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Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer fatalities in Western societies, characterized by high metastatic potential and resistance to chemotherapy. Critical molecular mechanisms of these phenotypical features still remain unknown, thus hampering the development of effective prognostic and therapeutic measures in PDAC. Here, we show that transcriptional co‐factor Transducin beta‐like (TBL) 1 was over‐expressed in both human and murine PDAC. Inactivation of TBL1 in human and mouse pancreatic cancer cells reduced cellular proliferation and invasiveness, correlating with diminished glucose uptake, glycolytic flux, and oncogenic PI3 kinase signaling which in turn could rescue TBL1 deficiency‐dependent phenotypes. TBL1 deficiency both prevented and reversed pancreatic tumor growth, mediated transcriptional PI3 kinase inhibition, and increased chemosensitivity of PDAC cells in vivo. As TBL1 mRNA levels were also found to correlate with PI3 kinase levels and overall survival in a cohort of human PDAC patients, TBL1 was identified as a checkpoint in the malignant behavior of pancreatic cancer and its expression may serve as a novel molecular target in the treatment of human PDAC.

Abstract Dilated cardiomyopathies (DCM) show remarkable variability in their age of onset, phenotypic presentation, and clinical course. Hence, disease mechanisms must exist that modify the occurrence and progression of DCM, either by genetic or epigenetic factors that may interact with environmental stimuli. In the present study, we examined genome‐wide cardiac DNA methylation in patients with idiopathic DCM and controls. We detected methylation differences in pathways related to heart disease, but also in genes with yet unknown function in DCM or heart failure, namely Lymphocyte antigen 75 (LY75), Tyrosine kinase‐type cell surface receptor HER3 (ERBB3), Homeobox B13 (HOXB13) and Adenosine receptor A2A (ADORA2A). Mass‐spectrometric analysis and bisulphite‐sequencing enabled confirmation of the observed DNA methylation changes in independent cohorts. Aberrant DNA methylation in DCM patients was associated with significant changes in LY75 and ADORA2A mRNA expression, but not in ERBB3 and HOXB13. In vivo studies of orthologous ly75 and adora2a in zebrafish demonstrate a functional role of these genes in adaptive or maladaptive pathways in heart failure.

In this paper, we establish necessary and sufficient conditions for the existence of line segments (or flats) in the sphere of the nuclear norm via the notion of simultaneous polarization and a refined expression for the subdifferential of the nuclear norm. This is then leveraged to provide (point-based) necessary and sufficient conditions for uniqueness of solutions for minimizing the nuclear norm over an affine subspace. We further establish an alternative set of sufficient conditions for uniqueness, based on the interplay of the subdifferential of the nuclear norm and the range of the problem-defining linear operator. Finally, we show how to transfer the uniqueness results for the original problem to a whole class of nuclear norm-regularized minimization problems with a strictly convex fidelity term. [ABSTRACT FROM AUTHOR]

Non-specific low back pain (LBP) is a major global disease burden and childhood adversity predisposes to its development. The mechanisms are largely unknown. Here, we investigated if adversity in young rats augments mechanical hyperalgesia and how spinal cord microglia contribute to this. Adolescent rats underwent restraint stress, control animals were handled. In adulthood, all rats received two intramuscular injections of NGF/saline or both into the lumbar multifidus muscle. Stress induced in rats at adolescence lowered low back pressure pain threshold (PPT; p = 0.0001) and paw withdrawal threshold (PWT; p = 0.0007). The lowered muscle PPT persisted throughout adulthood (p = 0.012). A subsequent NGF in adulthood lowered only PPT (d = 0.87). Immunohistochemistry revealed changes in microglia morphology: stress followed by NGF induced a significant increase in ameboid state (p < 0.05). Repeated NGF injections without stress showed significantly increased cell size in surveilling and bushy states (p < 0.05). Thus, stress in adolescence induced persistent muscle hyperalgesia that can be enhanced by a mild-nociceptive input. The accompanying morphological changes in microglia differ between priming by adolescent stress and by nociceptive inputs. This novel rodent model shows that adolescent stress is a risk factor for the development of LBP in adulthood and that morphological changes in microglia are signs of spinal mechanisms involved. [ABSTRACT FROM AUTHOR]

