Elevated Carbon Dioxide and Nitrogen Impact Wheat and Its Aphid Pest.

The rise in atmospheric carbon dioxide (CO2) generally increases wheat biomass and grain yield but decreases its nutritional value. This, in turn, can alter the metabolic rates, development, and performance of insect pests feeding on the crop. However, it is unclear how elevated CO2 (eCO2) and nitrogen (N) input affect insect pest biology through changes in wheat growth and tissue N content. We investigated the effect of three different N application rates (low, medium, and high) and two CO2 levels (ambient and elevated) on wheat growth and quality and the development and performance of the bird cherry-oat aphid, a major cereal pest worldwide, under controlled environmental conditions. We found that eCO2 significantly decreased total aphid fecundity and wheat N content by 22 and 39%, respectively, when compared to ambient CO2 (aCO2). Greater N application significantly increased total aphid fecundity and plant N content but did not offset the effects of eCO2. Our findings provide important information on aphid threats under future CO2 conditions, as the heavy infestation of the bird cherry-oat aphid is detrimental to wheat grain yield and quality.

Ferroportin mRNA is down-regulated in granulosa and cervical cells from infertile women.

OBJECTIVE: To explore the relationship between iron and infertility by investigating iron-related gene expression in granulosa and uterine cervical cells. DESIGN: Case-control study. SETTING: Two tertiary hospitals. PATIENT(S): Two independent cohorts of fertile (n = 18 and n = 17) and infertile (n = 31 and n = 35) women. INTERVENTION(S): In vitro fertilization. MAIN OUTCOME MEASURE(S): Gene expression levels of ferritin light chain (FTL), ferritin heavy chain (FTH), transferrin receptor (TFRC), and ferroportin (SLC40A1) mRNA were analyzed in granulosa and cervical cells. RESULT(S): In the first cohort, fertile and infertile women were similar in body mass index. Ferroportin mRNA levels were decreased in granulosa cells from infertile women in parallel with increased serum hepcidin levels. A positive association between ferroportin and TFRC mRNA, a gene associated with intracellular iron deficiency, was observed only in granulosa cells from fertile women. The major findings were replicated in a second independent cohort. CONCLUSION(S): Ferroportin mRNAs and circulating hepcidin identify a subset of infertile women and may constitute a target for therapy.

Single-distance phase retrieval algorithm for Bragg Magnifier microscope.

We present an improved, single-distance phase retrieval algorithm applicable for holographic X-ray imaging of biological objects for an in-line germanium Bragg Magnifier Microscope (BMM). The proposed algorithm takes advantage of a modified shrink-wrap algorithm for phase objects, robust unwrapping algorithm as well as other reasonable constraints applied to the wavefield at the object and the detector plane. The performance of the algorithm is analyzed on phantom objects and the results are shown and discussed. We demonstrated the suitability of the algorithm for the phase retrieval on a more complex biological specimen Tardigrade, where we achieved successful phase retrieval from only a single hologram. The spatial resolution obtained by Fourier spectral power method for biological objects is ∼ 300 nm, the same value as obtained from the reconstructed test pattern. Our results achieved using the new algorithm confirmed the potential of BMM for in-vivo, dose-efficient single-shot imaging of biological objects.

Thyroid Hormone Receptors Are Differentially Expressed in Granulosa and Cervical Cells of Infertile Women.

BACKGROUND: Thyroid hormones are known to exert an important role in reproduction. The objective of this study was to evaluate the expression of thyroid hormone receptors (TR) in granulosa (GC) and cervical cells (CC) of infertile euthyroid women. METHODS: In a cross-sectional study, 31 consecutive infertile and 18 fertile women undergoing oocyte retrieval procedures were investigated. The expression of TRα1, TRα2, and TRß was evaluated in GCs and uterine CC from infertile and fertile euthyroid women. ß2 adrenergic receptor (ADRß2) mRNA levels and the expression of genes linked to fertility such as gremlin-1 (GREM1), hyaluronan synthase 2 (HAS2), and prostaglandin-endoperoxide synthase 2 (PTGS2) were also evaluated. RESULTS: In GCs, the expression of the thyroid hormone receptor TRα2, which exerts a dominant negative effect, increased with age in all women tested. TRα2 mRNA was increased in infertile versus fertile women, in parallel to decreased ADRß2 mRNA. As expected, the expression of genes associated with fertility (i.e., GREM1 and PTGS2) was downregulated in infertile women, in parallel to decreased ADRß2 mRNA and increased TRα2 mRNA. In uterine CCs, a positive association of ADRß2 mRNA with TRα1:TRα2 ratio was observed. Importantly, GCs from infertile women whose oocytes did not result in pregnancy had increased expression of TRα2 (p = 0.017) and lower ADRß2 (p = 0.008), GREM1 (p = 0.003), and PTGS2 (p = 0.002) mRNAs than fertile women whose oocytes resulted in pregnancy. Infertile women also showed more TRα2 (p = 0.033) mRNA in CCs than fertile women whose oocytes resulted in pregnancy. CONCLUSIONS: The expression of different markers of intracellular thyroid function is linked to fertility status.

