5-aryl-pyrazolo[3,4-b]pyridazines: Potent inhibitors of glycogen synthase kinase-3 (GSK-3)

Introduction of a nitrogen atom into the 6-position of a series of pyrazolo[3,4-b]pyridines led to a dramatic improvement in the potency of GSK-3 inhibition. Rationalisation of the binding mode suggested participation of a putative structural water molecule, which was subsequently confirmed by X-ray crystallography. (C) 2003 Elsevier Science Ltd. All rights reserved.

Exchange systems and style in the Central Mediterranean. 4500-1700 b.c..:Unpublished PhD. Cambridge University Library

Malone, C.A.T., 1986, Unpublished PhD, Cambridge University, Cambridge.

Molecular dynamics simulation of nanoindentation of Fe3C and tetrahedral Fe4C

Study of nanomechanical response of iron carbides is important because presence of iron carbides greatly influences the performance and longevity of steel components. This work contributes to the literature by exploring nanoindentation of nanocrystalline Fe3C and tetrahedral-Fe4C using molecular dynamics simulation. The chemical interactions of iron and carbon were described through an analytical bond order inter-atomic potential (ABOP) energy function. The indentations were performed at an indentation speed of 50 m/sec and a repeat trial was performed at 5 m/sec. Load-displacement (P-h) curve for both these carbides showed residual indentation depth and maximum indentation depth (hf/hmax) ratio to be higher than 0.7 i.e. a circumstance where Oliver and Pharr method was not appropriate to be applied to evaluate the material properties. Alternate evaluation revealed Fe3C to be much harder than Fe4C. Gibbs free energy of formation and radial distribution function, coupled with state of the average local temperature and von Mises stresses indicate the formation of a new phase of iron-carbide. Formation of this newer phase was found to be due to deviatoric strain rather than the high temperature induced in the substrate during nanoindentation

Interpreting A-level Mathematics grades – as easy as A, B, C?

Many concerns have been expressed that students’ basic mathematical skills have deteriorated during the 1990s and there has been disquiet that current A-level grading does not distinguish adequately between the more able students. This study reports the author’s experiences of teaching maths to large classes of first-year engineering students and aims to enhance understanding of levels of mathematical competence in more recent years. Over the last four years, the classes have consisted of a very large proportion of highly qualified students – about 91% of them had at least grade B in A-level Mathematics. With a small group of students having followed a non-traditional route to university (no A-level maths) and another group having benefitted through taking A-level Further Mathematics at school, the classes have contained a very wide range of mathematical backgrounds. Despite the introductory maths course at university involving mainly repetition of A-level material, students’ marks were spread over a very wide range – for example, A-level Mathematics grade B students have scored across the range 16 – 97%. Analytical integration is the topic which produced the largest variation in performance across the class but, in contrast, the A-level students generally performed well in differentiation. Initial analysis suggests some stability in recent years in the mathematical proficiency of students with a particular A-level Mathematics grade. Allowing choice of applied maths modules as part of the A-level maths qualification increases the variety of students’ mathematical backgrounds and their selection from mechanics, statistics or decision maths is not clear from the final qualification.

Total Synthesis of the Antitumor Macrolides, (+)-Brefeldin A and 4‑Epi-Brefeldin A from D‑Glucose: Use of the Padwa Anionic Allenylsulfone [3+2]-Cycloadditive Elimination To Construct Trans-Configured Chiral Cyclopentane Systems

A new synthesis of (+)-brefeldin A is reported via Padwa allenylsulfone [3+2]-cycloadditive elimination. Cycloadduct 13 was initially elaborated into iodide
27, which, following treatment with Zn, gave aldehyde 28 whose C(9) stereocenter was epimerized. Further elaboration into enoate 38 and Julia−Kocienski olefination with 5 subsequently afforded 39, which was deprotected at C(1) and O(15). Yamaguchi macrolactonization of the seco-acid thereafter afforded a macrocycle that underwent O-desilylation and inversion at C(4) to give (+)-brefeldin A following deprotection

Physicochemical characterization of bioactive polyacrylic acid organogels as potential antimicrobial implants for the buccal cavity

