Toolbox A: Overcoming reduced activity and avoidance

2017 ◽  
pp. 207-230
Keyword(s):  
Reduced Activity

1210: Reduced Activity of Afferent Neurons Innervating Urinary Bladder in Rats with Dibetic Cystopathy

2005 ◽  
Vol 173 (4S) ◽  
pp. 328-328
Author(s):  
Yukio Hayashi ◽  
Kazumasa Torimoto ◽  
Michael B. Chancellor ◽  
William C. de Groat ◽  
Naoki Yoshimura
Keyword(s):  
Urinary Bladder ◽  
Afferent Neurons ◽  
Reduced Activity

Human Neuraminidases Have Reduced Activity Towards Modified Sialic Acids on Glycoproteins

2020 ◽  
Author(s):  
Carmanah D. Hunter ◽  
Elizabeth Porter ◽  
Christopher Cairo
Keyword(s):  
Substrate Specificity ◽  
General Trend ◽  
Sialic Acids ◽  
Enzyme Specificity ◽  
Naturally Occurring ◽  
Bovine Submaxillary Mucin ◽  
Reduced Activity

This work investigated the substrate specificity of hNEU enzymes for a glycoprotein substrate (bovine submaxillary mucin) containing 9-<i>O</i>-acetylated and Neu5Gc residues. Using this model substrate, we observe a general trend for hNEU tolerance of Neu5Ac>Neu5Gc>>>Neu5,9Ac<sub>2</sub>, consistent with our previous results with glycolipid substrates. These results expand our understanding of hNEU enzyme specificity and suggest that naturally occurring modifications of sialic acids can play a role in regulating hNEU activity.

NMR Assisted Antimicrobial Peptide Designing: Structure Based Modifications and Functional Correlation of a Designed Peptide VG16KRKP

2020 ◽  
Vol 27 (9) ◽  
pp. 1387-1404 ◽  
Author(s):  
Karishma Biswas ◽  
Humaira Ilyas ◽  
Aritreyee Datta ◽  
Anirban Bhunia
Keyword(s):  
Antimicrobial Agents ◽  
Biological Properties ◽  
Structure Characterization ◽  
Drug Resistant ◽  
Functional Correlation ◽  
Naturally Occurring ◽  
High Resolution Nmr ◽  
Different Types ◽  
Reduced Activity ◽  
Poor Stability

Antimicrobial Peptides (AMPs), within their realm incorporate a diverse group of structurally and functionally varied peptides, playing crucial roles in innate immunity. Over the last few decades, the field of AMP has seen a huge upsurge, mainly owing to the generation of the so-called drug resistant ‘superbugs’ as well as limitations associated with the existing antimicrobial agents. Due to their resilient biological properties, AMPs can very well form the sustainable alternative for nextgeneration therapeutic agents. Certain drawbacks associated with existing AMPs are, however, issues of major concern, circumventing which are imperative. These limitations mainly include proteolytic cleavage and hence poor stability inside the biological systems, reduced activity due to inadequate interaction with the microbial membrane, and ineffectiveness because of inappropriate delivery among others. In this context, the application of naturally occurring AMPs as an efficient prototype for generating various synthetic and designed counterparts has evolved as a new avenue in peptide-based therapy. Such designing approaches help to overcome the drawbacks of the parent AMPs while retaining the inherent activity. In this review, we summarize some of the basic NMR structure based approaches and techniques which aid in improving the activity of AMPs, using the example of a 16-residue dengue virus fusion protein derived peptide, VG16KRKP. Using first principle based designing technique and high resolution NMR-based structure characterization we validate different types of modifications of VG16KRKP, highlighting key motifs, which optimize its activity. The approaches and designing techniques presented can support our peers in their drug development work.

scholarly journals EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1198
Author(s):  
Juliana Gomez ◽  
Zammam Areeb ◽  
Sarah F. Stuart ◽  
Hong P. T. Nguyen ◽  
Lucia Paradiso ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Viability ◽  
Er Stress ◽  
Cell Survival ◽  
Glioblastoma Cells ◽  
Over Expression ◽  
Stress Markers ◽  
Apoptotic Protein ◽  
Novel Association ◽  
Reduced Activity

Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.

scholarly journals Interactions of COMT and ALDH2 Genetic Polymorphisms on Symptoms of Parkinson’s Disease