This paper is devoted to the study of the metric subregularity constraint qualification for general optimization problems, with the emphasis on the nonconvex setting. We elaborate on notions of directional pseudo- and quasi-normality, recently introduced by Bai et al., which combine the standard approach via pseudo- and quasi-normality with modern tools of directional variational analysis. We focus on applications to disjunctive programs, where (directional) pseudo-normality is characterized via an extremal condition. This, in turn, yields efficient tools to verify pseudo-normality and the metric subregularity constraint qualification, which include, but are not limited to, Robinson's result on polyhedral multifunctions and Gfrerer's second-order sufficient condition for metric subregularity. Finally, we refine our study by defining the new class of ortho-disjunctive programs which comprises prominent optimization problems such as mathematical programs with complementarity, vanishing or switching constraints. [ABSTRACT FROM AUTHOR]

Objective: Psychogenic non-epileptic seizures (PNES), a common phenomenon in neurological settings, are regarded as a paroxysmal type of functional neurological disorder (FND). In a substantial proportion, PNES are disabling with poor long-term outcomes and high economic costs. Despite the clinical and financial consequences of PNES, there is still a lack of controlled clinical trials on the treatment of this challenging disorder. The study aims to evaluate the feasibility and collect first evidence of the efficacy of a group based-intervention in PNES-patients. Methods: A pilot randomized controlled feasibility study with a parallel-group design was performed in adult outpatients with PNES to evaluate a new body-focused group therapy (CORDIS) versus guided self-help groups. Self-assessment of dissociation (Dissociation Experience Scale—DES-20) and seizure severity (Liverpool Seizure Severity Scale—LSSS) were assessed two weeks before and two weeks after the treatment intervention and also six months after treatment as primary outcome parameters. Results: A total of 53 patients were recruited from a specialized outpatient clinic, and out of those, 29 patients completed either the body-focused group therapy program (n = 15) or a guided self-help group (SHG) therapy (n = 14). When analyzing the ITT sample (n = 22 CORDIS group, n = 20 SHG), both groups showed an effect on seizure severity and level of dissociation. In the per protocol sample (n = 13 CORDIS group, n = 12 SHG), CORDIS was superior to the self-help group for reducing seizure severity 6 months after the treatment. Significance: CORDIS is a newly developed body-focused group therapy program for adults with PNES. Further studies should include a multicentric design with a higher number of participants. [ABSTRACT FROM AUTHOR]

Gold compounds have a long history of use as immunosuppressants, but their precise mechanism of action is not completely understood. Using our recently developed liver-on-a-chip platform we now show that gold compounds containing planar N-heterocyclic carbene (NHC) ligands are potent ligands for the aryl hydrocarbon receptor (AHR). Further studies showed that the lead compound (MC3) activates TGFβ1 signaling and suppresses CD4+ T-cell activation in vitro, in human and mouse T cells. Conversely, genetic knockdown or chemical inhibition of AHR activity or of TGFβ1-SMAD-mediated signaling offsets the MC3-mediated immunosuppression. In scurfy mice, a mouse model of human immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, MC3 treatment reduced autoimmune phenotypes and extended lifespan from 24 to 58 days. Our findings suggest that the immunosuppressive activity of gold compounds can be improved by introducing planar NHC ligands to activate the AHR-associated immunosuppressive pathway, thus expanding their potential clinical application for autoimmune diseases. Cheng, Haeberle et al. identify NHC–gold complexes as ligands of the aryl hydrocarbon receptor, which triggers TGFβ production for immune suppression. They find that the MC3 compound activates TGFβ signalling while reducing Il-2 expression and CD4+ T-cell activation and suppresses autoimmune phenotypes in a mouse model of IPEX syndrome. [ABSTRACT FROM AUTHOR]

This paper concerns smoothing by infimal convolution for two large classes of functions: convex, proper and lower semicontinous as well as for (the nonconvex class of) convex-composite functions. The smooth approximations are constructed so that they epi-converge (to the underlying nonsmooth function) and fulfill a desirable property with respect to graph convergence of the gradient mappings to the subdifferential of the original function under reasonable assumptions. The close connection between epi-convergence of the smoothing functions and coercivity properties of the smoothing kernel is established. [ABSTRACT FROM AUTHOR]

