ◽  
And Function

Different kinds of physiological stress cause mass changes in the cells, including the changes in the structure and function of the protein complexes and in separate molecules. The protein functions is determined by its folding (the spatial conclusion), which depends on the functioning of proteins of thermal shock- molecular chaperons (HSPs) or depends on the stress proteins, that are high-conservative; specialized proteins that are responsible for the correct proteinaceous folding. The family of the molecular chaperones/ chaperonins/ Hsp60 has a special place due to the its unique properties of activating the signaling cascades through the system of Toll-like receptors; it also stimulates the cells to produce anti- inflammatory cytokines, defensins, molecules of cell adhesion and the molecules of MHC; it functions as the intercellular signaling molecule. The pathological role of Hsp60 is established in a wide range of illnesses, from diabetes to atherosclerosis, where Hsp60 takes part in the regulation of both apoptosis and the autoimmune processes. The presence of the HSPs was found in different tissues that are related to the reproductive system. Key words: molecular chaperons (HSPs), Toll-like receptors, reproductive function, natural auto antibody.

scholarly journals Kinematic Analysis of Lower Limb Joint Asymmetry during Gait in People with Multiple Sclerosis

Symmetry ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 598
Author(s):  
Massimiliano Pau ◽  
Bruno Leban ◽  
Michela Deidda ◽  
Federica Putzolu ◽  
Micaela Porta ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Lower Limb ◽  
Sagittal Plane ◽  
Cross Sectional Study ◽  
Camera Motion ◽  
Cross Sectional ◽  
Temporal Parameters ◽  
Wide Range ◽  
Edss Score ◽  
Spatio Temporal

The majority of people with Multiple Sclerosis (pwMS), report lower limb motor dysfunctions, which may relevantly affect postural control, gait and a wide range of activities of daily living. While it is quite common to observe a different impact of the disease on the two limbs (i.e., one of them is more affected), less clear are the effects of such asymmetry on gait performance. The present retrospective cross-sectional study aimed to characterize the magnitude of interlimb asymmetry in pwMS, particularly as regards the joint kinematics, using parameters derived from angle-angle diagrams. To this end, we analyzed gait patterns of 101 pwMS (55 women, 46 men, mean age 46.3, average Expanded Disability Status Scale (EDSS) score 3.5, range 1–6.5) and 81 unaffected individuals age- and sex-matched who underwent 3D computerized gait analysis carried out using an eight-camera motion capture system. Spatio-temporal parameters and kinematics in the sagittal plane at hip, knee and ankle joints were considered for the analysis. The angular trends of left and right sides were processed to build synchronized angle–angle diagrams (cyclograms) for each joint, and symmetry was assessed by computing several geometrical features such as area, orientation and Trend Symmetry. Based on cyclogram orientation and Trend Symmetry, the results show that pwMS exhibit significantly greater asymmetry in all three joints with respect to unaffected individuals. In particular, orientation values were as follows: 5.1 of pwMS vs. 1.6 of unaffected individuals at hip joint, 7.0 vs. 1.5 at knee and 6.4 vs. 3.0 at ankle (p < 0.001 in all cases), while for Trend Symmetry we obtained at hip 1.7 of pwMS vs. 0.3 of unaffected individuals, 4.2 vs. 0.5 at knee and 8.5 vs. 1.5 at ankle (p < 0.001 in all cases). Moreover, the same parameters were sensitive enough to discriminate individuals of different disability levels. With few exceptions, all the calculated symmetry parameters were found significantly correlated with the main spatio-temporal parameters of gait and the EDSS score. In particular, large correlations were detected between Trend Symmetry and gait speed (with rho values in the range of –0.58 to –0.63 depending on the considered joint, p < 0.001) and between Trend Symmetry and EDSS score (rho = 0.62 to 0.69, p < 0.001). Such results suggest not only that MS is associated with significantly marked interlimb asymmetry during gait but also that such asymmetry worsens as the disease progresses and that it has a relevant impact on gait performances.

scholarly journals Intracellular Ionic Strength Sensing Using NanoLuc

2021 ◽  
Vol 22 (2) ◽  
pp. 677
Author(s):  
Tausif Altamash ◽  
Wesam Ahmed ◽  
Saad Rasool ◽  
Kabir H. Biswas
Keyword(s):  
Thermal Stability ◽  
Phase Separation ◽  
Drug Discovery ◽  
Ionic Strength ◽  
Cellular Signaling ◽  
Live Cells ◽  
Protein Activity ◽  
Cellular Survival ◽  
Cellular Processes ◽  
Wide Range

