Intrauterine growth restriction increases fetal hepatic gluconeogenic capacity and reduces messenger ribonucleic acid translation initiation and nutrient sensing in fetal liver and skeletal muscle.

Expression of key metabolic genes and proteins involved in mRNA translation, energy sensing, and glucose metabolism in liver and skeletal muscle were investigated in a late-gestation fetal sheep model of placental insufficiency intrauterine growth restriction (PI-IUGR). PI-IUGR fetuses weighed 55% less; had reduced oxygen, glucose, isoleucine, insulin, and IGF-I levels; and had 40% reduction in net branched chain amino acid uptake. In PI-IUGR skeletal muscle, levels of insulin receptor were increased 80%, whereas phosphoinositide-3 kinase (p85) and protein kinase B (AKT2) were reduced by 40%. Expression of eukaryotic initiation factor-4e was reduced 45% in liver, suggesting a unique mechanism limiting translation initiation in PI-IUGR liver. There was either no change (AMP activated kinase, mammalian target of rapamycin) or a paradoxical decrease (protein phosphatase 2A, eukaryotic initiation factor-2 alpha) in activation of major energy and cell stress sensors in PI-IUGR liver and skeletal muscle. A 13- to 20-fold increase in phosphoenolpyruvate carboxykinase and glucose 6 phosphatase mRNA expression in the PI-IUGR liver was-associated with a 3-fold increase in peroxisome proliferator-activated receptor-gamma coactivator-1 alpha mRNA and increased phosphorylation of cAMP response element binding protein. Thus PI-IUGR is-associated with reduced branched chain amino acid uptake and growth factors, yet up-regulation of proximal insulin signaling and a marked increase in the gluconeogenic pathway. Lack of activation of several energy and stress sensors in fetal liver and skeletal muscle, despite hypoxia and low energy status, suggests a novel strategy for survival in the PI-IUGR fetus but with potential maladaptive consequences for reduced nutrient sensing and insulin sensitivity in postnatal life

HySafe Standard benchmark Problem SBEP-V11: Predictions of hydrogen release and dispersion from a CGH2 bus in an underpass

One of the tasks of the HySafe Network of Excellence was the evaluation of available CFD tools and models for dispersion and combustion in selected hydrogen release scenarios identified as “standard benchmark problems” (SBEPs). This paper presents the results of the HySafe standard benchmark problem SBEP-V11. The situation considered is a high pressure hydrogen jet release from a compressed gaseous hydrogen (CGH2) bus in an underpass. The bus considered is equipped with 8 cylinders of 5 kg hydrogen each at 35 MPa storage pressure. The underpass is assumed to be of the common beam and slab type construction with I-beams spanning across the highway at 3 m centres (normal to the bus), plus cross bracing between the main beams, and light armatures parallel to the bus direction. The main goal of the present work was to evaluate the role of obstructions on the underside of the bridge deck on the dispersion patterns and assess the potential for hydrogen accumulation. Four HySafe partners participated in this benchmark, with 4 different CFD codes, ADREA-HF, CFX, FLACS and FLUENT. Four scenarios were examined in total. In the base case scenario 20 kg of hydrogen was released in the basic geometry. In Sensitivity Test 1 the release position was moved so that the hydrogen jet could hit directly the light armature on the roof of the underpass. In Sensitivity Test 2 the underside of the bridge deck was flat. In Sensitivity Test 3 the release was from one cylinder instead of four (5 kg instead of 20). The paper compares the results predicted by the four different computational approaches and attempts to identify the reasons for observed disagreements. The paper also concludes on the effects of the obstructions on the underside of the bridge deck

Unravelling ultraslow lithium-ion diffusion in γ-LiAlO2 : experiments with tracers, neutrons, and charge carriers

Lithium aluminum oxide (γ-LiAlO2) has been discussed and used for various applications, e.g., as electrode coating, membrane, or tritium breeder material. Although lithium-ion diffusion in this solid is essential for these purposes, it is still not sufficiently understood on the microscopic scale. Herein, we not only summarize and assess the available studies on diffusion in different crystalline forms of γ-LiAlO2, but also complement them with tracer-diffusion experiments on (001)- and conductivity spectroscopy on (100)-oriented single crystals, yielding activation energies of 1.20(5) and 1.12(1) eV, respectively. Scrutinous crystal-chemical considerations, Voronoi–Dirichlet partitioning, and Hirshfeld surface analysis are employed to identify possible diffusion pathways. The one-particle potential, as derived from high-temperature powder neutron diffraction data presented as well, reveals the major path to be strongly curved and to run between adjacent lithium positions with a migration barrier of 0.72(5) eV. This finding is substantiated by comparison with recently published computational results. For the first time, a complete model for lithium-ion diffusion in γ-LiAlO2, consistent with all available data, is presented.DFG, FOR 1277, Mobilität von Lithiumionen in Festkörpern (molife