In this review, we summarize design principles of organic solar cells with plasmonic nanostructures. A process for scalable vacuum processing of silver nanoparticles is presented. Approximations for losses inside plasmonic structures are derived with respect to particle size and absorber material. We evaluate the characteristic length scales of plasmonic near-field enhancement and backscattering. The thickness of the absorber layers can be significantly reduced in plasmonic devices showing increased power conversion efficiency. The strongest plasmonic effects are observed in coupling particle structures. [ABSTRACT FROM AUTHOR]

The aim of this study was to prospectively evaluate the needle visualization and placement error and use of an electromagnetic field-based tracking navigation device for puncture procedures based on C-arm CT (CACT) images. A commercially available navigation device was mounted on an angiographic X-ray system setup for CACT. After the target was defined, needle placement was performed under real-time visualization of the virtual needle in CACT images. The final, real needle position was assessed by CACT. Punctures were performed in phantoms (n = 76) and in twelve patients (eight biopsies, three drainages, one injection). Procedure times, system error, user error and total error were assessed. In phantoms, mean total error was 2.3 +/- 0.9 mm, user error was 1.4 +/- 0.8 mm and system error was 1.7 +/- 0.8 mm. In the patient study, the targeted puncture was successful in all twelve cases. The mean total error was 5.4 mm +/- 1.9 mm (maximum 8.1 mm), user error was 3.7 +/- 1.7 mm, system error was 3.2 +/- 1.4 mm and mean skin-to-target time was less than 1 min. The navigation device relying on CACT was accurate in terms of needle visualization and useful for needle placement under both experimental and clinical conditions. For more complex procedures, electromagnetic field-based tracking guidance might be of help in facilitating the puncture and reducing both the puncture risk and procedure time. [ABSTRACT FROM AUTHOR]

We consider a class of generalized Nash equilibrium problems, where both objective functions and constraints are allowed to depend on the decision variables of the other players. It is well known that this problem can be reformulated as a constrained optimization problem via the (regularized) Nikaido-Isoda-function, but this reformulation is usually nonsmooth. Here we observe that, under suitable conditions, this reformulation turns out to be the difference of two convex functions. This allows the application of the Toland-Singer duality theory in order to obtain a dual formulation, which provides an unconstrained and continuously differentiable optimization reformulation of the generalized Nash equilibrium problem. Moreover, based on a result from parametric optimization, the gradient of the unconstrained objective function is shown to be piecewise smooth. Some numerical results are presented to illustrate the theory. [ABSTRACT FROM AUTHOR]

The occurrence of chronic stress, depression, and anxiety can increase nociception in humans and may facilitate the transition from localized to chronic widespread pain. The mechanisms underlying chronic widespread pain are still unknown, hindering the development of effective pharmacological therapies. Here, we exposed C57BL/6J mice to chronic unpredictable stress (CUS) to investigate how persistent stress affects nociception. Next, mice were treated with multiple intramuscular nerve growth factor (NGF) injections, which induced chronic widespread nociception. Thus, combination of CUS and NGF served as a model where psychophysiological impairment coexists with long-lasting hyperalgesia. We found that CUS increased anxiety- and depression-like behavior and enhanced basal nociception in mice. When co-applied with repeated NGF injections, CUS elicited a sustained long-lasting widespread hyperalgesia. In order to evaluate a potential therapeutic strategy for the treatment of chronic pain associated with stress, we hypothesized that the endocannabinoid system (ECS) may represent a target signaling system. We found that URB597, an inhibitor of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), and JZL184, an inhibitor of the 2-arachidonoyl glycerol-degrading enzyme monoacylglycerol lipase (MAGL), increased eCB levels in the brain and periphery and were both effective in reducing CUS-induced anxiety measured by the light-dark test and CUS-induced thermal hyperalgesia. Remarkably, the long-lasting widespread hyperalgesia induced by combining CUS and NGF was effectively reduced by URB597, but not by JZL184. Simultaneous inhibition of FAAH and MAGL did not improve the overall therapeutic response. Therefore, our findings indicate that enhancement of anandamide signaling with URB597 is a promising pharmacological approach for the alleviation of chronic widespread nociception in stress-exposed mice, and thus, it could represent a potential treatment strategy for chronic pain associated with neuropsychiatric disorders in humans. [ABSTRACT FROM AUTHOR]

