Hypoglycemia and the Origin of Hypoxia-Induced Reduction in Human Fetal Growth

The most well known reproductive consequence of residence at high altitude (HA >2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA.Doppler and ultrasound were used to measure maternal uterine and fetal umbilical blood flows in 69 and 58 residents of 400 vs 3600 m. Arterial and venous blood samples from mother and fetus were collected at elective cesarean delivery and analyzed for glucose, lactate and insulin. Maternal delivery and fetal uptakes for oxygen and glucose were calculated.The maternal arterial – venous glucose concentration difference was greater at HA. However, umbilical venous and arterial glucose concentrations were markedly decreased, resulting in lower glucose delivery at 3600 m. Fetal glucose consumption was reduced by >28%, but strongly correlated with glucose delivery, highlighting the relevance of glucose concentration to fetal uptake. At altitude, fetal lactate levels were increased, insulin concentrations decreased, and the expression of GLUT1 glucose transporter protein in the placental basal membrane was reduced.Our results support that preferential anaerobic consumption of glucose by the placenta at high altitude spares oxygen for fetal use, but limits glucose availability for fetal growth. Thus reduced fetal growth at high altitude is associated with fetal hypoglycemia, hypoinsulinemia and a trend towards lactacidemia. Our data support that placentally-mediated reduction in glucose transport is an initiating factor for reduced fetal growth under conditions of chronic hypoxemia

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

OPERATIONAL ANALYSIS FOR OFFENSIVE MINE WARFARE

Includes supplementary materialOffensive mine warfare (OMW) is an often overlooked and underdeveloped potential benefit to the breadth of options available for current naval forces regarding enemy deterrence. By taking a modified systems engineering Vee approach and applying it to offensive mine warfare, this project provides a definition of existing operational concepts and projects the future potential of this methodology. This project defines two simulations utilizing OMW in both an open-ocean transit mission and an ocean strait escort mission. These mission scenarios help provide the composition of the interconnected system of systems involved with the deployment, loiter, engagement, and recovery functions of offensive mines. An emphasis is placed on the use of Advanced Undersea Weapons Systems to carry out these functions, specifically large-displacement unmanned underwater vehicles. Simulations provided within this project better map the interconnection of the deployment, loiter, engagement, and recovery functions as they pertain to the measures of effectiveness for each mission scenario. By decomposing the major functions of OMW, this project provides the initial framework for the inclusion of offensive mining into the current naval forces’ repertoire of enemy-deterrence options. Additionally, this project’s decomposition of offensive mining in its current iteration provides the framework for a further investigation into the future capabilities of this product.Civilian, Department of the NavyCivilian, Department of the NavyCivilian, Department of the NavyCivilian, Department of the NavyLieutenant, United States NavyApproved for public release. distribution is unlimite

Preparation of Phase-Pure M1 MoVTeNb Oxide Catalysts by Hydrothermal Synthesis - Influence of Reaction Parameters

This work presents a detailed investigation of the preparation of MoVTeNbOx catalysts by hydrothermal synthesis. Phase-pure synthesis of M1 has been achieved applying the metals in a molar ratio Mo/V/Te/Nb=1/0.25/0.23/0.12. Raman, UV/Vis spectroscopy, and SEM/EDX analysis show that the elements are inhomogeneously distributed in the initial suspension that is formed after mixing the metal salts in an aqueous medium. Iso- and heteropoly anions of molybdenum, free telluric acid as well as supra-molecular polyoxometalate clusters are observed in the solution, whereas all metals have been found in the precipitate. Complete rearrangement of molecular building blocks under hydrothermal conditions is essential for formation of phase-pure materials. Optimized synthesis conditions with respect to temperature and time result in the formation a precursor consisting of nano-structured M1 characterized by an extended periodic organization in the [001] direction and a fairly homogeneous distribution of the elements. Residual ammonium containing supra-molecular species in the precursor result in the formation of phase mixtures during the subsequent crystallization by heat treatment in inert gas. Phase-pure M1 exhibits a distinct degree of flexibility with respect to the chemical composition that becomes obvious by incorporating Nb not exclusively into pentagonal bi-pyramidal units, but also into octahedral coordinated positions as shown by EXAFS. Anisotropic growth of the needle-like M1 crystals has been observed during the final heat treatment performed at 873-923 K in inert atmosphere disclosing a potential method to control the catalytic properties of MoVTeNbOx catalysts