Cornforth–Evans Transition States in Stereocontrolled Allylborations of Epoxy Aldehydes

Allylboration reactions rank among the most reliable tools in organic synthesis. Herein, we report a general synthesis of trifunctionalized allylboronates and systematic investigations of their stereocontrolled transformations with substituted aldehyde substrates, in order to efficiently access diverse, highly substituted target substrates. A peculiar transition in stereocontrol was observed from the polar Felkin–Anh (PFA) to the Cornforth–Evans (CE) model for alkoxy‐ and epoxy‐substituted aldehydes. CE‐type transition states were uniformly identified as minima in advanced, DFT‐based computational studies of allylboration reactions of epoxy aldehydes, conforming well to the experimental data, and highlighting the underestimated relevance of this model. Furthermore, a mechanism‐based rationale for the substitution pattern of the epoxide was delineated that ensures high levels of stereocontrol and renders α,β‐epoxy aldehydes generally applicable substrates for target synthesis

Apoptosis and proliferation in the trigeminal placode

The neurogenic trigeminal placode develops from the crescent-shaped panplacodal primordium which delineates the neural plate anteriorly. We show that, in Tupaia belangeri, the trigeminal placode is represented by a field of focal ectodermal thickenings which over time changes positions from as far rostral as the level of the forebrain to as far caudal as opposite rhombomere 3. Delamination proceeds rostrocaudally from the ectoderm adjacent to the rostral midbrain, and contributes neurons to the trigeminal ganglion as well as to the ciliary ganglion/oculomotor complex. Proliferative events are centered on the field prior to the peak of delamination. They are preceded, paralleled and, finally, outnumbered by apoptotic events which proceed rostrocaudally from non-delaminating to delaminating parts of the field. Apoptosis persists upon regression of the placode, thereby exhibiting a massive “wedge” of apoptotic cells which includes the postulated position of the “ventrolateral postoptic placode” (Lee et al. in Dev Biol 263:176–190, 2003), merges with groups of lens-associated apoptotic cells, and disappears upon lens detachment. In conjunction with earlier work (Washausen et al. in Dev Biol 278:86–102, 2005) our findings suggest that apoptosis contributes repeatedly to the disintegration of the panplacodal primordium, to the elimination of subsets of premigratory placodal neuroblasts, and to the regression of placodes

Testing Biochemistry Revisited: How In Vivo Metabolism Can Be Understood from In Vitro Enzyme Kinetics

A decade ago, a team of biochemists including two of us, modeled yeast glycolysis and showed that one of the most studied biochemical pathways could not be quite understood in terms of the kinetic properties of the constituent enzymes as measured in cell extract. Moreover, when the same model was later applied to different experimental steady-state conditions, it often exhibited unrestrained metabolite accumulation

Comparison of total parathyroidectomy without autotransplantation and without thymectomy versus total parathyroidectomy with autotransplantation and with thymectomy for secondary hyperparathyroidism: TOPAR PILOT-Trial

<p>Abstract</p> <p>Background</p> <p>Secondary hyperparathyroidism (sHPT) is common in patients with chronic renal failure. Despite the initiation of new therapeutic agents, several patients will require parathyroidectomy (PTX). Total PTX with autotransplantation of parathyroid tissue (TPTX+AT) and subtotal parathyroidectomy (SPTX) are currently considered as standard surgical procedures in the treatment of sHPT. Recurrencerates after TPTX+AT or SPTX are between 10% and 12% (median follow up: 36 months).</p> <p>Recent retrospective studies demonstrated a lower rate of recurrent sHPT of 0–4% after PTX without autotransplantation and thymectomy (TPTX) with no higher morbidity when compared to the standard procedures. The observed superiority of TPTX is flawed due to different definitions of outcomes, varying follow up periods and different surgical treatment strategies (with and without thymectomy).</p> <p>Methods/Design</p> <p>Patients with sHPT (intact parathyroid hormone > 10 times above the upper limit of normal) on long term dialysis (>12 months) will be randomized either to TPTX or TPTX+AT and followed for 36 months. Outcome parameters are recurrence rates of sHPT, frequencies of reoperations due to refractory hypoparathyroidism or recurrent/persistent hyperparathyroidism, postoperative morbidity and mortality and quality of life. 50 patients per group will be randomized in order to obtain relevant frequencies of outcome parameters that will form the basis for a large scale confirmatory multicentred randomized controlled trial.</p> <p>Discussion</p> <p>sHPT is a disease with a high incidence in patients with chronic renal failure. Even a small difference in outcomes will be of clinical relevance. To assess sufficient data about the rate of recurrent sHPT after both methods, a multicentred, randomized controlled trial (MRCT) under standardized conditions is mandatory.</p> <p>Due to the existing uncertainties the calculated number of patients necessary in each treatment arm (n > 4000) makes it impossible to perform this study as a confirmatory trial. Therefore estimates of different outcomes are performed using a pilot MRCT comparing 50 versus 50 randomized patients in order to establish a hypothesis that can be tested thereafter.</p> <p>If TPTX proves to have a lower rate of recurrent sHPT, no relevant disadvantages and no higher morbidity than TPTX+AT, current surgical practice may be changed.</p> <p>Trial registration</p> <p>International Standard Randomized Controlled Trial Number Registration (ISRCTN86202793)</p

Identification of Early Requirements for Preplacodal Ectoderm and Sensory Organ Development

