Separating parental and treatment contributions to perinatal health after fresh and frozen embryo transfer in assisted reproduction: A cohort study with within-sibship analysis

BackgroundCompared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors.Methods and findingsThis registry-based cohort study with nationwide data from Denmark (1994–2014), Norway (1988–2015), and Sweden (1988–2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (<37 weeks, versus ≥37), and very preterm birth (<32 weeks, versus ≥32). Singletons born after fresh-ET had lower mean birthweight (−51 g, 95% CI −58 to −45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (−1.0 days, 95% CI −1.2 to −0.8, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking.ConclusionsWe found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias.Trial registrationClinicalTrials.gov ISRCTN11780826.

Kjersti Westvik-Johari and co-workers report on perinatal outcomes following fresh and frozen embryo transfer.     

Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass

Decreased β cell mass and function are hallmarks of type 2 diabetes. Here we identified, through a siRNA screen, beta site amyloid precursor protein cleaving enzyme 2 (Bace2) as the sheddase of the proproliferative plasma membrane protein Tmem27 in murine and human β cells. Mice with functionally inactive Bace2 and insulin-resistant mice treated with a newly identified Bace2 inhibitor both display augmented β cell mass and improved control of glucose homeostasis due to increased insulin levels. These results implicate Bace2 in the control of β cell maintenance and provide a rational strategy to inhibit this protease?for the expansion of functional pancreatic β cell mass.     

Church Festivals and the Visualization of Identity in Collingwood Bay,Papua New Guinea

In Collingwood Bay, people celebrate the individual saints after which each Anglican church is named. These church festivals are a combination of Christian worship and traditional music and dances. They vary from small, village-based happenings to large regional performances in which objects and food are exchanged. For the Maisin people, the festivals not only express dedication to the church, they also embody the spirit of past clan festivities that connected clans and commemorated clan ancestors. This article ¹ The research on which this article is based was financed by the Netherlands Foundation for the Advancement of Tropical Research (WOTRO) and the Radboud University of Nijmegen, Netherlands. An earlier version of this article was presented as a paper, “Performing Bodies—Constructing Identities: Church Festivals in Collingwood Bay, Papua New Guinea,” at the Annual Conference of the Australian Anthropological Society (AAS) in Melbourne in 2004. I thank the anonymous reviewer for Visual Anthropology for providing useful comments and suggestions. discusses how, for the Maisin people, church festivals provide a contemporary arena in which various identities, emotions, and knowledge as well as affiliations are actually embodied and expressed visually.     

Anti-c-myc antibody 9E10: epitope key positions and variability characterized using peptide spot synthesis on cellulose.

The 9E10 antibody epitope (EQKLISEEDL) derives from a protein sequence in the human proto-oncogen p62(c-myc) and is widely used as a protein fusion tag. This myc-tag is a powerful tool in protein localization, immunochemistry, ELISA or protein purification. Here, we characterize the myc-tag epitope by substitutional analysis and length variation using peptide spot synthesis on cellulose. The key amino acids of this interaction are the core residues LISE. The shortest peptide with a strong binding signal is KLISEEDL. Dissociation constants of selected peptide variants to the antibody 9E10 were determined. scFv constructs with the shortest possible myc-tags were successfully detected by Western blot and ELISA, giving a signal comparable to that of the original myc-tag.     

A Multiple-Relaxation-Time Lattice-Boltzmann Model for Bacterial Chemotaxis: Effects of Initial Concentration,Diffusion, and Hydrodynamic Dispersion on Traveling Bacterial Bands

Bacterial chemotaxis can enhance the bioremediation of contaminants in aqueous and subsurface environments if the contaminant is a chemoattractant that the bacteria degrade. The process can be promoted by traveling bands of chemotactic bacteria that form due to metabolism-generated gradients in chemoattractant concentration. We developed a multiple-relaxation-time (MRT) lattice-Boltzmann method (LBM) to model chemotaxis, because LBMs are well suited to model reactive transport in the complex geometries that are typical for subsurface porous media. This MRT-LBM can attain a better numerical stability than its corresponding single-relaxation-time LBM. We performed simulations to investigate the effects of substrate diffusion, initial bacterial concentration, and hydrodynamic dispersion on the formation, shape, and propagation of bacterial bands. Band formation requires a sufficiently high initial number of bacteria and a small substrate diffusion coefficient. Uniform flow does not affect the bands while shear flow does. Bacterial bands can move both upstream and downstream when the flow velocity is small. However, the bands disappear once the velocity becomes too large due to hydrodynamic dispersion. Generally bands can only be observed if the dimensionless ratio between the chemotactic sensitivity coefficient and the effective diffusion coefficient of the bacteria exceeds a critical value, that is, when the biased movement due to chemotaxis overcomes the diffusion-like movement due to the random motility and hydrodynamic dispersion.     

