scholarly journals Controlled Concealment of Exposed Clearance and Immunogenic Domains by Site-specific Polyethylene Glycol Attachment to Acetylcholinesterase Hypolysine Mutants

2007 ◽  
Vol 282 (49) ◽  
pp. 35491-35501 ◽  
Author(s):  
Ofer Cohen ◽  
Chanoch Kronman ◽  
Arie Lazar ◽  
Baruch Velan ◽  
Avigdor Shafferman
Keyword(s):  
Polyethylene Glycol ◽  
Sialic Acid ◽  
Chemical Modification ◽  
Inverse Relationship ◽  
Direct Relationship ◽  
Rank Order ◽  
Asialoglycoprotein Receptor ◽  
Protein Surface ◽  
Site Specific

Cholinesterases are efficient scavengers of organophosphates and are currently being developed as drugs for treatment against poisoning by such compounds. Recombinant ChE bioscavengers have very short circular longevity, a limitation that can be overcome by complex post-translation manipulations or by chemical modification such as polyethylene glycol conjugation. Series of multiple Lys-Ala mutants of human acetylcholinesterase were prepared allowing the generation of homogenous and well defined polyethylene-glycol conjugated AChEs with either one, two, three, four, or five appended polyethylene glycol (PEG) moieties/molecule. The rank order of circulatory longevity of these molecules was dependent on the number of PEG appendages up to a certain threshold: 5 = 4 > 3 > 2 > 1 > 0. Hypolysine acetylcholinesterases (AChEs) carrying the same number of PEGs, and therefore with identical masses, allowed us to demonstrate that circulatory longevity correlates with the predicted extent of concealment of the AChE surface. Furthermore, circulatory profiles of high number and low number PEG-AChEs differing in their sialic acid contents demonstrate a direct relationship between PEG loading and the effective seclusion of AChE from the hepatic asialoglycoprotein receptor clearance system. Finally, an inverse relationship is found between the extent of PEG loading and the ability of the human acetylcholinesterase to elicit specific anti-HuAChE antibodies. In conclusion, these findings suggest that for the extension of circulatory longevity, protein surface domain concealment exerted by polyethylene glycol attachment is at least as important as its effect on size enlargement and highlights the role of PEG attachment in masking interactions between biomolecules and their cognate receptors.

The sugar intake of businessmen and its inverse relationship with relative weight

1972 ◽  
Vol 27 (3) ◽  
pp. 449-460 ◽  
Author(s):  
J. F. Richardson
Keyword(s):  
Inverse Relationship ◽  
Direct Relationship ◽  
Relative Weight ◽  
Positive Association ◽  
Sugar Consumption ◽  
Self Administration ◽  
Future Studies ◽  
Actual Weight ◽  
Sugar Intake

1. Yudkin's (1967) questionnaire on the dietary intake of sugar was given to 415 businessmen for self-administration.1. The results showed an inverse relationship between sugar intake and relative weight (actual weight as a percentage of expected weight for height and age) and additional evidence suggests a direct relationship between sugar intake and adequate exercise.2. The statement that ‘sugar was restricted’ was shown to be a factor of considerable importance affecting the reported level of sugar intake and should be taken into account when comparing different series.3. The positive association between cigarette smoking and mean sugar consumption in this series was due to the low-sugar intake of ex-smokers.4. In future studies on the role of sucrose in the aetiology of ischaemic disease, both smoking habits and levels of activity should be recorded.

scholarly journals Protonation-Dependent Sequencing of 5-Formylcytidine in RNA

2021 ◽  
Author(s):  
Courtney N Link ◽  
Supuni Thalalla Gamage ◽  
Diamond A Gallimore ◽  
Robert Kopajtich ◽  
Christine N Evans ◽  
...  
Keyword(s):  
Chemical Modification ◽  
Molecular Orbital ◽  
Reactive Species ◽  
Sensitive Detection ◽  
Site Specific ◽  
Sequencing Technologies ◽  
Sensitive Site ◽  
Non Coding Rnas ◽  
Synthetic Oligonucleotides

Chemical modification of cytidine in non-coding RNAs plays a key role in regulating translation and disease. However, the distribution and dynamics of many of these modifications remains unknown due to a lack of sensitive site-specific sequencing technologies. Here we report a protonation-dependent sequencing reaction for detection of 5-formylcytidine (5fC) and 5-carboxycytidine (5caC) in RNA. First, we evaluate how protonation combined with electron-withdrawing substituents alters the molecular orbital energies and reduction of modified cytidine nucleosides, highlighting 5fC and 5caC as reactive species. Next, we apply this reaction to detect these modifications in synthetic oligonucleotides as well as endogenous human tRNA. Finally, we demonstrate the utility of our method to characterize a patient-derived model of 5fC-deficiency, where it enables facile monitoring of both pathogenic loss and exogenous rescue of NSUN3-dependent 5fC within the wobble base of human mitochondrial tRNAMet. These studies showcase the ability of protonation to enhance the reactivity and sensitive detection of 5fC in RNA, and provide a molecular foundation for applying optimized sequencing reactions to better understand the role of oxidized RNA cytidine nucleobases in disease.

scholarly journals Role of sialic acid for platelet life span: exposure of β-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor–expressing liver macrophages and hepatocytes

