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Presents information on a study which employed Fourier synthesis to obtain solutions to the coupled singular integrations which, according to the method of dislocation continua, represent equilibrium. Screw dislocation totally within a thin plate; Discussion of the edge dislocation normal to a free surface; Analysis of the dislocation continua through the singular integral equations.

Neonicotinoids are subjected to vigilance because of environmental contaminations and deleterious effects on bees. Imidacloprid (LMI) is one of the most representative insecticides of this family. At chronic exposure, concentration-effect relationships are non linear. An insect model should allow a better description of this toxicity. We compared the lethal concentration 50% (LC50) of IMI for a Drosophila-field strain, after acute and chronic exposure. Relative to the acute LC50, the chronic LC50 was lowered by a factor of 29 for males (1.3 mM/45 μM), 52 for larvae (157 μM/3 μM) and more than 172 for females (>3.1 mM/18 μM). Chronic exposure also revealed significant lethal and sublethal effects, at concentrations 3-5 orders of magnitude lower than the chronic LC50. Mean mortalities reached 28% (at 3.91 nM) and 27% (at 39.1 nM) for females and males, respectively. Fecundity decreased of 16% at 1.96 nM. Mating increased of 30% at 0.391 nM. The LOEC (lowest observed effect concentration: 0.391 nM) was 46 000 times lower than the chronic LC50 for males; it was 115 000 times lower than the chronic LC50 for females. This study illuminates effects that neonicotinoids can induce at very low concentrations. This is of particular interest for nontarget insects and for insect dependent species. [ABSTRACT FROM AUTHOR]

Nucleotide excision repair (NER) deals with bulky DNA damages. However, the regulation of this process is still unclear. Here, we show that both cell resistance to genotoxic agents that generate DNA lesions corrected by NER and in vitro NER activity are correlated with atypical protein kinase C (PKC) ζ expression levels. Moreover, repair intermediates are produced and eliminated more rapidly in UV-irradiated PKCζ-overexpressing cells. The expression levels of XPC and hHR23B, two NER proteins, are correlated with PKCζ expression. Altogether, these results strongly suggest that PKCζ could act as a modulator of NER activity by regulating the expression of XPC/hHR23B heterodimer. [Copyright &y& Elsevier]

The restraints to the motion of grain boundaries provided by voids and by particles are calculated as functions of boundary velocity and of temperature. [ABSTRACT FROM AUTHOR]

Microtubule-targeting agents are an important class of anti-cancer drugs; their full potential is however not realized because of significant myelotoxicity and neurotoxicity. We here report 3-nitropyridine analogues as a novel group of microtubule-targeting agents with potent anti-cancer effects against a broad range of cancer types. We show that these 3-nitropyridines induce cell cycle arrest in the G2-M phase and inhibit tubulin polymerization by interacting with tubulin. Determination of the tubulin–4AZA2996 structure by X-ray crystallography demonstrated that this class of compounds binds to the colchicine-site of tubulin. Furthermore, the anti-cancer effect was demonstrated both in vitro and in vivo in a murine heterotopic xenograft model of colon cancer. When administered intravenously, 4AZA2891 effectively inhibited cancer growth. Whereas 3-nitropyridine compounds do not induce myelotoxicity at pharmacological doses, the neurotoxicity associated with microtubule-targeting agents is still present. [ABSTRACT FROM AUTHOR]

The fluorinated piperidine iminosugars 2a-4a and their N -octyl and N -decyl derivatives 2b,c-4b,c were synthesized from d -mannose/ d -xylose using nucleophilic fluorination as the key step. The conformation of iminosugars 2 / 3 , either 2 C 5 or 5 C 2 , was assigned based on the 1 H NMR studies at different pH. Immunomodulatory activity of 2a,c-4a,c was examined using Mixed Lymphocyte Reaction (MLR) and B-cell assay. The N -alkylated fluorinated d - manno -iminosugars 3b/4b were found to be better immunosuppressive agents (IC 50  = 5–6  μ M) on T-cells. The fluorinated iminosugar 3a/4a act as potent and selective inhibitors of β -glucosidase (IC 50  = 4–8  μ M). The N -alkyl-iminosugars 4b-c were found to be moderate inhibitors of α -glucosidase (yeast) and α -galactosidase (coffee beans), respectively. [ABSTRACT FROM AUTHOR]