Nutrient availability and indirect (biotic) defence in a Malaysian ant-plant

Tropical plants of different genera defend themselves via symbiotic ant colonies, which are housed and often nourished by their host plant. Many studies deal with the defensive effects of the ants, but none has linked the plants' investment in this type of defence to the size and defensive efficacy of the symbiotic ant colony. We show here that ant-food production by the obligate myrmecophyte, Macaranga triloba, is limited by nutrient supply. The colony size of the ants in untreated plants (which had not been affected by experiments in advance of colony collection and determination of food body production) was significantly correlated with the amount of food produced by their hosts, and the plants' level of leaf damage was significantly and negatively correlated with the number of inhabiting ant workers. Our study provides the first field data that show that nutrient availability can directly influence a myrmecophyte's investment in its ants. Further studies are needed to evaluate whether soil nutrient contents in general can be a factor that limits the ability of myrmecophytes to defend themselves indirectly by nourishing symbiotic ants.     

Purification and characterization of a new sodium-transport decarboxylase. Methylmalonyl-CoA decarboxylase from Veillonella alcalescens

Upon resolution of the particulate cell fraction of Veillonella alcalescens by gel chromatography, membranes and ribosomes were clearly resolved. Methylmalonyl-CoA decarboxylase was bound to the membranes and not to ribosomes as reported earlier. Membrane vesicles containing methylmalonyl-CoA decarboxylase were prepared by disrupting V. alcalescens cells with a French pressure chamber. About 64% of the decarboxylase was oriented in these vesicles with the substrate binding site facing to the outside. The vesicles performed a rapid accumulation of Na+ ions in response to the decarboxylation of methylmalonyl-CoA. Decarboxylation and transport were highly uncoupled. The efficiency of the transport was considerably increased if methylmalonyl-CoA decarboxylation was retarded by using a low temperature or by slowly generating the substrate enzymically from propionyl-CoA. Under optimized conditions Na+ was concentrated inside the inverted vesicles eight-times higher than in the incubation medium. Methylmalonyl-CoA decarboxylase was solubilized from the membranes with Triton X-100 and purified about 20-fold by affinity chromatography on monomeric avidin-Sepharose columns. The decarboxylase was specifically activated by Na+ ions (apparent Km approximately equal to 0.6 mM). Whereas (S)-methylmalonyl-CoA was the superior substrate (apparent Km approximately equal to 7 microM), malonyl-CoA was also decarboxylated (apparent Km approximately equal to 35 microM). The decarboxylation of methylmalonyl-CoA yielded CO2 and not HCO-3 as the primary reaction product. Analysis of the purified enzyme by dodecylsulfate gel electrophoresis indicated the presence of four different polypeptides alpha, beta, gamma, delta with Mr 60 000, 33 000, 18 5000 and 14 000. The latter of these polypeptides was clearly visible only after silver staining but not after staining with Coomassie brilliant blue. A low molecular weight polypeptide with similar staining properties was also found in oxaloacetate decarboxylase. Methylmalonyl-CoA decarboxylase contained about 1 mol covalently bound biotin per 125 500 g protein which was localized exclusively in the gamma-subunit. This subunit therefore represents the biotin carboxyl carrier protein of methylmalonyl-CoA decarboxylase. A new very sensitive method for the detection of biotin-containing proteins is described.     

Life by a new decarboxylation-dependent energy conservation mechanism with Na as coupling ion

We report here a new mode of ATP synthesis in living cells. The anaerobic bacterium Propionigenium modestum gains its total energy for growth from the conversion of succinate to propionate according to: succinate + H₂O → propionate + HCO₃^- (G^o' = -20.6 kJ/mol). The small free energy change of this reaction does not allow a substrate-linked phosphorylation mechanism, and no electron transport phosphorylation takes place. Succinate was degraded by cell-free extracts to propionate and CO₂ via succinyl-CoA, methyl-malonyl-CoA and propionyl-CoA. This pathway involves a membrane-bound methylmalonyl-CoA decarboxylase which couples the exergonic decarboxylation with a Na⁺ ion transport across the membrane. The organism also contained a membrane-bound ATPase which was specifically activated by Na⁺ ions and catalyzed and transport of Na⁺ ions into inverted bacterial vesicles upon ATP hydrolysis. The transport was abolished by monensin but not by the uncoupler carbonylcyanide-p-trifluoromethoxy phenylhydrazone. Isolated membrane vesicles catalyzed the synthesis of ATP from ADP and inorganic phosphate when malonyl-CoA was decarboxylated and malonyl-CoA synthesis from acetyl-CoA when ATP was hydrolyzed. These syntheses were sensitive to monensin which indicates that Na⁺ functions as the coupling ion. We conclude from these results that ATP synthesis in P. modestum is driven by a Na⁺ ion gradient which is generated upon decarboxylation of methylmalonyl-CoA.     