A well-known technique for the solution of quasi-variational inequalities (QVIs) consists in the reformulation of this problem as a constrained or unconstrained optimization problem by means of so-called gap functions. In contrast to standard variational inequalities, however, these gap functions turn out to be nonsmooth in general. Here, it is shown that one can obtain an unconstrained optimization reformulation of a class of QVIs with affine operator by using a continuously differentiable dual gap function. This extends an idea from Dietrich (J. Math. Anal. Appl. 235:380-393 []). Some numerical results illustrate the practical behavior of this dual gap function approach. [ABSTRACT FROM AUTHOR]

The gold standard for determining the tumorigenic potential of human cancer cells is a xenotransplantation into immunodeficient mice. Higher tumorigenicity of cells is associated with earlier tumor onset. Here, we used xenotransplantation to assess the tumorigenic potential of human breast cancer cells following RNA interference-mediated inhibition of over 5000 genes. We identify 16 candidate tumor suppressors, one of which is the zinc-finger transcription factor SALL1. Analyzing this particular molecule in more detail, we show that inhibition of SALL1 correlates with reduced levels of CDH1, an important contributor to epithelial-to-mesenchymal transition. Furthermore, SALL1 expression led to an increased migration and more than twice as many cells expressing a cancer stem cell signature. Also, SALL1 expression correlates with the survival of breast cancer patients. These findings cast new light on a gene that has previously been described to be relevant during embryogenesis, but not carcinogenesis. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here, we determine the contribution of epigenetically silenced genes to the development of PDAC. We analyzed enriched, highly methylated DNAs from PDACs, chronic pancreatitis (CP) and normal tissues using CpG island microarrays and identified WNK2 as a prominent candidate tumor suppressor gene being downregulated early in PDAC development. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanIN), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in tumor than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expressions were lower in PDAC and CP compared with normal tissues both in patients and mouse models. Overexpression of WNK2 led to reduced cell growth, and WNK2 expression in tissues correlated negatively with pERK1/2 expression, a downstream target of WNK2 responsible for cell proliferation. Downregulation of WNK2 by promoter hypermethylation occurs early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway. [ABSTRACT FROM AUTHOR]

A novel strategy for fabrication of ordered ceramic-metal nanocomposites was demonstrated by multifunctional block copolymer/metal nanoparticle self-assembly. Hybrid organic-inorganic block copolymer poly(3-methacryloxypropyl-T8-heptaisobutyl-polyhedral oligomeric silsesquioxane- block- N, N-dimethylaminoethyl methacrylate) was synthesized and used as a bi-functional structure directing agent for ligand-stabilized platinum nanoparticles to form ordered organic-inorganic nanocomposites with dense loading of inorganic species in both microphase separated domains. Subsequently, thin films of the hybrid material were converted to ordered silica (ceramic)-platinum (metal) nanocomposites via UV-assisted ozonolysis. This is the first time ordered ceramic-metal nanocomposites were achieved through a bottom-up approach, opening up opportunities for the design and synthesis of a broad range of ordered inorganic-inorganic nanocomposites. [ABSTRACT FROM AUTHOR]

Copyright of NTM Zeitschrift für Geschichte der Wissenschaften, Technik und Medizin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We consider a numerical approach for the solution of a difficult class of optimization problems called mathematical programs with vanishing constraints. The basic idea is to reformulate the characteristic constraints of the program via a nonsmooth function and to eventually smooth it and regularize the feasible set with the aid of a certain smoothing- and regularization parameter t>0 such that the resulting problem is more tractable and coincides with the original program for t=0. We investigate the convergence behavior of a sequence of stationary points of the smooth and regularized problems by letting t tend to zero. Numerical results illustrating the performance of the approach are given. In particular, a large-scale example from topology optimization of mechanical structures with local stress constraints is investigated. [ABSTRACT FROM AUTHOR]

