Chemotherapeutic Agents from Natural Product Templates: The Design and Synthesis of Novel Indanone Analogues

Coumarin is a natural product found in many plants. Recently, simple coumarin analogues containing an α-methylene functional group have been synthesized and shown to exhibit cytotoxicity against cancer cell lines. The α,β-unsaturated carbonyl found in these analogues is thought to be responsible for their bioactivity. Other natural products containing this functional group have been shown to react with intracellular thiols causing tumor growth suppression. Using these analogues as a template, two new compounds have been designed that feature a novel α-methylene indanone structural framework. Since ketones are better electrophiles that esters, it is hypothesized that these analogues will react more rapidly with thiols that their coumarin counterparts. The two α-methylene indanone analogues, one incorporating an isopropyl and the other an n-butyl substituent, have been prepared in five and seven steps respectively. Both synthetic sequences feature a 1,4-organometallic addition reaction, in intramolecular Friedel-Crafts acylation, and an α-methylenation of the key inadone intermediates

MIPAS IMK/IAA CFC-11 (CCl3F) and CFC-12 (CCl2F2) Measurements: Accuracy, Precision and Long-Term Stability

Profiles of CFC-11 (CCl3F) and CFC-12 (CCl2F2) of the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) aboard the European satellite Envisat have been retrieved from versions MIPAS/4.61 to MI-PAS/4.62 and MIPAS/5.02 to MIPAS/5.06 level-1b data using the scientific level-2 processor run by Karlsruhe Institute of Technology (KIT), Institute of Meteorology and Climate Research (IMK) and Consejo Superior de Investigaciones Cientificas (CSIC), Instituto de Astrofisica de Andalucia (IAA). These profiles have been compared to measurements taken by the balloon-borne cryosampler, Mark IV (MkIV) and MIPAS-Balloon (MIPAS-B), the airborne MIPAS-STRatospheric aircraft (MIPAS-STR), the satellite-borne Atmospheric Chemistry Experiment Fourier transform spectrometer (ACE-FTS) and the High Resolution Dynamic Limb Sounder (HIRDLS), as well as the ground-based Halocarbon and other Atmospheric Trace Species (HATS) network for the reduced spectral resolution period (RR: January 2005-April 2012) of MIPAS. ACE-FTS, MkIV and HATS also provide measurements during the high spectral resolution period (full resolution, FR: July 2002-March 2004) and were used to validate MIPAS CFC-11 and CFC-12 products during that time, as well as profiles from the Improved Limb Atmospheric Spectrometer, ILAS-II. In general, we find that MIPAS shows slightly higher values for CFC-11 at the lower end of the profiles (below ~ 15 km) and in a comparison of HATS ground-based data and MIPAS measurements at 3 km below the tropopause. Differences range from approximately 10 to 50 pptv (~ 5-20 %) during the RR period. In general, differences are slightly smaller for the FR period. An indication of a slight high bias at the lower end of the profile exists for CFC-12 as well, but this bias is far less pronounced than for CFC-11 and is not as obvious in the relative differences between MIPAS and any of the comparison instruments. Differences at the lower end of the profile (below ~15 km) and in the comparison of HATS and MIPAS measurements taken at 3 km below the tropopause mainly stay within 10-50 pptv (corresponding to ~ 2-10% for CFC-12) for the RR and the FR period. Between similar to 15 and 30 km, most comparisons agree within 10-20 pptv (10-20 %), apart from ILAS-II, which shows large differences above similar to 17 km. Overall, relative differences are usually smaller for CFC-12 than for CFC-11. For both species -CFC-11 and CFC-12 - we find that differences at the lower end of the profile tend to be larger at higher latitudes than in tropical and subtropical regions. In addition, MIPAS profiles have a maximum in their mixing ratio around the tropopause, which is most obvious in tropical mean profiles. Comparisons of the standard deviation in a quiescent atmosphere (polar summer) show that only the CFC-12 FR error budget can fully explain the observed variability, while for the other products (CFC-11 FR and RR and CFC-12 RR) only two-thirds to three-quarters can be explained. Investigations regarding the temporal stability show very small negative drifts in MIPAS CFC-11 measurements. These instrument drifts vary between ~ 1 and 3% decade-1. For CFC-12, the drifts are also negative and close to zero up to similar to 30 km. Above that altitude, larger drifts of up to similar to 50% decade-1 appear which are negative up to similar to 35 km and positive, but of a similar magnitude, above

ALS2 mutations: Juvenile amyotrophic lateral sclerosis and generalized dystonia.

