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As part of the program to calibrate X-ray CCD detectors for the AXAF mission we have performed high-spectral resolution, absolute measurements of CCD quantum efficiency using the synchrotron radiation and grating monochromator facilities of the PTB radiometry laboratory at BESSY. We present here detailed measurements of the absolute quantum efficiency in the spectral region surrounding the oxygen K absorption edge for both front- and back-illuminated MIT Lincoln Laboratory CCDs. The absolute scale of the measurements is established by reference to an Electrical Substitution Radiometer. Near-edge absorption structure produces variations as large as 40% in the detection efficiency of the front-illuminated detectors. We find structure at energies immediately below the K absorption edge which we attribute to resonant absorption in the oxide layers of the CCD gate structure. The amplitude of edge structures in the back-illuminated devices is, as expected, much smaller. Finally, we demonstrate that edge structure can be reliably detected in CCD response using an electron impact source and a grating monochromator.

The detection efficiency and response function of a Si(Li) detector element for the SIXA spectrometer have been determined in the 500 eV to 5 keV energy range using synchrotron radiation emitted at a bending magnet of the electron storage ring BESSY, which is a primary radiation standard. The agreement between the measured spectrum and the model calculation is better than 2%. PACS: 95.55.Ka; 07.85.Nc; 29.40.Wk; 85.30.De Keywords: Si(Li) detectors, X-ray spectrometers, detector calibration, X-ray response, spectral lineshape, Comment: 11 pages, 11 PostScript figures, uses elsart.sty, submitted to Nucl. Instrum. Meth. A

A growing understanding of the biology and molecular mechanisms of melanoma has led to the identification of a number of driver mutations for this aggressive tumor. The most common mutations affect signaling of the Ras/Raf/MAPK (mitogen-activated protein kinase) pathway. This review will focus on mutations in genes encoding proteins that play a role in the MAPK pathway and that have been implicated in melanoma biology, such as BRAF, NRAS, and MEK (MAPK kinase), and detail the current understanding of their role in melanoma progression from a molecular biology perspective. Furthermore, this review will also consider some additional mutations in genes such as KIT, GNAQ, and GNA11, which can be seen in certain subtypes of melanoma and whose gene products interact with the MAPK pathway. In addition, the association of these molecular changes with clinical and classical histopathologic characteristics of melanoma will be outlined and their role in diagnosis of melanocytic lesions discussed. Finally, a basic overview of the current targeted therapy landscape, as far as relevant to the pathologist, will be provided.

The recent structural and functional analysis of the high affinity receptor for IgE (Fc epsilon RI) expressed on human epidermal Langerhans cells (LC) revealed new aspects of the biology of this structure. In contrast to basophils and mast cells where this receptor seems to be expressed constitutively at a constant level, the expression of Fc epsilon RI on LC varies on the donor and the inflammatory environment of the cells and lacks the classical beta-chain. This also implies functional differences most probably related to the expression level. Although the signalling pathway seems to be similar to that of basophils or mast cells, LC from individuals with atopic dermatitis are fully activated by receptor ligation while LC from normal individuals fail to exhibit calcium mobilization under the same conditions. Finally, LC from normal and atopic individuals use Fc epsilon RI to maximize antigen uptake via specific IgE and subsequent presentation to T cells. Thus, Fc epsilon RI expressed on LC differs in terms of structure and function from that expressed on effector cells of anaphylaxis.

Background: Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors, with a uniformly fatal prognosis. No effective systemic therapies exist. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR or combined RAF/MEK inhibition, but experienced a dramatic response when both drug regimens were combined. Methods and Results: Nine biopsies of the tumor were obtained between diagnosis and autopsy. Multi-region whole-exome sequencing revealed truncal BRAF and PIK3CA mutations, which are known to activate the MAPK and PI3K/AKT pathways respectively. We performed the largest meta-analysis of ATC to date and found a 7.4% co-occurrence of MAPK and PI3K pathway alterations in ATC. We analyzed 5,255 cancer exomes in the Cancer Genome Atlas (TCGA) to determine whether similar cancer genomes occurred outside of anaplastic thyroid carcinoma. We identified 11 tumors with BRAF V600E and non-silent PIK3CA mutations. These results indicate that this genotype occurs in other cancers and may predict response to combined therapy. Conclusions and future directions: We have identified a patient with ATC who had a dramatic response to combined inhibition of the MAPK and PI3K pathways, whereas neither MAPK inhibition nor PI3K inhibition alone was sufficient to produce tumor regression. These observations suggest that MAPK and PI3K/MTOR pathway blockade represents an effective dual therapy aimed at the founding oncogenic lesions in a subset of ATC. Citation Format: William J. Gibson, Daniel T. Ruan, Vera A. Paulson, Justine A. Barletta, Glenn J. Hanna, Stefan Kraft, Antonio Calles, Matthew Nehs, Francis Moore, Amaro Taylor-Weiner, Jeremiah Wala, Travis Zack, Thomas Lee, Fiona Fennessy, Erik Alexander, Tom Thomas, Pasi Jäne, Levi Garraway, Scott Carter, Rameen Beroukhim, Jochen Lorch, Eliezer Van Allen. Truncal activating MAPK and PI3K pathway alterations and exceptional response to dual pathway inhibition in anaplastic thyroid cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-227.

Aleukemic cutaneous myeloid sarcoma (CMS) represents an important yet rare entity denoting the presence of a cutaneous myeloid leukemic infiltrate without concurrent peripheral blood or bone marrow disease. The clinicopathologic diagnosis remains elusive due to isolated skin findings and variable immunostaining. Cytogenetic and molecular findings have infrequently been reported.Twenty-five patients with CMS were identified in the Massachusetts General Hospital pathology database between 2004 and 2012. Patients were excluded if concurrent blood or marrow acute myeloid leukemia (AML), myelodysplastic syndrome or lymphoproliferative disorder were diagnosed.Three patients were identified: a neonate with recurrent CMS and marrow disease that never met diagnostic criteria for AML and two patients relapsing as CMS without concurrent blood or marrow disease following chemotherapy-induced complete remission. Histology showed atypical mononuclear cell interstitial dermal infiltrates. All cases were CD68+, lysozyme+ and CD117-; one of two were CD34+; two of three were myeloperoxidase negative. 11q23 rearrangement, t(1;14), NPM1 (nucleophosmin I), FLT3-ITD (Fms-like tyrosine kinase 3-internal tandem duplication), and novel FLT3-D835 mutations were identified.An isolated atypical cutaneous infiltrate may represent aleukemic CMS and should prompt a search for other extramedullary sites of involvement. Immunohistochemistry, molecular and cytogenetic studies can help differentiate aleukemic CMS from benign and malignant, monocytic and histiocytic mimickers, and may potentially indicate therapy and prognosis.