Objective: Protein fermentation results in production of metabolites such as ammonia, amines and indolic, phenolic and sulfur-containing compounds. In vitro studies suggest that these metabolites might be toxic. However, human and animal studies do not consistently support these findings. We modified protein fermentation in healthy subjects to assess the effects on colonic metabolism and parameters of gut health, and to identify metabolites associated with toxicity. Design: After a 2-week run-in period with normal protein intake (NP), 20 healthy subjects followed an isocaloric high protein (HP) and low protein (LP) diet for 2 weeks in a cross-over design. Protein fermentation was estimated from urinary p-cresol excretion. Fecal metabolite profiles were analyzed using GC-MS and compared using cluster analysis. DGGE was used to analyze microbiota composition. Fecal water genotoxicity and cytotoxicity were determined using the Comet assay and the WST-1-assay, respectively, and were related to the metabolite profiles. Results: Dietary protein intake was significantly higher during the HP diet compared to the NP and LP diet. Urinary p-cresol excretion correlated positively with protein intake. Fecal water cytotoxicity correlated negatively with protein fermentation, while fecal water genotoxicity was not correlated with protein fermentation. Heptanal, 3-methyl-2-butanone, dimethyl disulfide and 2-propenyl ester of acetic acid are associated with genotoxicity and indole, 1-octanol, heptanal, 2,4- dithiapentane, allyl-isothiocyanate, 1-methyl-4-(1-methylethenyl)-benzene, propionic acid, octanoic acid, nonanoic acid and decanoic acid with cytotoxicity. Conclusion: This study does not support a role of protein fermentation in gut toxicity. The identified metabolites can provide new insight into colonic health. [ABSTRACT FROM AUTHOR]

The hMutSα (hMSH2-hMSH6) protein heterodimer plays a critical role in the detection of DNA mispairs in the mismatch repair (MMR) process. We recently reported that hMutSα proteins were degraded by the ubiquitin-proteasome pathway in a cell-type-dependent manner, indicating that one or several regulator(s) may interfere with hMutSα protein ubiquitination and degradation. On the other hand, we and others have shown that protein kinase C (PKC) is involved as a positive regulator of MMR activity. Here, we provide evidence that the atypical PKCζ regulates ubiquitination, degradation, and levels of hMutSα proteins. Using both PKCζ -transfected U937 and PKCζ siRNA-transfected MRC-5 cell lines, we found that PKCζ protein expression was correlated with that of hMutSα as well as with MMR activity, but was inversely correlated with hMutSα protein ubiquitination and degradation. Interestingly, PKCζ interacts with hMSH2 and hMSH6 proteins and phosphorylates both. Moreover, in an in vitro assay PKCζ mediates phosphorylation events decreasing hMutSα protein degradation via the ubiquitin-proteasome pathway. Altogether, our results indicate that PKCζ modulates hMutSα stability and protein levels, and suggest a role for PKCζ in genome stability by regulating MMR activity. [Copyright &y& Elsevier]

Powder metallurgy processing has been used to produce copper compacts with fine grain sizes (1-10µm) that are pinned by submicron-size to micron-size gas-filled voids in the volume fraction range 0.05-0.2. The effect of subsequent heat treatment on the grain size and void size and shape was quantified. These changes strong lydependedon whether the powder was consolidated using a coldpressing-and-sintering route, or hot pressing; thus the pressed and sintered compacts densified further whereas the hot-pressed compacts exhibited swelling during subsequent thermal exposure. Such materials were mechanically tested in compression and tension at room temperature, and high yield strength, attributed tograin-sizes trengthening, was recognized. Tensile ductility inexcess of 20% was simultaneously obtained although some unusual features, atypical of fcc metals, including upper and lower yield points and a low work-hardening rate were noted. Approximate calculations examining the interaction of dislocations with avoidpair, an assembly of voids and the particular case of all voids being located at grain boundaries indicate that direct strengthening due to the voids is not the principal contributor to the high strength; rather it is the refinement in grain size that is responsible for the observed yield strength level. [ABSTRACT FROM AUTHOR]