2021 ◽  
Vol 11 (3) ◽  
pp. 361
Author(s):  
Rwei-Ling Yu ◽  
Shao-Ching Tu ◽  
Ruey-Meei Wu ◽  
Pei-An Lu ◽  
Chun-Hsiang Tan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Detrimental Effect ◽  
Personal Hygiene ◽  
Nucleotide Polymorphisms ◽  
Monoamine Neurotransmitters ◽  
Single Nucleotide ◽  
Detrimental Impact ◽  
Reduced Activity ◽  
Insight Into

(1) Background: Monoamine neurotransmitters play essential roles in the normal functioning of our nervous system. However, the metabolism of monoamine neurotransmitters is accompanied by the production of neurotoxic metabolites, and inefficient removal of the metabolites has been suggested to cause neurodegeneration. (2) Methods: To examine the effect of reduced activity of catechol-O-methyltransferase (COMT) and aldehyde dehydrogenase 2 (ALDH2) conferred by single nucleotide polymorphisms COMT rs4680(A) and ALDH2 rs671(A) on the symptoms of patients with Parkinson’s disease (PD), a total of 114 PD patients were recruited cross-sectionally and received genotyping for rs4680 and rs671 along with MDS-UPDRS evaluation. (3) Results: We found that patients carrying rs4680(A) had more severe bradykinesia in the upper extremity and rest tremor. Besides, patients carrying rs671(A) had more difficulty maintaining personal hygiene, while patients with genotype rs671(GG) had higher scores in the item “depressed mood.” More importantly, we found the effect of rs4680 to be moderated by rs671 SNP for the symptom of “hand movements.” The detrimental impact of rs4680(A) is more pronounced in the presence of genotype rs671(GG). (4) Conclusions: This study facilitates a deeper understanding of the detrimental effect of reduced activity of COMT and ALDH2 conferred by genetic variation and provides novel insight into the interactions between enzymes metabolizing monoamine neurotransmitters in the pathogenesis of PD.

scholarly journals Restriction of cytosolic sucrose hydrolysis profoundly alters development, metabolism and gene expression in Arabidopsis roots

2020 ◽  
Author(s):  
Cristina Pignocchi ◽  
Alexander Ivakov ◽  
Regina Feil ◽  
Martin Trick ◽  
Marilyn Pike ◽  
...  
Keyword(s):  
Growth And Development ◽  
Low Carbon ◽  
Sucrose Hydrolysis ◽  
Developmental Defects ◽  
Altered Expression ◽  
Signalling Molecules ◽  
Exogenous Glucose ◽  
Rich Information ◽  
Sugar Levels ◽  
Reduced Activity

Abstract Plant roots depend on sucrose imported from leaves as the substrate for metabolism and growth. Sucrose and hexoses derived from it are also signalling molecules that modulate growth and development, but the importance for signalling of endogenous changes in sugar levels is poorly understood. We report that reduced activity of cytosolic invertase, which converts sucrose to hexoses, leads to pronounced metabolic, growth and developmental defects in roots of Arabidopsis (Arabidopsis thaliana) seedlings. In addition to altered sugar and downstream metabolite levels, roots of cinv1 cinv2 mutants have reduced elongation rates, cell and meristem size, abnormal meristematic cell division patterns, and altered expression of thousands of genes of diverse functions. Provision of exogenous glucose to mutant roots repairs relatively few of the defects. The extensive transcriptional differences between mutant and wild-type roots have hallmarks of both high sucrose and low hexose signalling. We conclude that the mutant phenotype reflects both low carbon availability for metabolism and growth and complex sugar signals derived from elevated sucrose and depressed hexose levels in the cytosol of mutant roots. Such reciprocal changes in endogenous sucrose and hexose levels potentially provide rich information about sugar status that translates into flexible adjustments of growth and development.

scholarly journals Novel FGFR1 Variants Are Associated with Congenital Scoliosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1126
Author(s):  
Shengru Wang ◽  
Xiran Chai ◽  
Zihui Yan ◽  
Sen Zhao ◽  
Yang Yang ◽  
...  
Keyword(s):  
Protein Function ◽  
Hypogonadotropic Hypogonadism ◽  
Congenital Scoliosis ◽  
Wild Type ◽  
Conservation Analysis ◽  
Gene Assay ◽  
Protein Expressions ◽  
Patient Series ◽  
Reduced Activity