Recent studies have described an encapsulated and an infiltrative form of follicular variant of papillary thyroid carcinoma (FVPTC). While encapsulated tumors have been reported to have virtually no metastatic potential or recurrence risk if angioinvasion and capsular penetration are absent, infiltrative tumors have been found to have a significant metastatic potential and a risk of recurrence. In our experience, a substantial number of FVPTCs are neither fully encapsulated nor infiltrative, but instead are partially-encapsulated (PE) or well-circumscribed (WC). Thus, the aim of this study was to investigate the metastatic potential and recurrence risk of PE/WC FVPTCs in comparison with that of encapsulated and infiltrative tumors.We studied 77 FVPTCs resected between 2000 and 2002 and characterized the tumors as encapsulated, PE/WC, or infiltrative. Histologic assessment was then correlated with lymph node status and clinical outcome.In our cohort, 27 (35%) tumors were encapsulated, 35 (45%) were PE/WC, and 15 (19%) were infiltrative. Lymph node status was similar between PE/WC and encapsulated tumors, but was significantly different between encapsulated and infiltrative groups (p0.001), and PE/WC and infiltrative groups (p0.001). Lymph node metastases were absent in all 15 cases of encapsulated tumors and all 9 cases of PE/WC tumors with sampled lymph nodes, but were present in 7 of 9 (78%) cases of infiltrative tumors with sampled lymph nodes. For patients with available clinical follow-up (66 cases, 86%), the median follow-up time was 111 months. No patients with encapsulated tumors recurred, one (3%) patient with a PE/WC tumor had recurrent/residual disease, and two (15%) patients with infiltrative tumors had recurrent/residual disease. The one patient with a PE/WC tumor who had recurrent/residual disease had a tumor bed recurrence 7 years after initial resection. Significantly, this was the only patient in the PE/WC group that had a positive resection margin.Our results demonstrate that PE/WC FVPTCs have a very low metastatic potential/recurrence risk, indicating that they should be distinguished from more aggressive infiltrative FVPTCs.

In addition to their compactness, scalability and specific task customization, optical MEMS could generate new functions not available with current technologies and are thus candidates for the design of future space instruments. Most mature components for space applications are the Digital Mirror Device (DMD) from Texas Instruments (TI), the micro-deformable mirrors, the Programmable Micro Diffraction Grating and the tiltable micro-mirrors. Among 20-30 MEMS-based payloads concepts, two concepts are selected. The first concept is a programmable slit for straylight control for space spectro-imagers. This instrument is a push-broom spectro-imager for which some images cannot be exploited because of bright sources in the field-of-view. The proposed concept consists in replacing the current entrance spectrometer slit by an active row of micro-mirrors. The MEMS will permit to dynamically remove the bright sources and then to obtain a field-of-view with an optically enhanced signal-to-noise ratio. The second concept is a push-broom imager for which the acquired spectrum can be tuned by optical MEMS. This system is composed of two diffractive elements and a TI’s DMD component. The first diffractive element spreads the spectrum. A micro-mirror array is set at the location of the spectral focal plane. By putting the micro-mirrors ON or OFF, we can select parts of field-of-view or spectrum. The second diffractive element then recombines the light on a push-broom detector. Dichroics filters, strip filter, band-pass filter could be replaced by a unique instrument.

High-grade neuroendocrine carcinoma of the head and neck is an aggressive neoplasm which rarely arises in the oropharynx. Here we report a series of 8 oropharyngeal neuroendocrine carcinomas associated with both human papillomavirus (HPV) infection and tobacco exposure. The tumor occurred predominantly in male patients (6 of 8) at a mean age of 59 years. Histologically, these cases were all classified as poorly differentiated neuroendocrine carcinoma (small cell carcinoma) with high mitotic activity [mean 53.3 mitoses per 10 HPF], necrosis, high nuclear-to-cytoplasmic ratio, and nuclear molding. One case also exhibited a moderately differentiated component, and one other case had a component of squamous cell carcinoma with basaloid features. Neuroendocrine differentiation was confirmed by immunoreactivity for synaptophysin and/or chromogranin A in all cases. P63 staining was negative, except in 1 case. Seven of the 8 cases showed strong and diffuse p16 expression, a surrogate marker for high-risk HPV infection. HPV infection was confirmed in 6 of these 7 cases by HPV in situ hybridization and/or polymerase chain reaction analysis. HPV subtypes 16, 18, and 33 were identified in 1 case each by polymerase chain reaction testing. Six of the 7 patients for whom clinical history was available presented with advanced disease (4 with regional lymph node metastases, 1 with distant metastases, and 1 with distant and locoregional metastases). Disease recurred in 5 of the 6 patients with available clinical follow-up, with 3 developing distant metastases to brain, bones, lung, pleura, adrenal glands, and pancreas. These 3 cases were all from the HPV-positive group. In summary, neuroendocrine carcinoma of the oropharynx represents a rare novel HPV-associated entity with high-grade histologic features and aggressive clinical behavior.

Amphiphilic reduced graphene oxide is obtained by oleo-functionalization with epoxidized methyl oleate (renewable feedstock) using a green process. The excellent diverse solvent-dispersivity of the oleo-reduced amphiphilic graphene and its reduction chemistry are confirmed in this study. Oleo-reduction of amphiphilic graphene is amenable to industrially viable processes to produce future graphene-based polymer composites and systems.

