Gestational age impacts birth to placental weight ratio and umbilical cord oxygen values with implications for the fetal oxygen margin of safety

Background: We determined the impact of gestational age (GA) from near term to term to post-term on birth/placental weight ratio and cord oxygen values with implications for placental transport efficiency for oxygen, fetal O2 consumption relative to delivery or fractional O2 extraction, and oxygen margin of safety. Materials and methods: A hospital database was used to obtain birth/placental weight ratios, cord PO2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA \u3e 34 completed weeks (N=69,852). Oxygen saturation was calculated from the cord PO2 and pH data, while fractional O2 extraction was calculated from the oxygen saturation data. The effect of GA grouping on birth/placental weight ratio, cord PO2, O2 saturation, and fractional O2 extraction values, was examined in all patients adjusting for pregnancy and labor/delivery covariates, and in a subset of low-risk patients. Results: Birth/placental weight ratio and umbilical venous O2 values increased with advancing GA, supporting the conjecture of increasing placental transport efficiency for oxygen. However, umbilical arterial O2 values decreased while fractional O2 extraction increased with successive GA groupings, indicating that fetal O2 consumption must be increasing relative to delivery. Conclusions: Fetal O2 consumption can be seen as ever ‘outgrowing’ O2 delivery over the last weeks of pregnancy and leading to a continued lowering in systemic oxygen levels. While this lowering in oxygen may trigger feedback mechanisms with survival benefit, the ‘oxygen margin of safety’ will also be lowered increasing perinatal morbidity and mortality which appear to be hypoxia related

Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

At least 120 non-olfactory G protein-coupled receptors in the human genome are ”orphans” for which endogenous ligands are unknown, and many have no selective ligands, hindering elucidation of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Yeast-based screens against GPR68 identified the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. Over 3000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators many of which were confirmed in functional assays. One potent GPR68 modulator—ogerin– suppressed recall in fear conditioning in wild-type, but not in GPR68 knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The impact of maternal diabetes on birth to placental weight ratio and umbilical cord oxygen values with implications for fetal-placental development

Introduction We determined the impact of gestational diabetes (GDM) and pre-existing diabetes (DM) on birth/placental weight and cord oxygen values with implications for placental efficiency and fetal-placental growth and development. Methods A hospital database was used to obtain birth/placental weight, cord PO2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA \u3e34 weeks (N = 69,854). Oxygen saturation was calculated from the cord PO2 and pH data, while fetal O2 extraction was calculated from the oxygen saturation data. The effect of diabetic status on birth/placental weight and cord oxygen values was examined adjusting for covariates. Results Birth/placental weights were stepwise decreased in GDM and DM compared to non-diabetics with placentas disproportionally larger indicating decreasing placental efficiency. Umbilical vein oxygen was marginally increased in GDM but decreased in DM attributed to the previously reported hyper-vascularization in diabetic placentas with absorbing surface area of capillaries initially increased, but then constrained by increasing distance from maternal blood within the intervillous space. Umbilical artery oxygen was unchanged in GDM and DM, with fetal O2 extraction decreased in DM indicating that fetal O2 delivery must be increased relative to O2 consumption and likely due to increased umbilical blood flow. Discussion Increased villous density/hyper-vascularization in GDM and DM with placentas disproportionately larger and umbilical blood flow increased, are postulated to normalize umbilical artery oxygen despite increased birth weights and growth-related O2 consumption. These findings have implications for mechanisms signaling fetal-placental growth and development in diabetic pregnancies and differ from that reported with maternal obesity

Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

At least 120 non-olfactory G protein-coupled receptors in the human genome are ”orphans” for which endogenous ligands are unknown, and many have no selective ligands, hindering elucidation of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Yeast-based screens against GPR68 identified the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. Over 3000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators many of which were confirmed in functional assays. One potent GPR68 modulator—ogerin– suppressed recall in fear conditioning in wild-type, but not in GPR68 knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs

The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy

Clozapine, by virtue of its absence of extrapyramidal side effects and greater efficacy, revolutionized the treatment of schizophrenia, although the mechanisms underlying this exceptional activity remain controversial. Combining an unbiased cheminformatics and physical screening approach, we evaluated clozapine's activity at >2350 distinct molecular targets. Clozapine, and the closely related atypical antipsychotic drug olanzapine, interacted potently with a unique spectrum of molecular targets. This distinct pattern, which was not shared with the typical antipsychotic drug haloperidol, suggested that the serotonergic neuronal system was a key determinant of clozapine's actions. To test this hypothesis, we used pet1−/− mice, which are deficient in serotonergic presynaptic markers. We discovered that the antipsychotic-like properties of the atypical antipsychotic drugs clozapine and olanzapine were abolished in a pharmacological model that mimics NMDA-receptor hypofunction in pet1−/− mice, whereas haloperidol's efficacy was unaffected. These results show that clozapine's ability to normalize NMDA-receptor hypofunction, which is characteristic of schizophrenia, depends on an intact presynaptic serotonergic neuronal system