Preplacodal ectoderm arises near the end of gastrulation as a narrow band of cells surrounding the anterior neural plate. This domain later resolves into discrete cranial placodes that, together with neural crest, produce paired sensory structures of the head. Unlike the better-characterized neural crest, little is known about early regulation of preplacodal development. Classical models of ectodermal patterning posit that preplacodal identity is specified by readout of a discrete level of Bmp signaling along a DV gradient. More recent studies indicate that Bmp-antagonists are critical for promoting preplacodal development. However, it is unclear whether Bmp-antagonists establish the proper level of Bmp signaling within a morphogen gradient or, alternatively, block Bmp altogether. To begin addressing these issues, we treated zebrafish embryos with a pharmacological inhibitor of Bmp, sometimes combined with heat shock-induction of Chordin and dominant-negative Bmp receptor, to fully block Bmp signaling at various developmental stages. We find that preplacodal development occurs in two phases with opposing Bmp requirements. Initially, Bmp is required before gastrulation to co-induce four transcription factors, Tfap2a, Tfap2c, Foxi1, and Gata3, which establish preplacodal competence throughout the nonneural ectoderm. Subsequently, Bmp must be fully blocked in late gastrulation by dorsally expressed Bmp-antagonists, together with dorsally expressed Fgf and Pdgf, to specify preplacodal identity within competent cells abutting the neural plate. Localized ventral misexpression of Fgf8 and Chordin can activate ectopic preplacodal development anywhere within the zone of competence, whereas dorsal misexpression of one or more competence factors can activate ectopic preplacodal development in the neural plate. Conversely, morpholino-knockdown of competence factors specifically ablates preplacodal development. Our work supports a relatively simple two-step model that traces regulation of preplacodal development to late blastula stage, resolves two distinct phases of Bmp dependence, and identifies the main factors required for preplacodal competence and specification

New System for the Acceleration of the Airflow in Wind Turbines

Background: This patent is based on the wind industry technology called Diffuser Augmented Wind Turbines (DAWTs). This technology consists of a horizontal axis wind turbine, which is housed inside a duct with diverging section in the direction of the free air stream. In this paper, a review of preceding patents related to this technology is carried out. Objective: This paper presents an innovative patent to improve the performance of horizontal axis wind turbines. In particular, this system is aimed at improving the performance of those turbines that otherwise might not be installed due to the low wind resource existing at certain locations. Methods: The most innovative elements of this patent are: (1) the semi-spherical grooves, which are mechanized on the surface of the two diffusers in order to guarantee a more energetic boundary layer; (2) the coaxial diffuser, which is located downwind following the first diffuser in order to increase the suction effect on the air mass close to the inlet; (3) the coaxial rings located around the first diffuser outlet, which are used to deflect the external airflow toward the turbine wake; and (4), the selforientating system to orientate the system by the prevailing wind direction. Results: An application of the patent for increasing the power generated by a horizontal axis wind turbine with three blades is presented. The patent is designed and its performance is evaluated by using a Computational Fluid Dynamics code. The numerical results show that this system rises the airflow going through the rotor of the turbine. Conclusion: The patented device is an original contribution aimed at enabling a more profitable installation of wind turbines in places where the wind resource is insufficient because of the wind shear caused both by the proximity of the earth and the obstacles on the earth surface.This work was supported by the OASIS Research Project that was cofinanced by CDTI (Spanish Science and Innovation Ministry) and developed with the Spanish companies: Iridium, OHL Concesiones, Abertis, Sice, Indra, Dragados, OHL, Geocisa, GMV, Asfaltos Augusta, Hidrofersa, Eipsa, PyG, CPS, AEC and Torre de Comares Arquitectos S.L and 16 research centres. The authors also acknowledge the partial funding with FEDER funds under the Research Project FC-15-GRUPIN14-004. Finally, we also thank Swanson Analysis Inc. for the use of ANSYS University Research programs as well as the Workbench simulation environment

DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.publishedVersionPeer reviewe

Receptor-Mediated In Vivo Targeting of Breast Cancer Cells with 17 alpha-Ethynylestradiol-Conjugated Silica-Coated Gold Nanoparticles

Efficient therapies for breast cancer remain elusive because of the lack of strategies for targeted transport and receptor-mediated uptake of synthetic drug molecules by cancer cells. Conjugation of nanoparticles (NPs) with active targeting ligands enabling selective molecular recognition of antigens expressed on the surface of cancer cells is promising for localization and treatment of malignant cells. In this study, covalent attachment of synthetic estrogen 17 alpha-ethynylestradiol on the silica (SiO2) shell of silica-gold NPs (SiO2@Au) was undertaken to improve the cancer-targeting ability of the nano-biotags. Chemical and structural analysis of the bioconjugates examined in solution (UV-vis and xi-potential) and solid state (Fourier transform infrared spectroscopy, X-ray diffractometry, and transmission electron microscopy) confirmed the identity of the carrier particles and surface-bound ligands. The mesoporous silica shell served as a reservoir for anticancer drugs (doxorubicin and quercetin) and to facilitate covalent attachment of receptor molecules by click chemistry protocols. The chemoselective recognition between the nanoconjugates and cell membranes was successfully demonstrated by the accumulation of nanoprobes in the tumor tissue of mice with subcutaneous breast cancer, whereas healthy cells were unaffected. The drug release studies showed sustained release kinetics over several weeks. These findings elaborate the exceptional selectivity and potential of estrogen-coated nano-biolabels in efficient diagnosis and detection of breast cancer cells