Atypical or mitotically active dermal smooth muscle neoplasms are uncommon lesions, which are most often termed "cutaneous leiomyosarcoma," although preexisting-mostly small-series suggest a low risk of aggressive behavior. To further investigate these tumors, 84 cases from consultation and institutional files were analyzed for pathologic and clinical characteristics. There was a striking male-to-female preponderance (4.3:1), with a mean age of 56 years (range, 6 to 82y). Nine patients had a history of malignancies (6 of the skin). Tumors measured 1.3 cm on average and were predominantly located on the trunk (32) and lower extremities (30). Histologically, all tumors were confined to the dermis or showed only very superficial, focal subcutaneous extension. The majority showed an infiltrative growth pattern with fascicles of atypical eosinophilic spindle cells ramifying between dermal collagen fibers. Primary tumors showed a mean mitotic rate of 4.7/10 high-power fields. By the Fédération Nationale des Centres de Lutte Contre le Cancer grading system, 97% of primary tumors were grade I lesions, with only 3% showing necrosis. All tumors were immunopositive for smooth muscle actin; 98% expressed desmin, 90% caldesmon, and 45% pankeratin (usually focal). Follow-up in 52 cases (mean, 51 mo) showed no metastases or tumor-related deaths. Eighteen tumors showed local recurrence at a mean interval of 43 months; 12 of the recurrent lesions showed positive margins in the primary excision and 1 showed margins0.2 cm. Margin status was not available for the other 5 cases, which recurred locally. Recurrent tumors showed, on average, 13.7 mitoses/10 high-power fields. Of recurrences, 47% were grade I lesions, 35% were grade II, and 18% were grade III, and 28% showed necrosis. The primary excision of tumors, which later recurred, showed no difference in grade, presence of necrosis, or mitotic rate, compared with those that did not recur; there were no discernible clinical differences either. In summary, these tumors, when confined to the dermis or showing only minimal subcutaneous involvement, seem to carry no evident risk of metastasis; hence, the designation "sarcoma" is inappropriate. Margin status is the most important predictor of recurrence. On excision with clear margins, the risk of local recurrence is very low. Hence, we propose the term "atypical intradermal smooth muscle neoplasm" as being more appropriate.

A concept of a compact imaging spectrometer component based on an integrated waveguide array is elaborated and its design rules presented. The component, a focal plane array spectrometer (FPAS), is used in a similar way as a CMOS detector array or a CCD in a camera. The classical spectrometer, for instance an optical grating spectrometer, disappears from the optical system. The whole instrument is therefore reduced to the imaging optics and the FPAS in the focal plane which takes over the function of the spectrometer and detector array. Its potential for very high spectral resolution, minimal size, simple instrument integration, modularity and ruggedness makes it interesting for commercial and special applications like space. Two typical space optical instruments are reconceived using the FPAS with the result of a potential volume reduction of a factor five to eight while keeping the same performances. Also the specifications of simple and generic spectrometers based on the proposed component concept are very promising with respect to spectral resolution, volume and simplicity of instrument design and manufacturing.

This Article describes the preparation and isolation of novel octahedral CH(2)-bridged bis-(N-heterocyclic carbene)palladium(IV) tetrachlorides of the general formula LPd(IV)Cl(4) [L = (NHC)CH(2)(NHC)] from LPd(II)Cl(2) and Cl(2). In intermolecular, nonchelation-controlled transformations LPd(IV)Cl(4) reacted with alkenes and alkynes to 1,2-dichlorination adducts. Aromatic, benzylic, and aliphatic C-H bonds were converted into C-Cl bonds. Detailed mechanistic investigations in the dichlorinations of alkenes were conducted on the 18VE Pd(IV) complex. Positive solvent effects as well as kinetic measurements probing the impact of cyclohexene and chloride concentrations on the rate of alkene chlorination support a Pd(IV)-Cl ionization in the first step. Product stereochemistry and product distributions from various alkenes also support Cl(+)-transfer from the pentacoordinated Pd(IV)-intermediate LPd(IV)Cl(3)(+) to olefins. 1-Hexene/3-hexene competition experiments rule out both the formation of π-complexes along the reaction coordinate as well as in situ generated Cl(2) from a reductive elimination process. Instead, a ligand-mediated direct Cl(+)-transfer from LPd(IV)Cl(3)(+) to the π-system is likely to occur. Similarly, C-H bond chlorinations proceed via an electrophilic process with in situ formed LPd(IV)Cl(3)(+). The presence of a large excess of added Cl(-) slows cyclohexene chlorination while the presence of stoichiometric amounts of chloride accelerates both Pd(IV)-Cl ionization and Cl(+)-transfer from LPd(IV)Cl(3)(+). (1)H NMR titrations, T1 relaxation time measurements, binding isotherms, and Job plot analysis point to the formation of a trifurcated Cl(-)···H-C bond in the NHC-ligand periphery as a supramolecular cause for the accelerated chemical events involving the metal center.

The electron-withdrawing SO2CF3 substituent of Cp(CO)2ReC(Tol)(C⋮CC6H4-p-SO2CF3) (1d) greatly accelerates rearrangement via a [1,3]-rhenium shift. The [1,3]-rhenium shift is proposed to proceed via an 18-electron dehydrometallacyclobutadiene intermediate formed by alkyne coordination concerted with an η5−η3 Cp ring slip.

In contrast to mast cells and basophils, the high affinity IgE receptor (FcΕRI) on antigen-presenting cells (APC) shows structural and functional differences. It consists only of a minimal structure of one α- and two γ-chains and enables APC to efficiently take up and present antigen in IgE-mediated delayed-type hypersensitivity reactions that are thought to play a pivotal role in atopic diseases. However, recent studies of FcΕRI signal transduction and function on APC suggest additional mechanisms by which FcΕRI engagement on APC could affect inflammatory reactions. FcΕRI ligation is able to induce major signaling events like protein tyrosine kinase activation including p72syk leading to PLC-γ1 phosphorylation and consecutive calcium influx. Late signaling events like the activation of transcription factors such as NF-ĸB provide a link to the release of proinflammatory cytokines and chemokines, Th-polarizing factors such as IL-12 and the induction of antiapoptotic factors. FcΕRI-mediated IL-10 production in monocytes could also influence their differentiation. Since there are hints that in vivo a functional FcΕRI signaling pathway only exists in individuals from an atopic background, we suggest that these unexpected mechanisms may have an effect on inflammatory reactions in atopic diseases.