Chen and Mangasarian (Comput Optim Appl 5:97-138, ) developed smoothing approximations to the plus function built on integral-convolution with density functions. X. Chen (Math Program 134:71-99, ) has recently picked up this idea constructing a large class of smoothing functions for nonsmooth minimization through composition with smooth mappings. In this paper, we generalize this idea by substituting the plus function for an arbitrary finite max-function. Calculus rules such as inner and outer composition with smooth mappings are provided, showing that the new class of smoothing functions satisfies, under reasonable assumptions, gradient consistency, a fundamental concept coined by Chen (Math Program 134:71-99, ). In particular, this guarantees the desired limiting behavior of critical points of the smooth approximations. [ABSTRACT FROM AUTHOR]

Packing constraints and precise placement of functional groups are the reason that organic molecules in the crystalline state often display unusual physical or chemical properties not observed in solution. Here we report a single-crystal-to-single-crystal dimerization of a bromodiacetylene that involves unusually large atom displacements as well as the cleavage and formation of several bonds. Density functional theory computations support a mechanism in which the dimerization is initiated by a [2 + 1] photocycloaddition favoured by the nature of carbon-carbon short contacts in the crystal structure. The reaction proceeded up to the theoretical degree of conversion without loss of crystallinity, and it was also performed on a preparative scale with good yield. Moreover, it represents the first synthetic pathway to (E)-1,2-dibromo-1,2-diethynylethenes, which could serve as synthetic intermediates for the preparation of molecular carbon scaffolds. Our findings both extend the scope of single-crystal-to-single-crystal reactions and highlight their potential as a synthetic tool for complex transformations. [ABSTRACT FROM AUTHOR]

Nociceptive information from muscle and skin is differently processed at many levels of the central nervous system. In most articles on this issue, noxious stimuli were used that also excited non-nociceptive receptors. The effects of a pure nociceptive input from muscle or skin on spinal neurones are largely unknown. The aim of the study was to find out whether the Fos-protein expression in dorsal horn neurones induced by an exclusively nociceptive muscle input differs from that of the skin. Fos-proteins are transcription factors that regulate neuronal gene expression and induce neuroplastic effects that are involved in the development of chronic pain. A pure nociceptive input was achieved by tetrodotoxin (TTX) that is known to block all TTX-sensitive afferents and leave the TTX-resistant (TTX-r), presumably nociceptive, afferent fibres intact. We studied the c-Fos and FosB expression in the spinal cord following electrical stimulation of TTX-r afferent fibres in the gastrocnemius-soleus nerve (muscle) and compared it to the sural nerve (skin). In the spinal dorsal horn, the main effect of a TTX-r input from muscle was an increase in FosB ( P < 0.05), but not in c-Fos expression ( P = 0.51). In contrast, an input from the skin induced both FosB ( P < 0.01) and c-Fos expression ( P < 0.05). The data indicate that in the spinal, dorsal horn nociceptive input from skin and muscle has different effects on the Fos expression. The only effect of muscle input was an increase in FosB expression while skin input increased both c-Fos and FosB expression. [ABSTRACT FROM AUTHOR]

Mathematical programs with equilibrium constraints (MPECs) are difficult optimization problems whose feasible sets do not satisfy most of the standard constraint qualifications. Hence MPECs cause difficulties both from a theoretical and a numerical point of view. As a consequence, a number of MPEC-tailored solution methods have been suggested during the last decade which are known to converge under suitable assumptions. Among these MPEC-tailored solution schemes, the relaxation methods are certainly one of the most prominent class of solution methods. Several different relaxation schemes are available in the meantime, and the aim of this paper is to provide a theoretical and numerical comparison of these schemes. More precisely, in the theoretical part, we improve the convergence theorems of several existing relaxation methods. There, we also take a closer look at the properties of the feasible sets of the relaxed problems and show which standard constraint qualifications are satisfied for these relaxed problems. Finally, the numerical comparison is based on the MacMPEC test problem collection. [ABSTRACT FROM AUTHOR]