This study describes the formulation and physicochemical characterization of poly(acrylic acid) (PAA) organogels, designed as bioactive implants for improved treatment of infectious diseases of the oral cavity. Organogels were formulated containing a range of concentrations of PAA (3-10% w/w) and metronidazole (2 or 5% w/w, representing a model antimicrobial agent) in different nonaqueous solvents, namely, glycerol (Gly), polyethylene glycol (PEG 400), or propylene glycol (PG). Characterization of the organogels was performed using flow rheometry, compressional analysis, oscillatory rheometry, in vitro mucoadhesion, moisture uptake, and drug release, methods that provide information pertaining to the nonclinical and clinical use of these systems. Increasing the concentration of PAA significantly increased the consistency, compressibility, storage modulus, loss modulus, dynamic viscosity, mucoadhesion, and the rate of drug release. These observations may be accredited to enhanced molecular polymer entanglement. In addition, the choice of solvent directly affected the physicochemical parameters of the organogels, with noticeable differences observed between the three solvents examined. These differences were accredited to the nature of the interaction of PAA with each solvent and, importantly, the density of the resultant physical cross-links. Good correlation was observed between the viscoelastic properties and drug release, with the exception of glycerol-based formulations containing 5 and 10% w/w PAA. This disparity was due to excessive swelling during the dissolution analysis. Ideally, formulations should exhibit controlled drug release, high viscoelasticity, and mucoadhesion, but should flow under minimal stresses. Based on these criteria, PEG 400-based organogels composed of 5% or 10% w/w PAA exhibited suitable physicochemical properties and are suggested to be a potentially interesting strategy for use as bioactive implants designed for use in the oral cavity. © 2008 American Chemical Society.

An examination of the rheological and mucoadhesive properties of poly(Acrylic acid) organogels designed as platforms for local drug delivery to the oral cavity

This study examined the rheological/mucoadhesive properties of poly (acrylic acid) PAA organogels as platforms for drug delivery to the oral cavity. Organogels were prepared using PAA (3%, 5%, 10% w/w) dissolved in ethylene glycol (EG), propylene glycol (PG), 1,3-propylene glycol (1,3-PG), 1,5-propanediol (1,5-PD), polyethylene glycol 400 (PEG 400), or glycerol. All organogels exhibited pseudoplastic flow. The increase in storage (G') and loss (G '') moduli of organogels as a function of frequency was minimal, G '' was greater than G '' (at all frequencies), and the loss tangent <1, indicative of gel behavior. Organogels prepared using EG, PG, and 1,3-propanediol (1,3-PD) exhibited similar flow/viscoelastic properties. Enhanced rheological structuring was associated with organogels prepared using glycerol (in particular) and PEG 400 due to their interaction with adjacent carboxylic acid groups on each chain and on adjacent chains. All organogels (with the exception of 1,5-PD) exhibited greater network structure than aqueous PAA gels. Organogel mucoadhesion increased with polymer concentration. Greatest mucoadhesion was associated with glycerol-based formulations, whereas aqueous PAA gels exhibited the lowest mucoadhesion. The enhanced network structure and the excellent mucoadhesive properties of these organogels, both of which may be engineered through choice of polymer concentration/solvent type, may be clinically useful for the delivery of drugs to the oral cavity.

A narrow-band ultraviolet B course improves vitamin D balance and alters cutaneous CYP27A1 and CYP27B1 mRNA expression levels in haemodialysis patients supplemented with oral vitamin D

Background: Chronic kidney disease (CKD) patients on dialysis are prone to vitamin D insufficiency despite oral vitamin D supplementation. Here, we studied whether narrow-band ultraviolet B (NB-UVB) exposures improve vitamin D balance.

Methods: 14 haemodialysis patients and 15 healthy subjects receiving oral cholecalciferol 20 µg daily got nine NB-UVB exposures on the entire body. Serum 25-hydroxyvitamin D (25(OH)D) was measured by radioimmunoassay. Cutaneous mRNA expression levels of CYP27A1 and CYP27B1, two enzymes required for hydroxylation of vitamin D into its active metabolite, were also measured.

Results: The baseline serum 25(OH)D concentration was 57.6 ± 18.2 nmol/l in the CKD patients and 74.3 ± 14.8 nmol/l in the healthy subjects. The NB-UVB course increased serum 25(OH)D by 14.0 nmol/l (95% CI 8.7-19.5) and 17.0 nmol/l (CI 13.7-20.2), respectively. At baseline the CKD patients showed significantly increased CYP27B1 levels compared to the healthy subjects.

Conclusions: A short NB-UVB course is an efficient way to improve vitamin D balance in CKD patients on dialysis who are receiving oral vitamin D supplementation. The increased cutaneous CYP27B1 levels in the CKD patients suggest that the loss of renal activity of this enzyme is at least partially compensated for by the skin.

DEAD-box helicase DP103 defines metastatic potential of human breast cancers

Despite advancement in breast cancer treatment, 30% of patients with early breast cancers experience relapse with distant metastasis. It is a challenge to identify patients at risk for relapse; therefore, the identification of markers and therapeutic targets for metastatic breast cancers is imperative. Here, we identified DP103 as a biomarker and metastasis-driving oncogene in human breast cancers and determined that DP103 elevates matrix metallopeptidase 9 (MMP9) levels, which are associated with metastasis and invasion through activation of NF-κB. In turn, NF-κB signaling positively activated DP103 expression. Furthermore, DP103 enhanced TGF-β-activated kinase-1 (TAK1) phosphorylation of NF-κB-activating IκB kinase 2 (IKK2), leading to increased NF-κB activity. Reduction of DP103 expression in invasive breast cancer cells reduced phosphorylation of IKK2, abrogated NF-κB-mediated MMP9 expression, and impeded metastasis in a murine xenograft model. In breast cancer patient tissues, elevated levels of DP103 correlated with enhanced MMP9, reduced overall survival, and reduced survival after relapse. Together, these data indicate that a positive DP103/NF-κB feedback loop promotes constitutive NF-κB activation in invasive breast cancers and activation of this pathway is linked to cancer progression and the acquisition of chemotherapy resistance. Furthermore, our results suggest that DP103 has potential as a therapeutic target for breast cancer treatment.