Evaluation of Potentially Predictive Markers for Anti-Angiogenic Therapy with Sunitinib in Recurrent Ovarian Cancer Patients

INTRODUCTION: In ovarian cancer, new therapeutic strategies are needed because the vast majority of patients develop a recurrence and resistance to platinum derivates. Attached to the AGO-OVAR2.11 study investigating the multityrosine kinase inhibitor sunitinib in recurrent platinum refractory ovarian cancers, this translational research project assesses the potential value of serum vascular endothelial growth factor (VEGF), soluble VEGF receptor-3 (sVEGFR-3), and angiopoietin-2 (Ang-2) levels for progression-free survival (PFS). MATERIALS AND METHODS: Longitudinal serum samples were taken while the patient was on study drugs. Serum concentration of VEGF, sVEGFR-3, and Ang-2 was determined by ELISA. The slope of the markers was correlated to the PFS. RESULTS: Patients showing a decrease in VEGF concentration had a median PFS of 10.5 months [confidence interval (CI), 2.89–12.25] compared to 2.9 months (CI, 1.48–5.32) in the case of an increase (P = .17). The stratified log-rank test showed a trend for longer PFS if a decrease of Ang-2 was observed (P = .089). Dichotomized in absolute decrease or increase, the PFS was 8.4 months (CI, 2.89–12.26) versus 2.7 months (CI, 1.05–5.32), respectively. Patients with a reduction of the sVEGFR-3 concentration had a median PFS of 4.76 months (CI 2.86–10.65) versus 8.61 months (CI, 1.05-not estimable) in patients with an increase of sVEGFR-3. This observation was statistically not significant in the log-rank test (P = .81). CONCLUSION: Ang-2 could potentially identify a patient population that might have a better PFS when under anti-angiogenic treatment, like the tyrosine kinase inhibitor sunitinib.     

Reduced chemical defence in ant‐plants? A critical re‐evaluation of a widely accepted hypothesis

Since its original formulation by Janzen in 1966, the hypothesis that obligate ant‐plants (myrmecophytes) defended effectively against herbivores by resident mutualistic ants have reduced their direct, chemical defence has been widely adopted. We tested this hypothesis by quantifying three classes of phenolic compounds (hydrolysable tannins, flavonoids, and condensed tannins) spectrophotometrically in the foliage of 20 ant‐plant and non‐ant‐plant species of the three unrelated genera Leonardoxa,Macaranga and Acacia (and three other closely related Mimosoideae from the genera Leucaena, Mimosa and Prosopis). We further determined biological activities of leaf extracts of the mimosoid species against fungal spore germination (as measure of pathogen resistance), seed germination (as measure of allelopathic activity), and caterpillar growth (as measure of anti‐herbivore defence).
Condensed tannin content in three of four populations of the non‐myrmecophytic Leonardoxa was significantly higher than in populations of the myrmecophyte. In contrast, we observed no consistent differences between ant‐plants and non‐ant‐plants in the Mimosoideae and in the genus Macaranga, though contents of phenolic compounds varied strongly among different species in each of these two plant groups. Similarly, among the investigated Mimosoideae, biological activity against spore or seed germination and caterpillar growth varied considerably but showed no clear relation with the existence of an obligate mutualism with ants. Our results did not support the hypothesis of ‘trade‐offs’ between indirect, biotic and direct, chemical defence in ant‐plants.
A critical re‐evaluation of the published data suggests that support for this hypothesis is more tenuous than is usually believed. The general and well‐established phenomenon that myrmecophytes are subject to severe attack by herbivores when deprived of their ants still lacks an explanation. It remains to be studied whether the trade‐off hypothesis holds true only for specific compounds (such as chitinases and amides whose cost may be the direct negative effects on plants’ ant mutualists), or whether the pattern of dramatically reduced direct defence of ant‐plants is caused by classes of defensive compounds not yet studied.