Treatment of de-epithelialized human corneas with riboflavin (RF) + long-wavelength ultraviolet light (UVA; RFUVA) increases corneal stroma tensile strength significantly. RFUVA treatment retards the progression of keratoconus, perhaps by cross-linking of collagen molecules, but exact molecular mechanisms remain unknown. Research described here tested possible chemical mechanisms of cross-linking.Corneas of rabbits and spiny dogfish sharks were de-epithelialized mechanically, subjected to various chemical pretreatments, exposed to RFUVA, and then subjected to destructive tensile stress measurements. Tensile strength was quantified with a digital force gauge to measure degree of tissue cross-linking.For both rabbit and shark corneas, RFUVA treatment causes significant cross-linking by mechanism(s) that can be blocked by the presence of sodium azide. Conversely, such cross-linking is greatly enhanced in the presence of deuterium oxide (D(2)O), even when RF is present at only one tenth the currently used clinical concentrations. Blocking carbonyl groups preexisting in the stroma with 2,4-dinitrophenylhydrazide or hydroxylamine blocks essentially all corneal cross-linking. In contrast, blocking free amine groups preexisting in the stroma with acetic anhydride or ethyl acetimidate does not affect RFUVA corneal cross-linking. When both carbonyl groups are blocked and singlet oxygen is quenched, no RFUVA cross-linking occurs, indicating the absence of other cross-linking mechanisms.RFUVA catalyzes cross-linking reactions that require production of singlet oxygen ((1)O(2)), whose half-life is extended by D(2)O. Carbonyl-based cross-linking reactions dominate in the corneal stroma, but other possible reaction schemes are proposed. The use of D(2)O as solution media for RF would enable concentration decreases or significant strength enhancement in treated corneas.

The PANTER X-ray Test Facility was originally designed to support the development and construction of the ROSAT mirror system. A large instrument chamber (length 12 m, diameter 3.5m) accommodates the optics to be analysed. The X-ray sources covering an 0.2 - 50 keV energy range are located at a distance of 123m from the entrance to the chamber to provide an almost parallel X-ray beam. Both are connected by a vacuum tube of 1m diameter. In addition to ROSAT a large number of astronomical systems like telescopes for Exosat, BeppoSAX, JET-X, ABRIXAS, XMM-Newton and Swift - but also gratings (e.g., LETG on Chandra), filters, and focal plane detectors have been measured at the facility. As a "growing facility" we are currently planning to apply changes to the facility layout to support measurements of instrumentation for future missions like XEUS. Currently a parallel beam is set up using a spare CDS mirror ("Coronal Diagnostic Spectrometer", for the SOHO mission) as condensor. Moreover, extensions to vacuum tube and instrument chamber are under consideration, both to allow calibration of systems with focal lengths significantly longer than XMM-Newton. A new focal plane camera using a CCD developed for the eROSITA mission will improve spatial and spectral resolution. Finally, the energy coverage shall be extended to lower and to higher energies. Already with the present configuration important issues like performance under low temperatures could be investigated.

It has been demonstrated that silicon pore optics can serve as the new technology for building the next generation of X-ray telescopes for astronomical missions. In order to build up an optic in Wolter-I configuration, the high performance pore optics (HPO) have to be co-aligned and integrated into pairs, forming so-called X-ray optical units (XOU). The stringent co-alignment requirements for a 50 m focal length telescope like XEUS (e.g. 1 arcsecond between parabolic and hyperbolic HPO) demand holistic alignment concepts, which integrate the metrology, the fixation and the performance verification. The application in space and the resulting thermal requirements in combination with launch loads and other mechanical restrictions must also be considered. Finite element modelling of different fixation mechanisms and XOU configurations allow one both to assess difficulties at an early stage and to validate solution strategies. This paper reports on the concepts, which have been developed. The most promising candidate has been selected to build a form fit function model. The experimental set-up to align the HPOs, the required metrology and first results of the performance verification at test facilities will be shown and discussed.

The XEUS petals encompass the optical bench structure of the stand alone X-Ray Optical Units (XOU) based on the high performance and light weight Silicon Pore Optics technology. The performance aspects under consideration of the design drivers, the related trade offs (e.g. mechanical concepts, material selection, XOU butting efficiency etc.) and the current development activities wrt. the design, manufacturing, assembly and the functional and environmental test verification approach of the Form Fit Function Model are described in this paper. Special emphasis is given to the critical external optical and mechanical interfaces coherent to the mission design, e.g. the Mirror S/C frame work structure and the Detector S/C. The technology program is based on the heritage achieved within the context of the XMM/Newton telescope development. The investigations of the correlated programmatic aspects towards the FM production by application of effective robot system supported assembly procedures shall be illustrated.

New astronomical science missions demand X-ray telescopes with an angular resolution better than 5" and effective areas of up to 5 m2 at 1 keV. Traditional technologies like nickel electro-forming or polished glass surfaces lead to long and heavy structures, which require prohibitive mass resources to achieve the required large collecting area. To overcome this problem an entirely novel technology using silicon wafers has been developed resulting in pore X-ray optics, which form very light, stiff and modular structures. The suitability of silicon wafers to be used as high quality optical material has been demonstrated and semiconductor industry have developed methods to structure the wafers such, that they can be assembled into segments of Wolter-I optics. For the assembly of these, so called High Performance Pore Optics (HPO), we have developed an automated production robot. The assembly process and the required metrology is described in detail and experimental methods are shown, which allow to assess the quality of the HPOs during production and to predict their performance when measured in synchrotron radiation facilities.© (2006) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

XEUS, the 'X-ray Early Universe Spectroscopy Mission', is a potential candidate for inclusion into the Cosmic Visions 1525 Science Programme of the European Space Agency ESA [1,2]. It is being studied jointly with the Japanese Aerospace Exploration Agency JAXA. The newly developed Silicon-based High resolution Pore Optics (HPO) combines low mass density with good angular resolution, and enables the development of novel mission design concepts for the implementation of a new generation of space based X-ray telescope [3, 4, 5]. This optics technology allows also for the application of complex reflective coatings [6], improving the effective area of the telescope and permitting an enhancement in the engineering of the desired response function. This paper gives an overview of the telescope optical design and optical bench architecture, including the deployment scheme. Further, the performance predictions based on ray tracing are discussed and the overall telescope design of XEUS is presented.