The Charité Grid Portal combines portal components from different groups and projects to provide domain researchers a gateway to Grid-based biomedical applications. Trusted users can securely access and employ Grid resources and services. In this paper, five portal components are presented: (1) The credential management administrates the user-credentials and authenticates them to the Grid. (2) The brain imaging data analysis (FSL) submits workflows to the Grid as part of Medical Image processing. (3) The integrated web services of Generic Workflow Execution Service (GWES) manage workflows executed by users in the Grid. (4) The data management component provides secure and efficient data management in a Grid environment, and enables high-speed data transports between user and Grid. (5) The lung sound analysis application provides twofold-pseudonymization before data-transferred to the Grid. The implementation as standardized portlets allows easy integration of specific components into different Grid portals such as the VO specific MediGRID and PneumoGrid portals. [ABSTRACT FROM AUTHOR]

DNA methylation patterns have been recognised as cancer-specific markers with high potential for clinical applications. We aimed at identifying methylation variations that differentiate between breast cancers and other breast tissue entities to establish a signature for diagnosis. Candidate genomic loci were analysed in 117 fresh-frozen breast specimens, which included cancer, benign and normal breast tissues from patients as well as material from healthy individuals. A cancer-specific DNA methylation signature was identified by microarray analysis in a test set of samples ( n = 52, p < 2.1 × 10) and its performance was assessed through bisulphite pyrosequencing in an independent validation set ( n = 65, p < 1.9 × 10). The signature is associated with SFRP2 and GHSR genes, and exhibited significant hypermethylation in cancers. Normal-appearing breast tissues from cancer patients were also methylated at these loci but to a markedly lower extent. This occurrence of methylated DNA in normal breast tissue of cancer patients is indicative of an epigenetic field defect. Concerning diagnosis, receiver operating characteristic curves and the corresponding area under the curve (AUC) analysis demonstrated a very high sensitivity and specificity of 89.3 and 100 %, respectively, for the GHSR methylation pattern (AUC >0.99). To date, this represents the DNA methylation marker of the highest sensitivity and specificity for breast cancer diagnosis. Functionally, ectopic expression of GHSR in a cell line model reduced breast cancer cell invasion without affecting cell viability upon stimulation of cells with ghrelin. Our data suggest a link between epigenetic down-regulation of GHSR and breast cancer cell invasion. [ABSTRACT FROM AUTHOR]

The constitutive models used for wood and timber have been formulated in different scales. The term clear wood corresponds to the macroscopic scale, where the orthotropic elastic model is commonly used. This model, which is typically applied to local modeling (e.g. connections), is defined by a compliance matrix composed of nine parameters, the elongations and angular distortions of which are uncoupled. The current experimental standard methods for obtaining these nine parameters are time consuming, as different specimen configurations and careful preparation for specific grain orientation are needed. As different specimens are used and the material properties of wood can vary greatly at a local level, this would have a notable influence on the outcome, as this method is not robust. Optical digital measurements (ODM) are changing and improving these traditional procedures. This work presents a new procedure for determining the compliance matrix of clear wood using just one rectangular prism as a specimen, with an orientation of the grain that does not coincide with the axes defined by the edges of the specimen. The specimen is loaded in the three mutually perpendicular directions defined by the prism, in a single axis load set up using a 3D ODM. The method was initially validated using ARAMIS® 3D, with 5 M pixels, on ash ( Fraxinus excelsior L). Reasonable results were obtained, according to the resolution used; however, a higher resolution is needed to attain proper accuracy. [ABSTRACT FROM AUTHOR]

We present an optofluidic system based on electromagnetic manipulation of a ferrofluid to tune a liquid lens. Both studies of the dynamics of fluid transport and of the optical properties of the liquid lens have been carried out. Thermal and magnetic field simulations of the microcoil actuators are presented. Proof-of-principle experiments demonstrating the adaption of the focal length of the lens have been carried out. It is shown that the lens adaption proceeds in a reversible and reproducible manner, given that the ferrofluid plug moves with a speed below a specific threshold value. Furthermore, the time delay between the actuation and the deflection of the lens surface is studied. [ABSTRACT FROM AUTHOR]