Many drugs are promiscuous and bind to multiple targets. On the one hand, these targets may be linked to unwanted side effects, but on the other, they may achieve a combined desired effect (polypharmacology) or represent multiple diseases (drug repositioning). With the growth of 3D structures of drug-target complexes, it is today possible to study drug promiscuity at the structural level and to screen vast amounts of drug-target interactions to predict side effects, polypharmacological potential, and repositioning opportunities. Here, we pursue such an approach to identify drugs inactivating B-cells, whose dysregulation can function as a driver of autoimmune diseases. Screening over 500 kinases, we identified 22 candidate targets, whose knock out impeded the activation of B-cells. Among these 22 is the gene KDR, whose gene product VEGFR2 is a prominent cancer target with anti-VEGFR2 drugs on the market for over a decade. The main result of this paper is that structure-based drug repositioning for the identified kinase targets identified the cancer drug ibrutinib as micromolar VEGFR2 inhibitor with a very high therapeutic index in B-cell inactivation. These findings prove that ibrutinib is not only acting on the Bruton's tyrosine kinase BTK, against which it was designed. Instead, it may be a polypharmacological drug, which additionally targets angiogenesis via inhibition of VEGFR2. Therefore ibrutinib carries potential to treat other VEGFR2 associated disease. Structure-based drug repositioning explains ibrutinib's anti VEGFR2 action through the conservation of a specific pattern of interactions of the drug with BTK and VEGFR2. Overall, structure-based drug repositioning was able to predict these findings at a fraction of the time and cost of a conventional screen. [ABSTRACT FROM AUTHOR]

B cells are pathogenic in various disease processes and therefore represent an interesting target for the development of novel immunosuppressants. In the search for new therapeutic molecules, we utilized an in vitro B cell activation assay with ODN2006-stimulated Namalwa cells to screen a chemical library of small molecules for B cell modulating effects. OSU-T315, described as an inhibitor of integrin-linked kinase (ILK), was hereby identified as a hit. On human and murine primary B cells, OSU-T315 potently suppressed the proliferation and the production of antibodies and cytokines upon stimulation, suggesting that ILK could be a promising target in the modulation of B cell activity. Mice with B cell-specific knockout of ILK were generated. Surprisingly, knockout of ILK in murine B cells did not affect B cell function as assessed by several in vivo and ex vivo B cell assays and did not alter the B cell immunosuppressive activity of OSU-T315. In conclusion, OSU-T315 displays potency as B cell modulator, probably through a mechanism of action independent of ILK, and might serve as lead drug molecule for the development of novel B cell-selective drugs. [ABSTRACT FROM AUTHOR]

B cell specific immunomodulatory drugs still remain an unmet medical need. Utilisation of validated simplified in vitro models would allow readily obtaining new insights in the complexity of B cell regulation. For this purpose we investigated which human B lymphocyte stimulation assays may be ideally suited to investigate new B lymphocyte immunosuppressants. Primary polyclonal human B cells underwent in vitro stimulation and their proliferation, production of immunoglobulins (Igs) and of cytokines, and expression of cell surface molecules were analysed using various stimuli. ODN2006, a toll-like receptor 9 (TLR9) agonist, was the most potent general B cell stimulus. Subsequently, we investigated on which human B cell lines ODN2006 evoked the broadest immunostimulatory effects. The Namalwa cell line proved to be the most responsive upon TLR9 stimulation and hence may serve as a relevant, homogeneous, and stable B cell model in an in vitro phenotypic assay for the discovery of new targets and inhibitors of the B cell activation processes. As for the read-out for such screening assay, it is proposed that the expression of activation and costimulatory surface markers reliably reflects B lymphocyte activation. [ABSTRACT FROM AUTHOR]