FGFR1 encodes a transmembrane cytokine receptor, which is involved in the early development of the human embryo and plays an important role in gastrulation, organ specification and patterning of various tissues. Pathogenic FGFR1 variants have been associated with Kallmann syndrome and hypogonadotropic hypogonadism. In our congenital scoliosis (CS) patient series of 424 sporadic CS patients under the framework of the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study, we identified four unrelated patients harboring FGFR1 variants, including one frameshift and three missense variants. These variants were predicted to be deleterious by in silico prediction and conservation analysis. Signaling activities and expression levels of the mutated protein were evaluated in vitro and compared to that of the wild type (WT) FGFR1. As a result, the overall protein expressions of c.2334dupC, c.2339T>C and c.1261A>G were reduced to 43.9%, 63.4% and 77.4%, respectively. By the reporter gene assay, we observed significantly reduced activity for c.2334dupC, c.2339T>C and c.1261A>G, indicating the diminished FGFR1 signaling pathway. In conclusion, FGFR1 variants identified in our patients led to only mild disruption to protein function, caused milder skeletal and cardiac phenotypes than those reported previously.

scholarly journals The Role of Arg13 in Protein Phosphatase M tPphA from Thermosynechococcus elongatus

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Jiyong Su ◽  
Karl Forchhammer
Keyword(s):  
Amino Acid ◽  
Protein Phosphatase ◽  
Arginine Residue ◽  
Side Chain ◽  
Wild Type ◽  
Catalytic Center ◽  
Nitrophenyl Phosphate ◽  
Reduced Activity ◽  
Amino Acid Variants

A highly conserved arginine residue is close to the catalytic center of PPM/PP2C-type protein phosphatases. Different crystal structures of PPM/PP2C homologues revealed that the guanidinium side chain of this arginine residue can adopt variable conformations and may bind ligands, suggesting an important role of this residue during catalysis. In this paper, we randomly mutated Arginine 13 of tPphA, a PPM/PP2C-type phosphatase from Thermosynechococcus elongatus, and obtained 18 different amino acid variants. The generated variants were tested towards p-nitrophenyl phosphate and various phosphopeptides. Towards p-nitrophenyl phosphate as substrate, twelve variants showed 3–7 times higher Km values than wild-type tPphA and four variants (R13D, R13F, R13L, and R13W) completely lost activity. Strikingly, these variants were still able to dephosphorylate phosphopeptides, although with strongly reduced activity. The specific inability of some Arg-13 variants to hydrolyze p-nitrophenyl phosphate highlights the importance of additional substrate interactions apart from the substrate phosphate for catalysis. The properties of the R13 variants indicate that this residue assists in substrate binding.

scholarly journals Atlantic Hurricanes and Climate Change. Part II: Role of Thermodynamic Changes in Decreased Hurricane Frequency

2013 ◽  
Vol 26 (21) ◽  
pp. 8513-8528 ◽  
Author(s):  
Megan S. Mallard ◽  
Gary M. Lackmann ◽  
Anantha Aiyyer
Keyword(s):  
Case Studies ◽  
Wind Shear ◽  
Vertical Wind Shear ◽  
Vertical Wind ◽  
Effect Of Temperature ◽  
Physical Processes ◽  
Thermodynamic Conditions ◽  
Atlantic Hurricanes ◽  
Reduced Activity

Abstract A method of downscaling that isolates the effect of temperature and moisture changes on tropical cyclone (TC) activity was presented in Part I of this study. By applying thermodynamic modifications to analyzed initial and boundary conditions from past TC seasons, initial disturbances and the strength of synoptic-scale vertical wind shear are preserved in future simulations. This experimental design allows comparison of TC genesis events in the same synoptic setting, but in current and future thermodynamic environments. Simulations of both an active (September 2005) and inactive (September 2009) portion of past hurricane seasons are presented. An ensemble of high-resolution simulations projects reductions in ensemble-average TC counts between 18% and 24%, consistent with previous studies. Robust decreases in TC and hurricane counts are simulated with 18- and 6-km grid lengths, for both active and inactive periods. Physical processes responsible for reduced activity are examined through comparison of monthly and spatially averaged genesis-relevant parameters, as well as case studies of development of corresponding initial disturbances in current and future thermodynamic conditions. These case studies show that reductions in TC counts are due to the presence of incipient disturbances in marginal moisture environments, where increases in the moist entropy saturation deficits in future conditions preclude genesis for some disturbances. Increased convective inhibition and reduced vertical velocity are also found in the future environment. It is concluded that a robust decrease in TC frequency can result from thermodynamic changes alone, without modification of vertical wind shear or the number of incipient disturbances.

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