A deaminative strategy for the borylation of aliphatic primary amines is described. Alkyl radicals derived from the single‐electron reduction of redox‐active pyridinium salts, which can be isolated ...or generated in situ, were borylated in a visible light‐mediated reaction with bis(catecholato)diboron. No catalyst or further additives were required. The key electron donor–acceptor complex was characterized in detail by both experimental and computational investigations. The synthetic potential of this mild protocol was demonstrated through the late‐stage functionalization of natural products and drug molecules.
Take it away: A deaminative strategy for the borylation of aliphatic amines is described. Alkyl radicals derived from redox‐active pyridinium salts were borylated in a visible light‐mediated reaction with bis(catecholato)diboron. The synthetic potential of this method was demonstrated by late‐stage functionalization of natural products and drug molecules. The key electron donor–acceptor complex is characterized in detail by various experiments as well as computational investigations.
Many useful principles of self-assembly have been elucidated through studies of systems where multiple components combine to create a single structure. More complex systems, where multiple product ...structures self-assemble in parallel from a shared set of precursors, are also of great interest, as biological systems exhibit this behavior. The greater complexity of such systems leads to an increased likelihood that discrete species will not be formed, however. Here we show how the kinetics of self-assembly govern the formation of multiple metal–organic architectures from a mixture of five building blocks, preventing the formation of a discrete structure of intermediate size. By varying ligand symmetry, denticity, and orientation, we explore how five distinct polyhedraa tetrahedron, an octahedron, a cube, a cuboctahedron, and a triangular prismassemble in concert around CoII template ions. The underlying rules dictating the organization of assemblies into specific shapes are deciphered, explaining the formation of only three discrete entities when five could form in principle.
A deaminative strategy for the visible‐light‐mediated generation of alkyl radicals from redox‐activated primary amine precursors is described. Abundant and inexpensive primary amine feedstocks, ...including amino acids, were converted in a single step into redox‐active pyridinium salts and subsequently into alkyl radicals by reaction with an excited‐state photocatalyst. The broad synthetic potential of this protocol was demonstrated by the alkylation of a number of heteroarenes under mild conditions.
Radical cut: In the title reaction alkyl radicals are generated from redox‐activated primary amine precursors. Abundant and inexpensive primary amine feedstocks, including amino acids, were converted in a single step into redox‐active pyridinium salts and subsequently into alkyl radicals by reaction with an excited‐state photocatalyst. The potential of this method was demonstrated by the alkylation of a number of heteroarenes.
Wave equation based inversions, such as full-waveform inversion and reverse-time migration, are challenging because of their computational costs, memory requirements and reliance on accurate initial ...models. To confront these issues, we propose a novel formulation of wave equation based inversion based on a penalty method. In this formulation, the objective function consists of a data-misfit term and a penalty term, which measures how accurately the wavefields satisfy the wave equation. This new approach is a major departure from current formulations where forward and adjoint wavefields, which both satisfy the wave equation, are correlated to compute updates for the unknown model parameters. Instead, we carry out the inversions over two alternating steps during which we first estimate the wavefield everywhere, given the current model parameters, source and observed data, followed by a second step during which we update the model parameters, given the estimate for the wavefield everywhere and the source. Because the inversion involves both the synthetic wavefields and the medium parameters, its search space is enlarged so that it suffers less from local minima. Compared to other formulations that extend the search space of wave equation based inversion, our method differs in several aspects, namely (i) it avoids storage and updates of the synthetic wavefields because we calculate these explicitly by finding solutions that obey the wave equation and
fit the observed data and (ii) no adjoint wavefields are required to update the model, instead our updates are calculated from these solutions directly, which leads to significant computational savings. We demonstrate the validity of our approach by carefully selected examples and discuss possible extensions and future research.
A cobalt‐catalyzed dehydrogenative cross‐coupling of thiols and indoles is reported. Using a cooperative reaction system, a new mode of action for the cobalt‐catalyzed C−heteroatom bond formation was ...found. The directed C−H activation catalysis overrides an undirected thiolation of indole in the 3‐position that occurs in the absence of cobalt. Mechanistic studies indicate a sequence of C−H activation, thiolate transfer, and reductive elimination.
Co‐laboration! A new method for the dehydrogenative cross‐coupling of thiols and indoles features a novel mode of action for the cobalt‐catalyzed formation of a C−heteroatom bond. Mechanistic studies indicate a sequence of C−H activation, thiolate transfer, and reductive elimination.
