Total syntheses of linear polythiazole/oxazole plantazolicin A and its biosynthetic precursor plantazolicin B.

Plantazolicin A, a linear decacyclic natural product, exhibits desirable selective activity against the causative agent of anthrax toxicity. The total synthesis of plantazolicin A and its biosynthetic precursor plantazolicin B was successfully achieved by an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4-concatenated oxazoles and the mild synthesis of thiazoles from natural amino acids. This report represents the first synthesis of plantazolicin B and includes the first complete characterization data for both natural products.

A systems approach towards an intelligent and self-controlling platform for integrated continuous reaction sequences.

Performing reactions in flow can offer major advantages over batch methods. However, laboratory flow chemistry processes are currently often limited to single steps or short sequences due to the complexity involved with operating a multi-step process. Using new modular components for downstream processing, coupled with control technologies, more advanced multi-step flow sequences can be realized.

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions.

A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide.

Adherence to healthy lifestyle and risk of gestational diabetes mellitus: prospective cohort study.

Objective: To quantify the association between a combination of healthy lifestyle factors before pregnancy (healthy body weight, healthy diet, regular exercise, and not smoking) and the risk of gestational diabetes.

Design: Prospective cohort study.

Setting: Nurses' Health Study II, United States.

Quantitative Emphysema Distribution in Anatomic and Non-anatomic Lung Regions.

Purpose: The change of emphysema distribution with increasing COPD severity is not yet assessed. Especially, involvement of the upper aspect of the lower lobe is unknown. The primary aim was to quantitatively determine regional distribution of emphysema in anatomically (lung lobes) and non-anatomically defined lung regions (upper/lower lung halves as well as core and rind regions) in a cohort covering equally all COPD severity stages using CT.

IKK-induced NF-κB1 p105 proteolysis is critical for B cell antibody responses to T cell-dependent antigen.

The importance of IκB kinase (IKK)-induced proteolysis of NF-κB1 p105 in B cells was investigated using Nfkb1(SSAA/SSAA) mice, in which this NF-κB signaling pathway is blocked. Nfkb1(SSAA) mutation had no effect on the development and homeostasis of follicular mature (FM) B cells. However, analysis of mixed bone marrow chimeras revealed that Nfkb1(SSAA/SSAA) FM B cells were completely unable to mediate T cell-dependent antibody responses.

Priming IKKβ kinase for action.

IKKβ (IκB kinase β) is a core component of signalling pathways that control the activation of NF-κB (nuclear factor κB) transcription factors, which regulate many physiological processes, including cell survival, immunity and DNA-damage responses. Like many kinases, activation of IKKβ requires phosphorylation of the activation loop of its kinase domain. Different upstream protein kinases, and IKKβ itself, have been reported to directly phosphorylate and activate IKKβ in vitro, but the exact molecular mechanism of IKKβ activation in cells has remained unclear.

Assessment of the relationship between morphological emphysema phenotype and corresponding pulmonary perfusion pattern on a segmental level.

Purpose: Distinct morphological emphysema phenotypes were assessed by CT to show characteristic perfusion defect patterns.

Material/methods: Forty-one patients with severe emphysema (GOLD III/IV) underwent three-dimensional high resolution computed tomography (3D-HRCT) and contrast-enhanced magnetic resonance (MR) perfusion. 3D-HRCT data was visually analyzed for emphysema phenotyping and quantification by consensus of three experts in chest-radiology.

Flow chemistry meets advanced functional materials.

Flow chemistry and continuous processing techniques are beginning to have a profound impact on the production of functional materials ranging from quantum dots, nanoparticles and metal organic frameworks to polymers and dyes. These techniques provide robust procedures which not only enable accurate control of the product material's properties but they are also ideally suited to conducting experiments on scale. The modular nature of flow and continuous processing equipment rapidly facilitates reaction optimisation and variation in function of the products.

Sulfonylurea use and incident cardiovascular disease among patients with type 2 diabetes: prospective cohort study among women.