Synthesis and Functionalization of Azetidine-Containing Small Macrocyclic Peptides

Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3-aminoazetidine (3-AAz) subunit as a new turn-inducing element for the efficient synthesis of small head-to-tail cyclic peptides. Greatly improved cyclizations of tetra-, penta- and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Post-cyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained four-membered azetidine. A special feature of this chemistry is that further late-stage modification of the resultant macrocyclic peptides can be achieved via the 3-AAz unit. This is done by: (i) chemoselective deprotection and substitution at the azetidine nitrogen, or by (ii) a click-based approach employing a 2-propynyl carbamate on the azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the azetidine ring encourages access to the less stable, all-trans conformation. Moreover, introduction of a 3-AAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle

Macrocyclisation of small peptides enabled by oxetane incorporation

Cyclic peptides are an important source of new drugs but are challenging to produce synthetically. We show that head-to-tail peptide macrocyclisations are greatly improved, as measured by isolated yields, reaction rates and product distribution, by substitution of one of the backbone amide C═O bonds with an oxetane ring. The cyclisation precursors are easily made by standard solution- or solid-phase peptide synthesis techniques. Macrocyclisations across a range of challenging ring sizes (tetra-, penta- and hexapeptides) are enabled by incorporation of this turn-inducing element. Oxetane incorporation is shown to be superior to other established amino acid modifications such as N-methylation. The positional dependence of the modification on cyclisation efficiency is mapped using a cyclic peptide of sequence LAGAY. We provide the first direct experimental evidence that oxetane modification induces a turn in linear peptide backbones, through the observation of dNN (i, i + 2) and dαN (i, i + 2) NOEs, which offers an explanation for these improvements. For cyclic peptide, cLAGAY, a combination of NMR derived distance restraints and molecular dynamics simulations are used to show that this modification alters the backbone conformation in proximity to the oxetane, with the flexibility of the ring reduced and a new intramolecular H-bond established. Finally, we incorporated an oxetane into a cyclic pentapeptide inhibitor of Aminopeptidase N, a transmembrane metalloprotease overexpressed on the surface of cancer cells. The inhibitor, cCNGRC, displayed similar IC50 values in the presence or absence of an oxetane at the glycine residue, indicating that bioactivity is fully retained upon amide C═O bond replacement

Results based on 124 cases of breast cancer and 97 controls from Taiwan suggest that the single nucleotide polymorphism (SNP309) in the MDM2 gene promoter is associated with earlier onset and increased risk of breast cancer

<p>Abstract</p> <p>Background</p> <p>It has been suggested that the single nucleotide polymorphism 309 (SNP309, T -> G) in the promoter region of the MDM2 gene is important for tumor development; however, with regards to breast cancer, inconsistent associations have been reported worldwide. It is speculated that these conflicting results may have arisen due to different patient subgroups and ethnicities studied. For the first time, this study explores the effect of the MDM2 SNP309 genotype on Taiwanese breast cancer patients.</p> <p>Methods</p> <p>Genomic DNA was obtained from the whole blood of 124 breast cancer patients and 97 cancer-free healthy women living in Taiwan. MDM2 SNP309 genotyping was carried out by restriction fragment length polymorphism (RFLP) assay. The multivariate logistic regression and the Kaplan-Meier method were used for analyzing the risk association and significance of age at diagnosis among different MDM2 SNP309 genotypes, respectively.</p> <p>Results</p> <p>Compared to the TT genotype, an increased risk association with breast cancer was apparent for the GG genotype (OR = 3.05, 95% CI = 1.04 to 8.95), and for the TG genotype (OR = 2.12, 95% CI = 0.90 to 5.00) after adjusting for age, cardiovascular disease/diabetes, oral contraceptive usage, and body mass index, which exhibits significant difference between cases and controls. Furthermore, the average ages at diagnosis for breast cancer patients were 53.6, 52 and 47 years for those harboring TT, TG and GG genotypes, respectively. A significant difference in median age of onset for breast cancer between GG and TT+TG genotypes was obtained by the log-rank test (p = 0.0067).</p> <p>Conclusion</p> <p>Findings based on the current sample size suggest that the MDM2 SNP309 GG genotype may be associated with both the risk of breast cancer and an earlier age of onset in Taiwanese women.</p