Silicon pore optics have been proposed earlier as modular optical X-ray units in large Wolter-I telescopes that would match effective area and resolution requirements imposed by missions such as XEUS. Since then the optics have been developed further and the feasibility of the production of high-performance pore optics has been demonstrated. Optimisation of the production and the assembly process allowed the generation of optics with larger areas with improved imaging performance; Silicon pore optics can now be manufactured with properties required for future X-ray telescopes. A suitable design that allows the implementation of pore optics into X-ray Optical Units in Wolter I configuration was derived and recently built including an appropriate telescope mounting structure with interfaces for the individual components. Based on the present experience the requirements for industrial mirror production, optics assembly, related metrology and performance verification are reviewed from a viewpoint of its implementation into a large scale production. Such production may lead to the provision of the large number of X-ray optical units that are required within reasonably short time scales and a feasible cost envelope. The present outcome of this investigation and the prospects to future production and test facilities will be presented.

The characteristics of the latest generation of assembled silicon pore X-ray optics are discussed in this paper. These very light, stiff and modular high performance pore optics (HPO) have been developed [1] for the next generation of astronomical X-ray telescopes, which require large collecting areas whilst achieving angular resolutions better than 5 arcseconds. The suitability of 12 inch silicon wafers as high quality optical mirrors and the automated assembly process are discussed elsewhere in this conference. HPOs with several tens of ribbed silicon plates are assembled by bending the plates into an accurate cylindrical shape and directly bonding them on top of each other. The achievable figure accuracy is measured during assembly and in test campaigns at X-ray testing facilities like BESSY-II and PANTER. Pencil beam measurements allow gaining information on the quality achieved by the production process with high spatial resolution. In combination with full beam illumination a complete picture of the excellent performance of these optics can be derived. Experimental results are presented and discussed in detail. The results of such campaigns are used to further improve the production process in order to match the challenging XEUS requirements [2] for imaging resolution and mass.

Recent developments of cerium-doped lanthanum-halide scintillators like LaBr3:Ce show a remarkable performance in gamma-ray spectroscopy. When high energy resolution in combination with stopping power is required they provide excellent gamma-ray detector candidates for the use in space missions. Moreover, irradiation tests have shown that such detectors are radiation tolerant. In this paper we discuss a possible application of LaBr in nuclear astrophysics missions. We show results on recent proton irradiation tests at KVI in Groningen (NL) and discuss the damage and activation effects after irradiation. A possible implementation for a focal plane detector in a gamma-ray telescope and the expected performance is presented.

Activation of the high-affinity receptor for IgE (FcepsilonRI) on allergic effector cells induces a multitude of positive signals via immunoreceptor tyrosine-based activation motifs, which leads to the rapid manifestation of allergic inflammatory reactions. As a counterbalance, the coaggregation of the IgG receptor FcgammaRIIB mediates inhibitory signals via immunoreceptor tyrosine-based inhibition motifs. Advances in the positive and negative regulation of Fc receptor expression and signaling have shed light on the role of Fc receptors in our immune system, indicating them to be bifunctional, inhibitory and activating structures. Based on these findings, exciting new therapeutic strategies have been developed, such as the use of chimeric fusion proteins, which concomitantly activate FcepsilonRI and FcgammaRIIB. These new approaches successfully take advantage of the bivalent character of Fc receptors and pave the way for innovative strategies to modulate allergic immune reactions.

Future missions that may be deployed in the European Space Agency's Cosmic Visions 2025 scientific programme may include high energy astrophysics observatories that require focusing optics with unprecedented collection area. We describe scientific drivers for such missions, and discuss various implementations of optics designs that could satisfy the requirements. Options for lightweight reflectors and a possible implementation scenario are described and trade-offs for various coatings are presented.

The next generation astronomical X-ray telescopes (such as the X-ray Evolving Universe Spectroscopy mission XEUS) require extremely large collecting areas (effective area of ~10 m2 at 1 keV) in combination with good angular resolution of ~5" or better. The existing technologies such as polished glass and nickel electroforming would lead to excessively heavy and expensive optics, and/or are not able to produce the required large area. We have developed an entirely novel technology for producing X-ray optics which results in very light, stiff and modular optics. These can be assembled into almost arbitrarily large apertures and are perfectly suited for future astrophysics missions such as XEUS. Indeed this crucial technology ensures that the ambitious mission profile is actually feasible. The technology makes use of commercially available silicon wafers from the semiconductor industry. The latest generation of 12 inch silicon wafers have a surface roughness that is sufficiently low (~0.3 nm) for X-ray reflection, almost perfect mechanical properties and are considerably cheaper than other high-quality optical materials. The wafers are bent into an accurate cone and assembled to form a stiff pore structure. The resulting light and stiff modules, which we term a High-performance Pore Optics (HPO), form a small segment of a Wolter-I optic, and are easily assembled into a modular optic with large collecting area. We have implemented an automated production process of HPOs on laboratory scale and describe facilities developed with ESA at the Cosine Research Centre. We present the status of the production and the results obtained with this highly innovative technology.

The Xeus mission is designed to explore the X-ray emission from objects in the Universe at high redshifts, and the success of the mission depends critically on the deployment of a 10 square metre class telescope system in a suitable orbit for science observations. The minimisation of the telescope mass and volume becomes of critical importance for such a large facility. We describe developments of novel light weight optics that enable a reduction in mass per unit area of more than an order of magnitude, compared with traditional replication optics technology. With such a large collection area, image confusion limits become a scientific driver as well, demanding arcsecond class resolution. We describe measurements that demonstrate the improvement in resolution that gives very high confidence that these requirements can be met. Some implementation details of the mission are briefly mentioned.

Producing the next generation of X-ray optics, both for large astrophysics missions and smaller missions such as planetary exploration, requires much lower mass and therefore much thinner mirrors. The use of pore structures allows very thin mirrors in a stiff structure. Over the last few years we have been developing ultra-low mass pore optics based on microchannel plate technology in glass, resulting in square, open-core glass fibres in a concentric geometry. The surface roughness inside the pores can be as low as 0.5 nm due to the extreme stretching of the surface during production. We show how improvements in the production process have led to an improved quality of the fibers and the quality of stacking the fibers in the required geometry. To achieve een higher imaging quality as required for XEUS we have developed in parallel a novel pore optics technology based on silicon wafers. The production process of silicon wafers is extremely optimised by the semiconductor industry, leading to optical qualities that are sufficient for high-resolution X-ray focussing. We have developed the technology to stack these wafers into accurate X-ray optics, set up automated assembly facilities for the production of these stacks and present very promising X-ray test results of 5.3 arcsec HEW from single reflection off such a stack, showing the great potential of this technology for XEUS and other high-resolution low mass X-ray optics.