An efficient and practical strategy for the synthesis of (3 R ,4 s ,5 S )-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N -alkyl derivatives 8a – f , starting from the d -glucose, is reported. The chiral pool methodology involves preparation of the C -3-allyl-α- d -ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13 . Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the γ-hydroxyethyl substituted piperidine iminosugar 8a that was N -alkylated to get N -alkyl derivatives 8b – f . Iminosugars 8a – f were screened against glycosidase enzymes. Amongst synthetic N -alkylated iminosugars, 8b and 8c were found to be α-galactosidase inhibitors while 8d and 8e were selective and moderate α-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a – f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel pyrimidine analogues were synthesized and evaluated for immunosuppressive activity in the Mixed Lymphocyte Reaction assay, which is well-known as the in vitro model for in vivo rejection after organ transplantation. Systematic variation of the substituents at positions 2, 4 and 6 of the pyrimidine scaffold led to the discovery of 2-benzylthio-5-cyano-6-(4-methoxyphenyl)-4-morpholinopyrimidine with an IC50 value of 1.6μM in the MLR assay. [Copyright &y& Elsevier]

Abstract: In preclinical research, genetic studies have made considerable progress as a result of the development of transgenic animal models of human diseases. Consequently, there is now a need for higher resolution MRI to provide finer details for studies of small animals (rats, mice) or very small animals (insects). One way to address this issue is to work with high-magnetic-field spectrometers (dedicated to small animal imaging) with strong magnetic field gradients. It is also necessary to develop a complete methodology (transmit/receive coil, pulse sequence, fixing system, air supply, anesthesia capabilities, etc.). In this study, we developed noninvasive protocols, both in vitro and in vivo (from coil construction to image generation), for drosophila MRI at 9.4 T. The 10*10*80-μm resolution makes it possible to visualize whole drosophila (head, thorax, abdomen) and internal organs (ovaries, longitudinal and transverse muscles, bowel, proboscis, antennae and optical lobes). We also provide some results obtained with a Drosophila model of muscle degeneration. This opens the way for new applications of structural genetic modification studies using MRI of drosophila. [Copyright &y& Elsevier]

A series of 5-substituted 2′-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC50value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC50> 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor. [ABSTRACT FROM AUTHOR]

Herein we describe the synthesis and in vitro and in vivo activity of thiazolo[5,4-d]pyrimidines as a novel class of immunosuppressive agents, useful for preventing graft rejection after organ transplantation. This research resulted in the discovery of a series of compounds with potent activity in the mixed lymphocyte reaction (MLR) assay, which is well-known as the in vitro model for in vivo rejection after organ transplantation. The most potent congeners displayed IC50values of less than 50 nM in this MLR assay and hence are equipotent to cyclosporin A, a clinically used immunosuppressive drug. One representative of this series was further evaluated in a preclinical animal model of organ transplantation and showed excellent in vivo efficacy. It validates these compounds as new promising immunosuppressive drugs. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of a new series of 4-N-piperazinyl-thieno[2,3-d]pyrimidines is described. The synthetic route allows introducing structural variety at positions 2, 4 and 6 of the scaffold. Evaluation of their immunosuppressive activity in a Mixed Lymphocyte Reaction (MLR) assay revealed that the most potent compound has an IC50-value of 66nM and therefore deserves attention for further medicinal chemistry optimization. [Copyright &y& Elsevier]

In order to better understand the tectonic framework of the Northern Molucca Sea area, we inverted satellite and sea-surface gravity data into an iterative scheme including a priori seismological and geological data. The resulting 3-D density model images the various tectonic units from the surface down to 40 km. We proceed to various tests to assess the stability and robustness of our inversion. In particular, we performed an offset and average smoothing method to properly refine our results. The resulting model shows a striking vertical regularity of the structures through the different layers, whereas the density contrasts appear strongly uneven in the horizontal direction.The density model emphasizes the complexity of the upper lithospheric structure in the northern Molucca Sea, which is clearly dominated by the interaction between ophiolitic ridges, sedimentary wedges and rigid blocks of the Philippine Sea Plate. It also provides new, hard information that can be used in discussion of the evolution of the region.Large density variations are concentrated in the central part of northern Molucca Sea and dominate the upper lithospheric. North–south trending density structures along the Central Ridge and west dipping thrust faults on the western side of the region are clearly imaged. In the eastern part of the region, we distinguish several blocks, especially the Snellius Plateau which seems to be split into two parts. We interpret this as an oceanic plateau associated with thicker crust that previously belonged to the Philippine Sea Plate. This crust is now trapped between the Molucca Sea complex collision zone and the Philippine Trench, due to the development of a new subduction zone in its eastern side. [Copyright &y& Elsevier]

