ABSTRACT
During vaginal delivery, the delivery requires the fetal head to mold to accommodate the geometric constraints of the birth canal. Excessive molding can produce brain injuries and long-term sequelae. Understanding the loading of the fetal brain during the second stage of labor (fully dilated cervix, active pushing, and expulsion of fetus) could thus help predict the safety of the newborn during vaginal delivery. To this end, this study proposes a finite element model of the fetal head and maternal canal environment that is capable of predicting the stresses experienced by the fetal brain at the onset of the second phase of labor. Both fetal and maternal models were adapted from existing studies to represent the geometry of full-term pregnancy. Two fetal positions were compared: left-occiput-anterior and left-occiput-posterior. The results demonstrate that left-occiput-anterior position reduces the maternal tissue deformation, at the cost of higher stress in the fetal brain. In both cases, stress is concentrated underneath the sutures, though the location varies depending on the presentation. In summary, this study provides a patient-specific simulation platform for the study of vaginal delivery and its effect on both the fetal brain and maternal anatomy. Finally, it is suggested that such an approach has the potential to be used by obstetricians to support their decision-making processes through the simulation of various delivery scenarios.
Subject(s)
Brain , Finite Element Analysis , Labor Stage, Second , Humans , Female , Pregnancy , Brain/physiology , Brain/embryology , Labor Stage, Second/physiology , Fetus/physiology , Stress, Mechanical , Weight-Bearing , Biomechanical PhenomenaABSTRACT
We have previously developed a new class of inhibitors and chemical probes for glycosyltransferases through base-modification of the sugar-nucleotide donor. The key feature of these donor analogues is the presence of an additional substituent at the nucleobase. To date, the application of this general concept has been limited to UDP-sugars and UDP-sugar-dependent glycosyltransferases. Herein, we report for the first time the application of our approach to a GDP-mannose-dependent mannosyltransferase. We have prepared four GDP-mannose derivatives with an additional substituent at either position 6 or 8 of the nucleobase. These donor analogues were recognised as donor substrates by the mannosyltransferase Kre2p from yeast, albeit with significantly lower turnover rates than the natural donor GDP-mannose. The presence of the additional substituent also redirected enzyme activity from glycosyl transfer to donor hydrolysis. Taken together, our results suggest that modification of the donor nucleobase is, in principle, a viable strategy for probe and inhibitor development against GDP-mannose-dependent GTs.
Subject(s)
Guanosine Diphosphate Mannose/metabolism , Mannosyltransferases/metabolism , Saccharomyces cerevisiae/metabolism , Guanosine Diphosphate Mannose/chemistry , Substrate SpecificityABSTRACT
The direct structural modification of GDP-mannose via the bromination and Suzuki-Miyaura cross-coupling of the unprotected sugar-nucleotide, to produce 8-substituted fluorescent analogues of GDP-mannose.
Subject(s)
Guanosine Diphosphate Sugars/chemistry , Guanosine Diphosphate Sugars/chemical synthesis , Guanosine/chemistry , Guanosine Monophosphate/chemistry , Mannose/chemistry , Molecular Structure , Spectrometry, Fluorescence , Time FactorsABSTRACT
We report a simple and high-yielding two-step procedure for the preparation of 8-arylated guanosine mono- and triphosphates (8-aryl GXPs). The key step of our synthesis is the Suzuki-Miyaura coupling of unprotected 8-bromo GMP and 8-bromo GTP with various arylboronic acids in aqueous solution. The 8-bromoguanosine 5'-phosphates required as cross-coupling substrates were prepared from 8-bromoguanosine via an optimised Yoshikawa procedure.