Comorbidities significantly influence the clinical course of idiopathic pulmonary fibrosis (IPF). However, their prognostic impact is not fully understood. We therefore aimed to determine the impact ...of comorbidities, as individual and as whole, on survival in IPF.
The database of a tertiary referral centre for interstitial lung diseases was reviewed for comorbidities, their treatments, their frequency and survival in IPF patients.
272 patients were identified of which 12% had no, 58% 1-3 and 30% 4-7 comorbidities, mainly cardiovascular, pulmonary and oncologic comorbidities. Median survival according to the frequency of comorbidities differed significantly with 66 months for patients without comorbidities, 48 months when 1-3 comorbidities were reported and 35 months when 4-7 comorbidities were prevalent (p = 0.004). A multivariate Cox proportional hazard analyses identified other cardiac diseases and lung cancer as significant predictors of death, gastro-oesophageal reflux disease (GERD) and diastolic dysfunction had a significant positive impact on survival. A significant impact of comorbidities associated therapies on survival was not discovered. This included the use of proton pump inhibitors at baseline, which was not associated with a survival benefit (p = 0.718). We also established a predictive tool for highly prevalent comorbidities, termed IPF comorbidome which demonstrates a new relationship of IPF and comorbidities.
Comorbidities are frequent in IPF patients. Some comorbidities, especially lung cancer, mainly influence survival in IPF, while others such as GERD may inherit a more favourable effect. Moreover, their cumulative incidence impacts survival.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cryoelectron tomography provides unprecedented insights into the macromolecular and supramolecular organization of cells in a close-to-living state. However because of the limited thickness range ...(< 0.5–1 μm) that is accessible with today’s intermediate voltage electron microscopes only small prokaryotic cells or peripheral regions of eukaryotic cells can be examined directly. Key to overcoming this limitation is the ability to prepare sufficiently thin samples. Cryosectioning can be used to prepare thin enough sections but suffers from severe artefacts, such as substantial compression. Here we describe a procedure, based upon focused ion beam (FIB) milling for the preparation of thin (200–500 nm) lamellae from vitrified cells grown on electron microscopy (EM) grids. The self-supporting lamellae are apparently free of distortions or other artefacts and open up large windows into the cell’s interior allowing tomographic studies to be performed on any chosen part of the cell. We illustrate the quality of sample preservation with a structure of the nuclear pore complex obtained from a single tomogram.
Zooming in to see the bigger picture Hol, Felix J. H.; Dekker, Cees
Science (American Association for the Advancement of Science),
10/2014, Letnik:
346, Številka:
6208
Journal Article
Recenzirano
The spatial structure of natural habitats strongly affects bacterial life, ranging from nanoscale structural features that individual cells exploit for surface attachment, to micro- and ...millimeter-scale chemical gradients that drive population-level processes. Nanofabrication and microfluidics are ideally suited to manipulate the environment at those scales and have emerged as powerful tools with which to study bacteria. Here, we review the new scientific insights gained by using a diverse set of nanofabrication and microfluidic techniques to study individual bacteria and multispecies communities. This toolbox is beginning to elucidate disparate bacterial phenomena-including aging, electron transport, and quorum sensing-and enables the dissection of environmental communities through single-cell genomics. A more intimate integration of microfluidics, nanofabrication, and microbiology will enable further exploration of bacterial life at the smallest scales.
The molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. α-Syn inclusions were long thought to consist mainly of α-Syn ...fibrils, but recent reports pointed to intracellular membranes as the major inclusion component. Here, we use cryo-electron tomography (cryo-ET) to image neuronal α-Syn inclusions in situ at molecular resolution. We show that inclusions seeded by α-Syn aggregates produced recombinantly or purified from patient brain consist of α-Syn fibrils crisscrossing a variety of cellular organelles. Using gold-labeled seeds, we find that aggregate seeding is predominantly mediated by small α-Syn fibrils, from which cytoplasmic fibrils grow unidirectionally. Detailed analysis of membrane interactions revealed that α-Syn fibrils do not contact membranes directly, and that α-Syn does not drive membrane clustering. Altogether, we conclusively demonstrate that neuronal α-Syn inclusions consist of α-Syn fibrils intermixed with membranous organelles, and illuminate the mechanism of aggregate seeding and cellular interaction.
PDF