Determination of the sequence of the human genome and knowledge of the genetic code have allowed rapid progress in the identification of mammalian proteins. However, far less is known about the molecular mechanisms that control expression of human genes and about the variations in gene expression that underlie many pathological states, including cancer. This is caused in part by lack of information about the binding specificities of DNA-binding proteins and particularly regulative important molecules such as transcription factors. It is consequently crucial to develop new technologies or improve existing ones for the analysis of DNA-protein interaction in order to identify and characterise DNA response elements and the related transcription factors or other DNA-binding proteins. The techniques that are currently available vary with respect to the type of result that can be expected from the assay: a mere qualitative demonstration of binding; the identification of response element sequences at high throughput; or a quantitative characterisation of affinities. This article gives an overview of early and recent methodologies applied to such ends. [ABSTRACT FROM AUTHOR]

Only limited data have been published about the therapeutic use of anakinra in patients with psoriatic arthritis. We undertook this study to evaluate the efficacy and safety of anakinra in patients with active psoriatic arthritis. In a prospective open-label single-center study, 20 patients were treated with 100 mg anakinra everyday either alone or in combination with ongoing methotrexate over 6 months. Safety and efficacy was evaluated using Psoriasis Arthritis Response Criteria (PsARC), Disease Activity Score (DAS) 28, American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), Psoriasis Area and Severity Index Score, Dactylitis Score and Health Assessment Questionnaire (HAQ), and the C-reactive protein, and erythrocyte sedimentation rate. Of the 20 patients enrolled, six completed 24 weeks, 18 completed 12 weeks, and 19 completed 4 weeks of treatment. Early-treatment termination was mainly due to inefficacy (13 patients) and only one drop-out occurred because of an unrelated adverse event. Six patients fulfilled continuously the PsARC until week 24. A moderate EULAR response was achieved by four patients and a good EULAR response by three patients in week 24. Five patients reached ACR 20, four patients ACR 50, and two patients ACR 70 in week 24. HAQ improved slightly throughout the study ( n = 19, mean (SD); baseline, 1.127 (0.671); week 24, 1.055 (0.812)) just as DAS 28 ( n = 16; baseline, 4.7(1.5); week 24, 4.0(2.0)). Only nine patients showed skin manifestations affecting >3% of their body surface area which improved in two, worsened in four, stabilized in two patients, and newly evolved in one patient. Adverse events were mainly mild (95%). Fifteen (75%) patients showed injection site reactions. No serious infections occurred. Anakinra was well tolerated with no occurrence of serious drug-associated adverse events and lead to improvement of signs and symptoms in nine out of 19 patients, therefore providing a potential therapeutic option in patients with active psoriatic arthritis. [ABSTRACT FROM AUTHOR]

Copyright of Medizinische Klinik (Urban & Vogel) is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We report a flexible method for selective capture of sequence fragments from complex, eukaryotic genome libraries for next-generation sequencing based on hybridization to DNA microarrays. Using microfluidic array architecture and integrated hardware, the process is amenable to complete automation and does not introduce amplification steps into the standard library preparation workflow, thereby avoiding bias of sequence distribution and fragment lengths. We captured a discontiguous human genomic target region of 185 kb using a tiling design with 50mer probes. Analysis by high-throughput sequencing using an Illumina/Solexa 1G Genome Analyzer revealed 2150-fold enrichment with mean per base coverage between 4.6 and 107.5-fold for the individual target regions. This method represents a flexible and cost-effective approach for large-scale resequencing of complex genomes. [ABSTRACT FROM AUTHOR]

Copyright of Medizinische Klinik (Urban & Vogel) is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We show that reductive methylation of proteins can be used for highly sensitive NMR identification of conformational changes induced by metal- and small molecule binding, as well as protein–protein interactions. Reductive methylation of proteins introduces two 13C-methyl groups on each lysine in the protein of interest. This method works well even when the lysines are not actively involved in the interaction, due to changes in the microenvironments of lysine residues. Most lysine residues are located on the protein exterior, and the exposed 13C-methyl groups may exhibit rapid localized motions. These motions could be faster than the tumbling rate of the molecule as a whole. Thus, this technique has great potential in the study of large molecular weight systems which are currently beyond the scope of conventional NMR methods. [ABSTRACT FROM AUTHOR]