To determine the genetic etiology in 2 consanguineous families who presented a novel phenotype of autosomal recessive juvenile amyotrophic lateral sclerosis associated with generalized dystonia

First Observation Of The Spin Rotational Structure Of The Hydroxymethyl Radical (h2coh) In The Ch2 Asymmetric Mode

Rotationally-resolved direct infrared absorption spectra of hydroxymethyl radical (H$_{2}$COH) in the CH$_{2}$ asymmetric mode (\nub{2}) were observed for the first time using the Boulder difference frequency generation infrared spectrometer. Hydroxymethyl radical was formed with chemical selectivity via the reaction of Cl radical with CH$_{3}$OH in a discharge slit-jet supersonic expansion. As a result of sub-Doppler linewidth and low rotational temperature, the \textit{b}-type rotational structure and spin-rotation splitting were fully resolved. In particular, tunneling splitting was observed due to the large-amplitude COH torsional mode. Because of the feasible permutation of hydrogens in the methylenic group, nuclear spin intensity alternation was given as: 3:1 for \textit{K$_{a}$}=even, odd in the 0$^{+}$ level, and 1:3 for \textit{K$_{a}$}=even, odd in the 0$^{-}$ level of the ground vibrational state. The assignments were confirmed rigorously by four-line ground state combination differences, which agreed within the experimental frequency uncertainty (10 MHz). The identified transitions were fit with a Watson \textit{A}-reduction Hamiltonian including the spin rotational interaction, leading to unambiguous determination of asymmetric top spectroscopic constants, as well as spin rotational constants ($\epsilon$$_{aa}$, $\epsilon$$_{bb}$, $\epsilon$$_{cc}$) for the first time

Effect of the dual endothelin receptor antagonist bosentan on untreatable skin ulcers in a patient with diabetes: a case report

<p>Abstract</p> <p>Introduction</p> <p>Refractory skin ulcers are a major burden in patients with diabetes. Their pathogenesis is multifactorial, and data increasingly implicate endothelin as a mediator of diabetic macro- and microvasculopathy. Here we describe the first reported case of an endothelin receptor antagonist being used to successfully treat refractory skin ulcers in a patient with diabetes.</p> <p>Case presentation</p> <p>An 85-year-old Caucasian man with a 30-year history of type 2 diabetes developed multiple skin ulcerations, including a right heel ulcer. Despite appropriate treatment, the ulcer showed little improvement and the risk of amputation was high. The patient was treated with the dual endothelin receptor antagonist bosentan. After three weeks of treatment, major improvements were observed, and after 21 weeks, all ulcers had healed. No abnormalities were observed during monitoring of blood pressure, erythrocyte sedimentation rate or serum aminotransferase levels.</p> <p>Conclusion</p> <p>In patients with refractory ulceration associated with diabetes, bosentan may be of real benefit, especially in terms of amputation prevention. This case supports the proposed role for endothelin in the pathogenesis of skin ulceration in diabetes and is suggestive of a potential benefit of bosentan in this patient type. This case report is of interest to diabetologists and dermatologists.</p

The Role of Sulfur Dioxide in Stratospheric Aerosol Formation Evaluated Using In Situ Measurements in the Tropical Lower Stratosphere

Stratospheric aerosols (SAs) are a variable component of the Earth's albedo that may be intentionally enhanced in the future to offset greenhouse gases (geoengineering). The role of tropospheric-sourced sulfur dioxide (SO2) in maintaining background SAs has been debated for decades without in-situ measurements of SO2 at the tropical tropopause to inform this issue. Here we clarify the role of SO2 in maintaining SAs by using new in-situ SO2 measurements to evaluate climate models and satellite retrievals. We then use the observed tropical tropopause SO2 mixing ratios to estimate the global flux of SO2 across the tropical tropopause. These analyses show that the tropopause background SO2 is about 5 times smaller than reported by the average satellite observations that have been used recently to test atmospheric models. This shifts the view of SO2 as a dominant source of SAs to a near-negligible one, possibly revealing a significant gap in the SA budget