Future planetary missions will require advanced, smart, low resource payloads and satellites to enable the exploration of our solar system in a more frequent, timely and multi-mission manner. A viable route towards low resource science instrumentation is the concept of Highly Integrated Payload Suites (HIPS), which was introduced during the re-assessment of the payload of the BepiColombo (BC) Mercury Planetary Orbiter (MPO). Considerable mass and power savings were demonstrated throughout the instrumentation by improved definition of the instrument design, a higher level of integration, and identification of resource drivers. The higher integration and associated synergy effects permitted optimisation of the payload performance at minimum investment while still meeting the demanding science requirements. For the specific example of the BepiColombo MPO, the mass reduction by designing the instruments towards a Highly Integrated Payload Suite was found to be about 60%. This has endorsed the acceptance of a number of additional instruments as core payload of the BC MPO thereby enhancing the scientific return. This promising strategic approach and concept is now applied to a set of planetary mission studies for future exploration of the solar system. Innovative technologies, miniaturised electronics and advanced remote sensing technologies are the baseline for a generic approach to payload integration, which is here investigated also in the context of largely differing mission requirements. A review of the approach and the implications to the generic concept as found from the applications to the mission studies are presented.

The success of the XEUS mission depends critically on the deployment of a 10 square metre class telescope system in a suitable orbit for science observations. The minimisation of the telescope mass and volume becomes of critical importance for such a large facility. We describe developments of novel light weight optics that enable a reduction in mass per unit area of more than an order of magnitude, compared with traditional replication optics technology. With such a large collection area, image confusion limits become a scientific driver as well, demanding arcsecond class resolution. We describe measurements that demonstrate the improvement in resolution that gives very high confidence that these requirements can be met.

The next generation astronomical X-ray telescopes (e.g. XEUS) require extremely large collecting area (10 m2) in combination with good angular resolution (5 arcsec). The existing technologies such as polished glass, nickel electroforming and foil optics would lead to excessively heavy and expensive optics, and/or are not able to produce the required large area or resolution. We have developed an entirely novel technology for producing X-ray optics which results in very light, stiff and modular optics which can be assembled into almost arbitrarily large apertures, and which are perfectly suited for XEUS. The technology makes use of commercially available silicon wafers from the semiconductor industry. The latest generation silicon wafers have a surface roughness that is sufficiently low for X-ray reflection, are planparallel to better than a micrometer, have almost perfect mechanical properties and are considerably cheaper than other high-quality optical materials. The wafers are bent into an accurate cone and assembled to form a light and stiff pore structure with pores of the order of a millimeter. The resulting modules form a small segment of a Wolter-I optic, and are easily assembled into an optic with large collecting area. We present the production principle of these silicon pore optics, the facilities that have been set up to produce these modules and experimental results showing the excellent performance of the first modules that have been produced. With further improvement we expect to be able to match the XEUS requirements for imaging resolution and mass.

The high affinity receptor for IgE, FcepsilonRI, is a multimeric surface receptor that is expressed exclusively as a tetramer on rodent cells, but exists as a tetramer or trimer on human cells. The tetrameric form is expressed on effector cells of allergic responses such as mast cells and basophils and is composed of an IgE-binding alpha-subunit, a beta-subunit and a gamma-subunit dimer. Complexes lacking the beta-subunit are found on human antigen-presenting cells. On mast cells and basophils, FcepsilonRI is essential for IgE-mediated acute allergic reactions. Crosslinking of FcepsilonRI by IgE and multivalent antigen induces a signaling cascade that culminates in the release of preformed mediators and the synthesis of lipid mediators and cytokines. The beta-subunit functions as an amplifier of FcepsilonRI expression and signaling. As a consequence, strongly enhanced mast cell effector functions and in vivo allergic reactions can be observed in the presence of FcepsilonRIbeta. In contrast, a truncated beta-isoform (betaT) that is produced by alternative splicing acts as an inhibitor of FcepsilonRI surface expression. Thus, by producing two proteins with antagonistic functions, the FcepsilonRIbeta gene could serve as a potent regulator of allergic responses. In addition, the genomic region encompassing the beta-chain has been linked to atopy and a number of polymorphisms within the FcepsilonRIbeta gene are associated with various atopic diseases. It remains to be elucidated how these polymorphisms might affect the allergic phenotype. These functions of the beta-chain together with the described genetic linkages to atopy make it a candidate for a role in the pathophysiology of allergic diseases.

A convenient synthesis of trisamido molybdenum(VI) alkylidyne complexes has been developed, in which the key step is the addition of a geminal dichloride to a trisamido molybdenum(III) complex in the presence of magnesium to continuously recycle unwanted side product 4, selectively generating the desired alkylidyne complexes in high yield.

In the Science Payload Technology Division of the European Space Agency X-ray optics are being developed for space based astrophysics observatories and planetary missions. Due to the gazing incidence geometries required in the x-ray regions of interest, and the high angular resolutions required, the mass of the optics becomes a major driver in mission design. New technologies have to be explored for future applications, simultaneously achieving good angular resolution and low mass while maintaining collecting aperture. The cosmology mission XEUS requires very large effective area, 30m2 at 1keV, x-ray optics with high angular resolution of below 5" with a goal of 2". This implies a large aperture for a single telescope system, which will necessarily require assembly or deployment in space, and which will be formed by basic mirror modules known as petals. The petals must remain compatible with compact ground handling and production tools and will require minimum modifications to existing calibration facilities. The technology for the implementation of this Wolter-I design is currently based on the European heritage of x-ray optics development and production, dating back to Exosat, launched in 1983, to the currently operating XMM-Newton observatory. Substantial further research and development is required, however, with the key aspects therefore being low mass design and industrialization of the production. New approaches are being considered in parallel to evolutions of the current state-of-the-art technologies. In addition to the XEUS mission optics options, extremely low mass Wolter-I optics are being developed for applications in very deep orbits or planetary remote sensing, having even stronger mass constraints, but having a more relaxed angular resolution requirement. Such optics systems feature dramatically reduced mirror thickness and therefore mass. The current state of development of the ultra-lightweight x-ray optics systems will be presented together with future development plans.