Objective: Evidence is inconsistent for the association between sulfonylurea use and risk of cardiovascular disease among patients with diabetes. We aimed to prospectively evaluate this association using the Nurses' Health Study (NHS), a well-established cohort of U.S.

Regioselective preparation of saturated spirocyclic and ring-expanded fused pyrazoles.

Saturated bicyclic pyrazoles represent an important class of biologically active molecules, but their preparation can be hampered by labor-intensive synthesis of required starting materials. A convenient one- or two-step procedure for the synthesis of saturated spirocyclic and fused pyrazoles is reported. The synthesis benefits from the use of readily available alkynes and bench-stable tosylhydrazones, which are easily prepared from their parent ketones.

Expedient preparation of nazlinine and a small library of indole alkaloids using flow electrochemistry as an enabling technology.

An expedient synthesis of the indole alkaloid nazlinine is reported. Judicious choice of flow electrochemistry as an enabling technology has permitted the rapid generation of a small library of unnatural relatives of this biologically active molecule. Furthermore, by conducting the key electrochemical Shono oxidation in a flow cell, the loading of electrolyte can be significantly reduced to 20 mol % while maintaining a stable, broadly applicable process.

Tuberculosis in Papua New Guinea: from yesterday until today.

Little is known about the situation of tuberculosis in Papua New Guinea despite its high TB burden, emerging drug resistance and rising HIV co-infection. This review gives an overview on the current situation of TB in PNG and identifies knowledge gaps that should urgently be addressed in the future.

Magnetic resonance assessment of pulmonary (QP) to systemic (QS) flows using 4D phase-contrast imaging: pilot study comparison with standard through-plane 2D phase-contrast imaging.

Rationale And Objectives: To investigate four-dimensional (4D) phase-contrast (PC) magnetic resonance (MR) in the evaluation of intracardiac shunts by simultaneous assessment of pulmonary (QP) and systemic (QS) flows in a pilot study and to compare results to through-plane two-dimensional (2D) PC MR.

Materials And Methods: Institutional review board approval and written informed consent were obtained. Nineteen patients with suspected intracardiac shunts underwent cardiac MR at 1.

Synthesis of riboflavines, quinoxalinones and benzodiazepines through chemoselective flow based hydrogenations.

Robust chemical routes towards valuable bioactive entities such as riboflavines, quinoxalinones and benzodiazepines are described. These make use of modern flow hydrogenation protocols enabling the chemoselective reduction of nitro group containing building blocks in order to rapidly generate the desired amine intermediates in situ. In order to exploit the benefits of continuous processing the individual steps were transformed into a telescoped flow process delivering selected benzodiazepine products on scales of 50 mmol and 120 mmol respectively.

Impact of early synchronous lip and palatal repair on speech.

Aims: The purpose of this study was to describe articulation and resonance characteristics of Ugandan English-speaking children with cleft lip and palate (CLP) after synchronous lip and palatal closure (Sommerlad technique) prior to the age of 6 months in comparison with an age- and gender-matched control group.

Methods: Eleven Ugandan patients with CLP (mean age 4;9 years), repaired during a synchronous lip and (soft and hard) palatal closure at a mean age of 3.4 months, were included as well as a control group (n = 22) consisting of 2 Ugandan age- and gender-matched noncleft children for each patient (mean age 4;10 years).

Automatic lung segmentation method for MRI-based lung perfusion studies of patients with chronic obstructive pulmonary disease.

Purpose: A novel fully automatic lung segmentation method for magnetic resonance (MR) images of patients with chronic obstructive pulmonary disease (COPD) is presented. The main goal of this work was to ease the tedious and time-consuming task of manual lung segmentation, which is required for region-based volumetric analysis of four-dimensional MR perfusion studies which goes beyond the analysis of small regions of interest.

Methods: The first step in the automatic algorithm is the segmentation of the lungs in morphological MR images with higher spatial resolution than corresponding perfusion MR images.