La determinación de B-HCG el día 12 de la transferencia embrionaria como predictor del resultado gestacional en técnicas de Reproducción Asistida / B-HCG levels on day 12 after embryo transfer as a predictor of ongoing pregnancy in IVF cycles

OBJETIVOS: Encontrar un valor de β-HCG que prevea el resultado evolutivo de la gestación en una única determinación hormonal en nuestra población. Como objetivos secundarios nos planteamos valorar si ese valor tiene que ser ajustado en función del IMC y de la edad de la paciente. Ámbito: Pacientes sometidas a un ciclo FIV en nuestro centro Hospital Universitari de Girona Dr. Josep Trueta, entre julio de 2010 y diciembre de 2013. DISEÑO: Estudio retrospectivo descriptivo. MATERIAL Y MÉTODOS: Se incluyen 50 ciclos con β-HCG positiva a los 12 días de la transferencia embrionaria de un total de 139 pacientes sometidas a un ciclo FIV en nuestro centro entre julio de 2010 y diciembre de 2013. RESULTADOS: Las diferencias en el nivel de β-HCG el día 12 son estadísticamente significativas entre los diferentes grupos en función del resultado gestacional (p < 0.05). Si comparamos solamente las gestaciones viables con las gestaciones no viables las diferencias son todavía más significativas. Con una β-HCG media de 300,53 para las gestaciones viables y una B-HCG media de 88,66 para las no viables (p < 0,01). La curva ROC sugiere que un valor de β-HCG de 77 mUI/ml sería un buen nivel para prever una gestación viable, con una sensibilidad del 90,63% y una especificidad del 80%. No existen diferencias estadísticamente significativas del valor de β-HCG en función del IMC ni de la edad. CONCLUSIONES: Con un valor de β-HCG igual o superior a 77mUI/ml podemos orientar mejor a la paciente, y prever una gestación exitosa, ayudando a planificar el manejo médico así como disminuir la ansiedad materna. Este valor, además, y según nuestro estudio, no necesita ser ajustado por edad o IMC de la pacientes

OBJECTIVES: The aim of our study is to find a value of β-HCG to predict the outcome of pregnancies in a single hormone determination in our population. As secondary objectives, we will assess whether this value has to be adjusted for BMI and age of the patient. SETTING: Patients subjected to an IVF cycle at our center Hospital Universitari de Girona Dr. Josep Trueta, between July 2010 and December 2013. DESIGN: Retrospective and descriptive study. MATERIAL AND METHODS: A total of 50 cycles with a positive β-HCG the day 12 after the embryo tranfer were analyzed with respect to pregnancy outcome from a total of 139 patients subjected to an IVF cycle at our center between July 2010 and December 2013. RESULTS: The differences in the level of β-HCG at day 12 are statistically significant between different groups based on gestational outcome (p < 0,05). Comparing only viable pregnancies with nonviable pregnancies the differences are even more significant. With a β-HCG 300,53 average for viable pregnancies and average β-HCG for nonviable 88,66 (p < 0,01). The ROC curve suggests that a value of β-HCG 77 mIU / ml would be a good level to predict a viable pregnancy with a sensitivity of 90.63 % and a specificity of 80 %. There are not statistically significant differences in the value of β-HCG in terms of BMI or age. CONCLUSIONS: With a value of β-HCG of 77mUI/ml or more, we can better guide the patient and provide for a successful pregnancy, helping to plan medical management and reduce maternal anxiety. This value, in addition and according to our study, does not need to be adjusted for age or BMI of the patient

EURADOS intercomparison on emergency radiobioassay.

Nine laboratories participated in an intercomparison exercise organised by the European Radiation Dosimetry Group (EURADOS) for emergency radiobioassay involving four high-risk radionuclides ((239)Pu, (241)Am, (90)Sr and (226)Ra). Diverse methods of analysis were used by the participating laboratories for the in vitro determination of each of the four radionuclides in urine samples. Almost all the methods used are sensitive enough to meet the requirements for emergency radiobioassay derived for this project in reference to the Clinical Decision Guide introduced by the NCRP. Results from most of the methods meet the requirements of ISO 28218 on accuracy in terms of relative bias and relative precision. However, some technical gaps have been identified. For example, some laboratories do not have the ability to assay samples containing (226)Ra, and sample turnaround time would be expected to be much shorter than that reported by many laboratories, as timely results for internal contamination and early decisions on medical intervention are highly desired. Participating laboratories are expected to learn from each other on the methods used to improve the interoperability among these laboratories.

Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity.

Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.

Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.

The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.