A decade ago, the discovery of the high-affinity receptor for IgE (FcϵRI) on epidermal Langerhans cells documented the end of the dogma that FcϵRI is only expressed on effector cells of anaphylaxis. Since then, the functional significance of this receptor on antigen-presenting cells (APCs) has been an area of intense research work. Scientists have focused on a better understanding of the molecular structure, regulation, and role of FcϵRI on APCs in the human immune system. Insights into the cellular events linked to the activation of APCs on ligation of FcϵRI by IgE and allergens might provide the basis for new aspects in the pathophysiology of allergic diseases and the design of future diagnostic and therapeutic strategies. This review is dedicated to the 10th anniversary of the discovery of FcϵRI on APCs and describes the numerous areas of research in this field. (J Allergy Clin Immunol 2003;111:38-44.)

The trimeric high-affinity IgE receptor (FcepsilonRI) on human epidermal Langerhans cells mediates IgE-dependent antigen uptake and subsequent antigen focusing. Its expression is upregulated on Langerhans cells (FcepsilonRIhigh Langerhans cells) and inflammatory dendritic epidermal cells (FcepsilonRIhigh inflammatory dendritic epidermal cells) in the skin of patients with atopic dermatitis. In the absence of the amplifying beta-chain in these cells, FcepsilonRI signaling (indicated by calcium mobilization and activation of the transcription factor nuclear factor-kappaB) is only detectable in FcepsilonRIhigh Langerhans cells from atopics, but not FcepsilonRIlow Langerhans cells from nonatopics. Therefore we investigated protein-tyrosine kinases putatively involved in FcepsilonRI signaling in Langerhans cells and asked whether differences in their expression and FcepsilonRI-induced activity could explain the dichotomic responses observed in atopic vs nonatopic individuals. First, we found the src protein-tyrosine kinases p53/56lyn, p59fyn, p56/59hck, p55c-fgr, and p60c-src to be expressed in Langerhans cells from all donors. In addition, whereas p56lck was lacking, p72syk and the negative regulatory p50csk were detected. Upon terminal maturation of Langerhans cells in vitro, no significant change of the protein- tyrosine kinase expression profile except downregulation of p56/59hck was observed. In contrast, significant upregulation of all protein-tyrosine kinase expressed except p50csk was detected in FcepsilonRIhigh Langerhans cells, but not in FcepsilonRIhigh inflammatory dendritic epidermal cells. Finally, the important protein-tyrosine kinases substrate phospholipase C-gamma1, which is also essential for downstream calcium mobilization, was only phosphorylated upon FcepsilonRI triggering in FcepsilonRIhigh Langerhans cells from atopics, but not in FcepsilonRIlow Langerhans cells from nonatopics. Therefore, upregulation of FcepsilonRI and protein-tyrosine kinase expression as well as subsequent protein-tyrosine kinase activity may explain, at least in part, that an efficient signaling pathway in terms of calcium mobilization is restricted to FcepsilonRIhigh Langerhans cells from atopic individuals. Key words

Langerhans cells (LC) are a unique population of dendritic cells (DC) found in the epidermis where they can be identified by the expression of CD1a, E-cadherin and cytoplasmic Birbeck granules (BG) as their hallmark. Over the past years many techniques have been described to generate LC in vitro from either monocytes or CD34(+) hematopoietic cell progenitors. Antibodies against Lag and Langerin (two epitopes associated with BG) and E-cadherin (a Ca(2+)-dependent homophilic adhesion molecule) have been used to detect in vitro-generated LC. In this study we investigated whether the expression of E-cadherin on in vitro-generated CD1a(+) from either CD34(+) cells or monocytes is able to discriminate LC from other DC. Our results demonstrate that E-cadherin alone is not a reliable marker to specifically identify in vitro-generated LC.

In contrast to mast cells and basophils, the high-affinity IgE receptor (Fc(epsilon)RI) on monocytes and dendritic cells (DC), including epidermal Langerhans cells, is not constitutively expressed and lacks the beta-chain. Fc(epsilon)RI is upregulated on Langerhans cells of atopic individuals, particularly in atopic dermatitis skin. Although Fc(epsilon)RI provides IgE-mediated antigen focusing on monocytes and DC/Langerhans cells, its relevance for cell activation remains elusive, and the transcription factors regulating Fc(epsilon)RI-induced genes are unknown. We show that NF-kappaB, known to regulate genes essential for inflammatory responses and DC differentiation and function, is activated upon Fc(epsilon)RI ligation in primary human monocytes and DC. In Langerhans cells isolated from epidermis, NF-kappaB activation is restricted to donors expressing high Fc(epsilon)RI amounts. Fc(epsilon)RI-induced NF-kappaB complexes in monocytes and DC contain p50 and p65, but no other NF-kappaB subunits despite increased RelB expression during differentiation. NF-kappaB activation is preceded by serine phosphorylation and degradation of its inhibitory protein IkappaB-alpha without involving other IkappaB proteins. Finally, we show that Fc(epsilon)RI ligation on monocytes and DC leads to synthesis and release of tumor necrosis factor-alpha and monocyte chemoattractant protein-1, which is decreased by two mechanistically distinct inhibitors of NF-kappaB activation. Thus NF-kappaB activation represents a novel mechanism by which Fc(epsilon)RI on monocytes and DC potentially controls inflammatory reactions.