The paper presents an interpretation of the complete Bouguer gravity anomaly for the Molucca Sea area (northeast of Indonesia) in order to investigate the structure and interrelation of the main tectonic units of the region. Data on the gravity field and topography incorporate all available shipboard and satellite-derived data, including data collected during a 1994 R/V L’Atalante cruise in the Molucca Sea (MODEC). These data were compiled by weighted interpolation of surface and satellite data. The anomalous gravity field of the area contains components of different wavelengths, which we separated into regional and local anomalies using a spherical analogue of Kolmogorov–Wiener optimal (mean-square) filtering. Position and depth of the shallow lithospheric gravity sources were then estimated from the local field component by applying a new approach to Euler solution selection based on a recently developed fuzzy logic clustering method, called RODIN. The spatial distribution and depth of Euler solutions provide new information on the tectonic structure of the upper lithosphere resulting from the convergence of the Philippine Sea, Eurasian and Australian plates. The local Bouguer anomalies and dense clusters of Euler solutions make it easy to trace the Sangihe Trench further north, up to 5.5°N, joining it to the Pujada and Miangas ridges and to trace the Miangas Ridge southwards to its junction with the Central Ridge. Seismic data revealing compressive structure and dense shallow clusters of Euler solutions suggest that the Pujada Ridge overthrusts the Miangas Ridge from the west. Clusters of Euler solutions also clearly outline an ophiolite body of the Talaud Archipelago, show main thrust zones bounding it, and trace the southern termination of the Philippine Fault horsetail structure up to 5.5–6°N in the area southeast of Mindanao Island. Our results support the hypothesis that the Talaud Archipelago was formed in situ as an uplifted Central Ridge block. We suggest that the structure of the Archipelago and of the area to the east developed under compression caused by docking of the Snellius Plateau. The docking shifted the Philippine subduction zone eastwards and underthrust slivers of forearc lithosphere below the Talaud Archipelago. [Copyright &y& Elsevier]

We report experimental coupling of chiral magnetism and superconductivity in [IrFeCoPt]/Nb heterostructures. The stray field of skyrmions with radius ≈50  nm is sufficient to nucleate antivortices in a 25 nm Nb film, with unique signatures in the magnetization, critical current, and flux dynamics, corroborated via simulations. We also detect a thermally tunable Rashba-Edelstein exchange coupling in the isolated skyrmion phase. This realization of a strongly interacting skyrmion-(anti)vortex system opens a path toward controllable topological hybrid materials, unattainable to date. [ABSTRACT FROM AUTHOR]

5d iridium oxides are of huge interest due to the potential for new quantum states driven by strong spin-orbit coupling. The strontium iridate Sr2IrO4 is particularly in the spotlight because of the so-called jeff=1/2 state consisting of a quantum superposition of the three local t2g orbitals with, in its simplest version, nearly equal populations, which stabilizes an unconventional Mott insulating state. Here, we report an anisotropic and aspherical magnetization density distribution measured by polarized neutron diffraction in a magnetic field up to 5 T at 4 K, which strongly deviates from a local jeff=1/2 picture even when distortion-induced deviations from the equal weights of the orbital populations are taken into account. Once reconstructed by the maximum entropy method and multipole expansion model refinement, the magnetization density shows four cross-shaped positive lobes along the crystallographic tetragonal axes with a large spatial extent, showing that the xy orbital contribution is dominant. The analogy to the superconducting copper oxide systems might then be weaker than commonly thought. [ABSTRACT FROM AUTHOR]

With optical spectroscopy we provide evidence that the insulator-metal transition in Sr2Ir1-xRhxO4 occurs close to a crossover from the Mott- to the Slater-type. The Mott gap at x=0 persists to high temperature and evolves without an anomaly across the Néel temperature, TN. Upon Rh doping, it collapses rather rapidly and vanishes around x=0.055. Notably, just as the Mott gap vanishes yet another gap appears that is of the Slater-type and develops right below TN. This Slater gap is only partial and is accompanied by a reduced scattering rate of the remaining free carriers, similar as in the parent compounds of the iron arsenide superconductors. [ABSTRACT FROM AUTHOR]