Comet C/2012 S1 (ISON): Observations of the Dust Grains from SOFIA and of the Atomic Gas from NSO Dunn and McMath-Pierce Solar Telescopes (Invited)

Comet C/2012 S1 (ISON) is unique in that it is a dynamically new comet derived from the Oort cloud reservoir of comets with a sun-grazing orbit. Infrared (IR) and visible wavelength observing campaigns were planned on NASA's Stratospheric Observatory For Infrared Astronomy (SOFIA) and on National Solar Observatory Dunn (DST) and McMath-Pierce Solar Telescopes, respectively. We highlight our early results. SOFIA (+FORCAST [1]) mid- to far-IR images and spectroscopy (~5-35 μm) of the dust in the coma of ISON are to be obtained by the ISON-SOFIA Team during a flight window 2013 Oct 21-23 UT (r_h≈1.18 AU). Dust characteristics, identified through the 10 μm silicate emission feature and its strength [2], as well as spectral features from cometary crystalline silicates (Forsterite) at 11.05-11.2 μm, and near 16, 19, 23.5, 27.5, and 33 μm are compared with other Oort cloud comets that span the range of small and/or highly porous grains (e.g., C/1995 O1 (Hale-Bopp) [3,4,5] and C/2001 Q4 (NEAT) [6]) to large and/or compact grains (e.g., C/2007 N4 (Lulin) [7] and C/2006 P1 (McNaught) [8]). Measurement of the crystalline peaks in contrast to the broad 10 and 20 μm amorphous silicate features yields the cometary silicate crystalline mass fraction [9], which is a benchmark for radial transport in our protoplanetary disk [10]. The central wavelength positions, relative intensities, and feature asymmetries for the crystalline peaks may constrain the shapes of the crystals [11]. Only SOFIA can look for cometary organics in the 5-8 μm region. Spatially resolved measurements of atoms and simple molecules from when comet ISON is near the Sun (r_h<0.4 AU, near Nov-20--Dec-03 UT) were proposed for by the ISON-DST Team. Comet ISON is the first comet since comet Ikeya-Seki (1965f) [12,13] suitable for studying the alkalai metals Na and K and the atoms specifically attributed to dust grains including Mg, Si, Fe, as well as Ca. DST's Horizontal Grating Spectrometer (HGS) measures 4 settings: Na I, K, C2 to sample cometary organics (along with Mg I), and [O I] as a proxy for activity from water [14] (along with Si I and Fe I). State-of-the-art instruments that will also be employed include IBIS [15], which is a Fabry-Perot spectral imaging system that concurrently measures lines of Na, K, Ca II, or Fe, and ROSA (CSUN/QUB) [16], which is a rapid imager that simultaneously monitors Ca II or CN. From McMath-Pierce, the Solar-Stellar Spectrograph also will target ISON (320-900 nm, R~21,000, r_h

Ca2+ current and Ca(2+)-activated chloride current in isolated smooth muscle cells of the sheep urethra.

1. Isolated sheep urethral cells were studied using the perforated patch clamp technique (T = 37 degrees C). Depolarizing steps ranging from -40 to -10 mV evoked an inward current that peaked within 10 ms and a slower inward current. Stepping back to the holding potential of -80 mV evoked large inward tail currents. All three currents were abolished by nifedipine (1 microM). Substitution of external Ca2+ with Ba2+ resulted in potentiation of the fast inward current and blockade of the slow current and tails. 2. Changing the chloride equilibrium potential (ECl) from 0 to +27 mV shifted the reversal potential of the tail currents from 1 +/- 1 to 27 +/- 1 mV (number of cells, n = 5). Chloride channel blockers, niflumic acid (10 microM) and anthracene-9-carboxylic acid (9AC, 1 mM), reduced the slow current and tails suggesting that these were Ca(2+)-activated Cl- currents, ICl(Ca). 4. Caffeine (10 mM) induced currents that reversed at ECl and were blocked by niflumic acid (10 microM). 5. In current clamp mode, some cells developed spontaneous transient depolarizations (STDs) and action potentials. Short exposure to nifedipine blocked the action potentials and unmasked STDs. In contrast, 9AC and niflumic acid reduced the amplitude of the STDs and blocked the action potentials. 6. In conclusion, these cells have both L-type ICa and ICl(Ca). The former appears to be responsible for the upstroke of the action potential, while the latter may act as a pacemaker current.