Intracellular ionic strength regulates myriad cellular processes that are fundamental to cellular survival and proliferation, including protein activity, aggregation, phase separation, and cell volume. It could be altered by changes in the activity of cellular signaling pathways, such as those that impact the activity of membrane-localized ion channels or by alterations in the microenvironmental osmolarity. Therefore, there is a demand for the development of sensitive tools for real-time monitoring of intracellular ionic strength. Here, we developed a bioluminescence-based intracellular ionic strength sensing strategy using the Nano Luciferase (NanoLuc) protein that has gained tremendous utility due to its high, long-lived bioluminescence output and thermal stability. Biochemical experiments using a recombinantly purified protein showed that NanoLuc bioluminescence is dependent on the ionic strength of the reaction buffer for a wide range of ionic strength conditions. Importantly, the decrease in the NanoLuc activity observed at higher ionic strengths could be reversed by decreasing the ionic strength of the reaction, thus making it suitable for sensing intracellular ionic strength alterations. Finally, we used an mNeonGreen–NanoLuc fusion protein to successfully monitor ionic strength alterations in a ratiometric manner through independent fluorescence and bioluminescence measurements in cell lysates and live cells. We envisage that the biosensing strategy developed here for detecting alterations in intracellular ionic strength will be applicable in a wide range of experiments, including high throughput cellular signaling, ion channel functional genomics, and drug discovery.

Forest path condition monitoring based on crowd-based trajectory data analysis

2020 ◽  
pp. 1-18
Author(s):  
Francisco Arcas-Tunez ◽  
Fernando Terroso-Saenz
Keyword(s):  
Information Acquisition ◽  
Road Network ◽  
Road Networks ◽  
Trajectory Data ◽  
Country Road ◽  
Wide Range ◽  
Sport Activities ◽  
Path Condition ◽  
Spatio Temporal ◽  
The City

The development of Road Information Acquisition Systems (RIASs) based on the Mobile Crowdsensing (MCS) paradigm has been widely studied for the last years. In that sense, most of the existing MCS-based RIASs focus on urban road networks and assume a car-based scenario. However, there exist a scarcity of approaches that pay attention to rural and country road networks. In that sense, forest paths are used for a wide range of recreational and sport activities by many different people and they can be also affected by different problems or obstacles blocking them. As a result, this work introduces SAMARITAN, a framework for rural-road network monitoring based on MCS. SAMARITAN analyzes the spatio-temporal trajectories from cyclists extracted from the fitness application Strava so as to uncover potential obstacles in a target road network. The framework has been evaluated in a real-world network of forest paths in the city of Cieza (Spain) showing quite promising results.

Predicting Human Mobility with Reinforcement-Learning-Based Long-Term Periodicity Modeling

2021 ◽  
Vol 12 (6) ◽  
pp. 1-23
Author(s):  
Shuo Tao ◽  
Jingang Jiang ◽  
Defu Lian ◽  
Kai Zheng ◽  
Enhong Chen
Keyword(s):  
Reinforcement Learning ◽  
Human Mobility ◽  
Recurrent Network ◽  
Mobility Prediction ◽  
Learning Framework ◽  
Temporal Features ◽  
Wide Range ◽  
Spatio Temporal ◽  
Historical Trajectory

Mobility prediction plays an important role in a wide range of location-based applications and services. However, there are three problems in the existing literature: (1) explicit high-order interactions of spatio-temporal features are not systemically modeled; (2) most existing algorithms place attention mechanisms on top of recurrent network, so they can not allow for full parallelism and are inferior to self-attention for capturing long-range dependence; (3) most literature does not make good use of long-term historical information and do not effectively model the long-term periodicity of users. To this end, we propose MoveNet and RLMoveNet. MoveNet is a self-attention-based sequential model, predicting each user’s next destination based on her most recent visits and historical trajectory. MoveNet first introduces a cross-based learning framework for modeling feature interactions. With self-attention on both the most recent visits and historical trajectory, MoveNet can use an attention mechanism to capture the user’s long-term regularity in a more efficient way. Based on MoveNet, to model long-term periodicity more effectively, we add the reinforcement learning layer and named RLMoveNet. RLMoveNet regards the human mobility prediction as a reinforcement learning problem, using the reinforcement learning layer as the regularization part to drive the model to pay attention to the behavior with periodic actions, which can help us make the algorithm more effective. We evaluate both of them with three real-world mobility datasets. MoveNet outperforms the state-of-the-art mobility predictor by around 10% in terms of accuracy, and simultaneously achieves faster convergence and over 4x training speedup. Moreover, RLMoveNet achieves higher prediction accuracy than MoveNet, which proves that modeling periodicity explicitly from the perspective of reinforcement learning is more effective.

scholarly journals Tracking elusive cargo: Illuminating spatio-temporal Type 3 effector protein dynamics using reporters

2017 ◽  
Vol 20 (1) ◽  
pp. e12797 ◽  
Author(s):  
Nicky O'Boyle ◽  
James P. R. Connolly ◽  
Andrew J. Roe
Keyword(s):  
Protein Dynamics ◽  
Effector Protein ◽  
Spatio Temporal ◽  
Type 3
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