Highly regioselective lithiation of pyridines bearing an oxetane unit by n-butyllithium.

The first regioselective ortho-lithiation at the 4-position of simple pyridine derivatives containing a 3-oxetane unit has been achieved using n-butyllithium as base. Electrophilic quenching of the resulting lithio species provides a rapid access to a broad range of new functionalized pyridine oxetane building blocks.

IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases.

The MEK-1/2 kinase TPL-2 is critical for Toll-like receptor activation of the ERK-1/2 MAP kinase pathway during inflammatory responses, but it can transform cells following C-terminal truncation. IκB kinase (IKK) complex phosphorylation of the TPL-2 C terminus regulates full-length TPL-2 activation of ERK-1/2 by a mechanism that has remained obscure. Here, we show that TPL-2 Ser-400 phosphorylation by IKK and TPL-2 Ser-443 autophosphorylation cooperated to trigger TPL-2 association with 14-3-3.

Prevention and management of type 2 diabetes: dietary components and nutritional strategies.

In the past couple of decades, evidence from prospective observational studies and clinical trials has converged to support the importance of individual nutrients, foods, and dietary patterns in the prevention and management of type 2 diabetes. The quality of dietary fats and carbohydrates consumed is more crucial than is the quantity of these macronutrients. Diets rich in wholegrains, fruits, vegetables, legumes, and nuts; moderate in alcohol consumption; and lower in refined grains, red or processed meats, and sugar-sweetened beverages have been shown to reduce the risk of diabetes and improve glycaemic control and blood lipids in patients with diabetes.

Flow Synthesis and Biological Studies of an Analgesic Adamantane Derivative That Inhibits P2X7-Evoked Glutamate Release.

We report the biological evaluation of a class of adamantane derivatives, which were achieved via modified telescoped machine-assisted flow procedure. Among the series of compounds tested in this work, 5 demonstrated outstanding analgesic properties. This compound showed that its action was not mediated through direct interaction with opioid and/or cannabinoid receptors.

Assessment of aortic morphology and compliance in children and adolescents with Ullrich-Turner syndrome (UTS) using magnetic resonance imaging (MRI).

Aim: The aim of this study was to evaluate the morphology and elastic properties of the aorta in children and adolescents with Ullrich-Turner syndrome (UTS) treated with growth hormone, by using magnetic resonance imaging (MRI).

Methods: Thirty-seven conscious UTS patients were examined using a 1.5-T whole-body MRI.

Noninvasive pressure difference mapping derived from 4D flow MRI in patients with unrepaired and repaired aortic coarctation.

Purpose: To develop a method for computing and visualizing pressure differences derived from time-resolved velocity-encoded three-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) and to compare pressure difference maps of patients with unrepaired and repaired aortic coarctation to young healthy volunteers.

Methods: 4D flow MRI data of four patients with aortic coarctation either before or after repair (mean age 17 years, age range 3-28, one female, three males) and four young healthy volunteers without history of cardiovascular disease (mean age 24 years, age range 20-27, one female, three males) was acquired using a 1.5-T clinical MR scanner.

Preparation of unsymmetrical ketones from tosylhydrazones and aromatic aldehydes via formyl C-H bond insertion.

Preparation of ketones by insertion of diazo compounds into the formyl C-H bond of an aldehyde is an attractive procedure, but use of structurally diverse diazo compounds is hampered by preparation and safety issues. A convenient procedure for the synthesis of unsymmetrical ketones from bench-stable tosylhydrazones and aryl aldehydes is reported. The procedure can be performed in one pot from the parent carbonyl compound and needs only a base, with no additional promoters being required.

Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide.

Here we describe the use of a new open-source software package and a Raspberry Pi(®) computer for the simultaneous control of multiple flow chemistry devices and its application to a machine-assisted, multi-step flow preparation of pyrazine-2-carboxamide - a component of Rifater(®), used in the treatment of tuberculosis - and its reduced derivative piperazine-2-carboxamide.