The analysis of mutations that are associated with the occurrence of drug resistance is important for monitoring the antiretroviral therapy of patients infected with human immunodeficiency virus (HIV). Here, we describe the establishment and successful application of Arrayed Primer Extension (APEX) for genotypic resistance testing in HIV as a rapid and economical alternative to standard sequencing. The assay is based on an array of oligonucleotide primers that are immobilised via their 5′-ends. Upon hybridisation of template DNA, a primer extension reaction is performed in the presence of the four dideoxynucleotides, each labelled with a distinct fluorophore. The inserted label immediately indicates the sequence at the respective position. Any mutation changes the colour pattern. We designed a microarray for the analysis of 26 and 33 codons in the HIV protease and reverse transcriptase, respectively, which are of special interest with respect to drug resistance. The enormous genome variability of HIV represents a big challenge for genotypic resistance tests, which include a hybridisation step, both in terms of specificity and probe numbers. The use of degenerated oligonucleotides resulted in a significant reduction in the number of primers needed. For validation, DNA of 94 and 48 patients that exhibited resistance to inhibitors of HIV protease and reverse transcriptase, respectively, were analysed. The validation included HIV subtype B, prevalent in industrialised countries, as well as non-subtype B samples that are more common elsewhere. [ABSTRACT FROM AUTHOR]

Abstract  We consider a special class of optimization problems that we call Mathematical Programs with Vanishing Constraints, MPVC for short, which serves as a unified framework for several applications in structural and topology optimization. Since an MPVC most often violates stronger standard constraint qualification, first-order necessary optimality conditions, weaker than the standard KKT-conditions, were recently investigated in depth. This paper enlarges the set of optimality criteria by stating first-order sufficient and second-order necessary and sufficient optimality conditions for MPVCs. [ABSTRACT FROM AUTHOR]

The genomic DNA methylation pattern (methylome) is a cell epigenetic program that controls the expression of genetic information. The methylation pattern substantially changes in early carcinogenesis. A detailed survey of the methylcytosine distribution in the genome in norm and pathology is of immense importance for a better understanding of the etiology of cancer and its early diagnosis. The techniques available make it possible to simultaneously examine many samples (high-throughput analysis) and to examine large genome loci or even the total methylome (large-scale analysis). The review considers the main trends in the development of new approaches to DNA methylation and describes the techniques most commonly used in the field, their application, and results. Emphasis is placed on the use of various DNA microarrays (oligonucleotide microarrays, BAC arrays, etc.) as a method of choice for epigenetic analysis of tumors. Alternative sequence-based techniques of methylation analysis are discussed. The use of large-scale analysis to identify new epigenetic markers and to develop an epigenetic classification of neoplasms is considered. [ABSTRACT FROM AUTHOR]

Abstract  Pancreatic neoplasms have been reliably classified on the basis of their histopathology and immunophenotype. In this study, we report on a pancreatic tumor whose phenotype and genotype could not be assigned to any known tumor entity. The tumor was observed in the pancreatic head of a 54-year-old woman. It was found to be a solid infiltrating carcinoma with abundant clear cells. Apart from cytokeratin, the tumor cells expressed vimentin, S100, and MUC-1. DNA microarray analysis revealed a transcription profile clearly differing from that of normal pancreatic tissue and pancreatic ductal adenocarcinoma. Despite metastatic behavior, the tumor displayed a more favorable course than conventional pancreatic ductal adenocarcinoma. We suggest that this tumor be called solid type clear cell carcinoma of the pancreas. [ABSTRACT FROM AUTHOR]

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Copyright of Medizinische Klinik (Urban & Vogel) is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The article reflects that, spectral fluorescence imaging microscopy is an appropriate method for imaging single molecules in living cells. Many methods have been proposed for analyzing single cells, over the last decade. However, some optical methods like fluorescence spectroscopy, are advanced and simple. The article also presents that because of their high sensitivity, spectrally resolved fluorescence lifetime imaging microscopy (SFLIM) requires only a few molecules to be probed.