Dimerization of the alkynylcarbene complex Cp(CO)(2)Re=C(Tol)C(triple bond)CCH(3) (8) occurs at 100 degrees C to give a 1.2:1 mixture of enediyne complexes [Cp(CO)(2)Re](2)[eta(2),eta(2)-TolC(triple bond)CC(CH(3))=C(CH(3))C(triple bond)CTol] (10-Eand 10-Z), showing no intrinsic bias toward trans-enediyne complexes. The cyclopropyl-substituted alkynylcarbene complex Cp(CO)(2)Re=C(Tol)C(triple bond)CC(3)H(5) (11) dimerizes at 120 degrees C to give a 5:1 ratio of enediyne complexes [Cp(CO)(2)Re](2)[eta(2),eta(2)-TolC(triple bond)C(C(3)H(5))C=C(C(3)H(5))C(triple bond)CTol] (12-E and 12-Z); no ring expansion product was observed. This suggests that if intermediate A formed by a [1,1.5] Re shift and having carbene character at the remote alkynyl carbon is involved, then interaction of the neighboring Re with the carbene center greatly diminishes the carbene character as compared with that of free cyclopropyl carbenes. The tethered bis-(alkynylcarbene) complex Cp(CO)(2)Re=C(Tol)C(triple bond)CCH(2)CH(2)CH(2)C(triple bond)CC(Tol)= Re(CO)(2)Cp (13) dimerizes rapidly at 12 degrees C to give the cyclic cis-enediyne complex [Cp(CO)(2)Re](2)[eta(2),eta(2)-TolC(triple bond)CC(CH(2)CH(2)CH(2))=CC(triple bond)CTol] (15). Attempted synthesis of the 1,8-disubstituted naphthalene derivative 1,8-[Cp(CO)(2)Re=C(Tol)C(triple bond)C](2)C(10)H(6) (16), in which the alkynylcarbene units are constrained to a parallel geometry, leads to dimerization to [Cp(CO)(2)Re](2)(eta(2),eta(2)-1,2-(tolylethynyl)acenaphthylene] (17). The very rapid dimerizations of both 13 and 16 provide compelling evidence against mechanisms involving cyclopropene intermediates. A mechanism is proposed which involves rate-determining addition of the carbene center of A to the remote alkynyl carbon of a second alkynylcarbene complex to generate vinyl carbene intermediate C, and rearrangement of C to the enediyne complex by a [1,1.5] Re shift.

The photoconductor detector arrays for the PACS instrument (Photoconductor Array Camera and Spectrometer) aboard the future ESA telescope Herschel have been developed during the engineering phase in 1999. In early 2000 the construction of the qualification models began for both, the highly and low stressed Ge:Ga arrays, which consist of 12 linear modules each. These two types of photoconductor arrays are dedicated for different wavelengths bands in the spectrometer section of the instrument. While the performance of a few engineering arrays has been studied and presented earlier, additional data are meanwhile available on the absolute responsivity and quantum efficiency of the detectors. Furthermore, experience has been obtained during manufacture of a larger series of arrays giving better statistics on performance aspects, such as uniformity of the cutoff wavelengths and of the responsivity or the maximum stress obtainable within such arrays. Considerable progress has also been made in the development and manufacture of the 4 Kelvin Cold Read-out Electronics (CRE), which will integrate and multiplex the signals generated in each linear array with its 16 detector pixels. Manufacture of the detector arrays for the qualification model is scheduled to be completed by this summer, and manufacture of the flight model has already started. The qualification model will be delivered to the test facilities, where absolute spectral performance of the 24 linear modules will be determined. In this paper we give a summary of the related activities and results as obtained during manufacturing and testing.

IgE receptors are implicated as important components of the immunological pathway in allergic and inflammatory diseases. Recent investigations have begun to unravel the structure, signal transduction and function of IgE receptors from different cell types in rodent and human systems. Studies of the mechanisms involved might provide opportunities for therapeutic intervention strategies in the treatment of allergic and hypersensitivity reactions.

Professional antigen-presenting cells (APC) such as monocytes and dendritic cells (DC) bearing high-affinity IgE receptors (FcΕRI) efficiently present IgE-bound antigens to T cells. FcΕRI expression is upregulated on APC from atopic donors, especially in inflamed tissues. These data suggest a pathophysiological concept of an IgE-mediated delayed-type hypersensitivity reaction in atopic diseases. However, FcΕRI ligation also leads to the synthesis of proinflammatory cytokines and other molecules involved in inflammatory reactions. The investigation of transcription factors mediating these effects has only recently commenced. In general, members of the NF-ĸB family are known to regulate APC function and differentiation, with the RelB subunit being especially important in DC generation. In addition, Ikaros and PU.1 have also been shown to be essential factors for DC differentiation, whereas Oct-2 is upregulated by differentiation towards macrophages. Recently, FcΕRI has been demonstrated to induce NF-ĸB activation via IĸB-α serine phosphorylation and degradation in monocytes and DC. Inhibitors of NF-ĸB activation such as N-acetylcysteine or N-tosyl-L-phenylalanine chloromethyl ketone can suppress FcΕRI-induced TNF-α and MCP-1 release. Interestingly, in human epidermal Langerhans’ cells (LC), NF-ĸB activation can only be observed when large amounts of FcΕRI are present. In addition, the composition of NF-ĸB complexes differs between monocytes, monocyte-derived DC and LC, suggesting a cell type-specific regulation. Moreover, the transcription factor NFAT is induced upon FcΕRI ligation in human APC. The elucidation of further transcription factors involved in FcΕRI signaling in APC should contribute to the employment of new inhibition strategies for the treatment of atopic and other inflammatory diseases.

The High Energy Transmission Grating Spectrometer of the Chandra X-Ray Observatory is a high spectral resolution instrument utilizing gold X-ray transmission gratings. The gratings have been subjected to a rigorous program of calibration, including testing at synchrotron facilities for the purpose of refining and testing the grating model. Here we conclude our investigation of the optical constants of gold, extending it below 2 keV to complete the coverage over the Chandra energy range. We investigate the carbon, nitrogen, oxygen and chromium edge structures introduced by the grating support membrane. Finally, we summarize the state of the grating model, identifying those energy regions where the residuals are most significant and suggesting where the model might be improved.© (2000) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

For the instrument PACS (Photoconductor Array Camera and Spectrometer) aboard FIRST two photoconductor arrays dedicated for different wavelengths bands are foreseen in the spectrometer section. Each camera consists of 25 linear arrays of 16 stressed Ge:Ga crystals. The arrays with 2 X 400 pixels will be used for imaging line spectroscopy in the wavelengths ranges 60 micrometers to 110 micrometers and 110 micrometers to 210 micrometers . The detectors are read out by a new generation of integrating and multiplexing cryogenic read-out electronics, which is currently under redesign and further development. The development of the arrays has passed the engineering phase and entered the qualification status. We summarize the results obtained with the engineering arrays and the first 6 qualification models with respect to their performance such as uniformity of current sensitivity and cutoff wavelength. The impacts of the result of the first 6 linear arrays on the qualification model are described together with the final design which is supposed to fulfill the specifications and requirements of the instrument PACS.