Human RECQ1 helicase-driven DNA unwinding, annealing, and branch migration : insights from DNA complex structures

RecQ helicases are a widely conserved family of ATP-dependent motors with diverse roles in nearly every aspect of bacterial and eukaryotic genome maintenance. However, the physical mechanisms by which RecQ helicases recognize and process specific DNA replication and repair intermediates are largely unknown. Here, we solved crystal structures of the human RECQ1 helicase in complexes with tailed-duplex DNA and ssDNA. The structures map the interactions of the ssDNA tail and the branch point along the helicase and Zn-binding domains, which, together with reported structures of other helicases, define the catalytic stages of helicase action. We also identify a strand-separating pin, which (uniquely in RECQ1) is buttressed by the protein dimer interface. A duplex DNA-binding surface on the C-terminal domain is shown to play a role in DNA unwinding, strand annealing, and Holliday junction (HJ) branch migration. We have combined EM and analytical ultracentrifugation approaches to show that RECQ1 can form what appears to be a flat, homotetrameric complex and propose that RECQ1 tetramers are involved in HJ recognition. This tetrameric arrangement suggests a platform for coordinated activity at the advancing and receding duplexes of an HJ during branch migration

Occlusive dressing-induced secretomes influence the migration and proliferation of mesenchymal stem cells and fibroblasts differently

Background: Fingertip injuries treated with occlusive dressings (ODs) lead to nearly scar-free, functionally, and aesthetically pleasing results. We hypothesized that paracrine factors in the wound fluid (secretome) may influence migration and proliferation of mesenchymal stem cells (MSCs) and fibroblasts and modulate the wound-healing process. Methods: We could collect wound fluid samples from 4 fingertip injuries and 7 split skin donor sites at the 5th day during dressing change. Blood serum samples served as controls. The proliferation rate of MSCs and fibroblasts (HS27) was continuously measured through impedance analysis for 60h and by Alamarblue analysis after 72h. Cell migration was evaluated continuously for 15h and confirmed by the in vitro wound-healing assay. Results: Migration of MSCs under the influence of both wound fluids was significantly faster than controls from 4 to 6h after incubation and reversed after 9h. MSC proliferation in wound fluid groups showed a significant increase at 5 and 10h and was significantly decreased after 45h. Fibroblasts in wound fluid groups showed overall a significant increase in migration and a significant decrease in proliferation compared to controls. Conclusion: OD-induced secretomes influence MSCs and fibroblasts and thereby possibly modulate wound healing and scar tissue formation

c.207C>G mutation in sepiapterin reductase causes autosomal dominant dopa-responsive dystonia

Objective: To elucidate the genetic cause of an Egyptian family with dopa-responsive dystonia (DRD), a childhood-onset dystonia, responding therapeutically to levodopa, which is caused by mutations in various genes. Methods: Rare variants in all coding exons of GCH1 were excluded by Sanger sequencing. Exome sequencing was applied for 1 unaffected and 2 affected family members. To investigate the functional consequences of detected genetic variants, urinary sepiapterin concentrations were determined by high-performance liquid chromatography. Results: A heterozygous rare nonsynonymous variant in exon 1 of sepiapterin reductase (SPR, c.207C>G, p.Asp69Glu) was found in all affected family members. Urinary concentrations of sepiapterin were above the standard of normal controls in most SPR mutation carriers, suggesting functional biochemical consequences of the mutation. Variant filtering of all genes involved in the tetrahydrobiopterin pathway, required for levodopa synthesis, revealed an additional common variant in dihydrofolate reductase (DHFR, rs70991108). The presence of both variants was significantly stronger associated with the biochemical abnormality and the clinical disease state as opposed to 1 variant only. Conclusions: The rare SPR mutation can cause autosomal dominant DRD with incomplete penetrance. The common DHFR variant might have synergistic effects on production of tetrahydrobiopterin and levodopa, thereby increasing penetrance