Blood ◽  
2009 ◽  
Vol 114 (8) ◽  
pp. 1645-1654 ◽  
Author(s):  
Anne Louise Sørensen ◽  
Viktoria Rumjantseva ◽  
Sara Nayeb-Hashemi ◽  
Henrik Clausen ◽  
John H. Hartwig ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Blood Cells ◽  
Asialoglycoprotein Receptor ◽  
Platelet Surface ◽  
Terminal Galactose ◽  
Report Data ◽  
Rapid Clearance ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractAlthough surface sialic acid is considered a key determinant for the survival of circulating blood cells and glycoproteins, its role in platelet circulation lifetime is not fully clarified. We show that thrombocytopenia in mice deficient in the St3gal4 sialyltransferase gene (St3Gal-IV−/− mice) is caused by the recognition of terminal galactose residues exposed on the platelet surface in the absence of sialylation. This results in accelerated platelet clearance by asialoglycoprotein receptor-expressing scavenger cells, a mechanism that was recently shown to induce thrombocytopenia during Streptococcus pneumoniae sepsis. We now identify platelet GPIbα as a major counterreceptor on ST3Gal-IV−/− platelets for asialoglycoprotein receptors. Moreover, we report data that establish the importance of sialylation of the von Willebrand factor in its function.

Organizational Justice and Employee Sustainability: The Mediating Role of Organizational Commitment

2020 ◽  
Vol 3 (3) ◽  
pp. 12-22
Author(s):  
Mehreen Fatima ◽  
Zeeshan Izhar ◽  
Zaheer Abbas Kazmi
Keyword(s):  
Organizational Commitment ◽  
Organizational Justice ◽  
Developing Country ◽  
Design Methodology ◽  
Direct Relationship ◽  
Banking Sector ◽  
Mediating Role ◽  
Research Gap ◽  
The Impact

Purpose- The primary purpose of the study is to determine the impact of organizational justice (OJ) on employee sustainability. Along with that, it also describes how organizational commitment mediates this direct relationship. This study includes all dimensions of OJ which are distributive, procedural and interactional (interpersonal & informational) within the context of a developing country (Pakistan). Design/Methodology- This study has considered employees working in the banking sector of Pakistan. Two hundred ten questionnaires were received back from employees. Regression analysis was used to analyze direct relationships between variables, while smart partial least squares (PLS) were used for mediation analysis. Findings- Results demonstrated that all hypothesis were accepted and it was also confirmed that organizational commitment (OC) mediates the direct relationship between OJ and employee sustainability (ES). Originality/value- Multidimensional construct of organizational justice was tested in this study, in the context of a developing country (Pakistan), to address the research gap.

The Impact of Bioconjugation on the Interfacial Activity of a Protein Biosurfactant

2018 ◽  
Author(s):  
Hossam H Tayeb ◽  
Marina Stienecker ◽  
Anton Middelberg ◽  
Frank Sainsbury
Keyword(s):  
Polyethylene Glycol ◽  
Colloidal Stability ◽  
Point Mutations ◽  
Pharmaceutical Formulations ◽  
Industrial Processes ◽  
Parent Molecule ◽  
Site Specific ◽  
Interfacial Activity ◽  
Surface Active ◽  
The Impact

Biosurfactants, are surface active molecules that can be produced by renewable, industrially scalable biologic processes. DAMP4, a designer biosurfactant, enables the modification of interfaces via genetic or chemical fusion to functional moieties. However, bioconjugation of addressable amines introduces heterogeneity that limits the precision of functionalization as well as the resolution of interfacial characterization. Here we designed DAMP4 variants with cysteine point mutations to allow for site-specific bioconjugation. The DAMP4 variants were shown to retain the structural stability and interfacial activity characteristic of the parent molecule, while permitting efficient and specific conjugation of polyethylene glycol (PEG). PEGylation results in a considerable reduction on the interfacial activity of both single and double mutants. Comparison of conjugates with one or two conjugation sites shows that both the number of conjugates as well as the mass of conjugated material impacts the interfacial activity of DAMP4. As a result, the ability of DAMP4 variants with multiple PEG conjugates to impart colloidal stability on peptide-stabilized emulsions is reduced. We suggest that this is due to constraints on the structure of amphiphilic helices at the interface. Specific and efficient bioconjugation permits the exploration and investigation of the interfacial properties of designer protein biosurfactants with molecular precision. Our findings should therefore inform the design and modification of biosurfactants for their increasing use in industrial processes, and nutritional and pharmaceutical formulations.

scholarly journals Sialic Acid—Modified Nanoparticles—New Approaches in the Glioma Management—Perspective Review

2021 ◽  
Vol 22 (14) ◽  
pp. 7494
Author(s):  
Przemyslaw Wielgat ◽  
Katarzyna Niemirowicz-Laskowska ◽  
Agnieszka Z. Wilczewska ◽  
Halina Car
Keyword(s):  
Sialic Acid ◽  
Clinical Observation ◽  
Malignant Cell ◽  
Cellular Heterogeneity ◽  
Molecular Processes ◽  
Management Perspective ◽  
Therapeutic Tools ◽  
And Function ◽  
Worse Prognosis

The cell surface is covered by a dense and complex network of glycans attached to the membrane proteins and lipids. In gliomas, the aberrant sialylation, as the final stage of glycosylation, is an important regulatory mechanism of malignant cell behavior and correlates with worse prognosis. Better understanding of the role of sialylation in cellular and molecular processes opens a new way in the development of therapeutic tools for human brain tumors. According to the recent clinical observation, the cellular heterogeneity, activity of brain cancer stem cells (BCSCs), immune evasion, and function of the blood–brain barrier (BBB) are attractive targets for new therapeutic strategies. In this review, we summarize the importance of sialic acid-modified nanoparticles in brain tumor progression.

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