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The research field of “Macromolecular chemistry” has changed considerably during the last 10 years. There has been unexpected break throughs in the area of bulk polymers despite the fact that research in this area could have been considered to be complete. The metallocene catalysts open up the synthesis of new polymer combinations with completely new structures. Their potential has not yet been exhausted. The trend toward building polymeric structures with small dimensions and to nanotechnology is decisive. Many workgroups within germany and abroad have been working on nano-particles and layers and with reactions at interfaces with respect to their technological and biochemical application. Evidently this trend has been promoted though the foundation of competence centers of nanotechnology. The following report for the year 1998 gives some information on these developments without claiming to be complete.

We have made heat pulse measurements of the phonon emission by warm two-dimensional electrons in gallium arsenide quantum wells that range in width from 3 to 15 nm. As the power dissipated in the sample is increased, a characteristic change in the phonon time-of-flight traces is observed. This is identified with the onset of the emission of optic phonons at an electron temperature of about 50 K. We find that the onset of optic phonon emission occurs at a higher power in the narrower wells. We account for these observations in terms of the increase of the energy loss rate due to the emission of other modes owing to the relaxation of the perpendicular momentum conservation requirement in narrower wells.

We report a detailed theoretical study of the angular and polarization dependence of the acoustic phonon emission by a hot two-dimensional electron gas (2DEG) in GaAs/AlGaAs heterojunctions and quantum wells (QW) and compare the results with some recent heat pulse measurements. We use a model which not only includes the dynamical screening of electron–phonon interaction but also takes proper account of the finite “thickness” of the 2D gas and above all, considers the strong acoustic anisotropy of the electron–phonon matrix elements and the propagation process. For QW with different widths we demonstrate the strong dependence of the angular distribution on the well width. For heterostructures in the (0 0 1)-plane, we can explain, in contrast to earlier theoretical studies, the phenomena of missing longitudinal modes for phonon emission close to the two-dimenional electron gas (2DEG) normal.

A mass spectrometric method for the quantification of free cholesterol in cells and subcellular membranes is presented. The method is based on a simple one-step chemical derivatization of cholesterol to cholesterol-3-sulfate by a sulfur trioxide-pyridine complex. Quantification is performed by nano-electrospray ionization tandem mass spectrometry (nanoESI-MS/MS) using a stable isotope labeled internal standard. The determination of free cholesterol is demonstrated in about 250 cells of a Chinese hamster ovary (CHO) cell line. With this method a molar ratio of free cholesterol to total phospholipids of 0.34 mol/mol in CHO cells was determined. In a subcellular membrane fraction enriched in Golgi membranes, a molar ratio of free cholesterol to total phospholipids of 0.57 mol/mol was determined. The method should be of value for quantification of other sterols as demonstrated for ergosterol and stigmasterol.—Sandhoff, R., B. Brügger, D. Jeckel, W. D. Lehmann, and F. T. Wieland. Determination of cholesterol at the low picomole level by nano-electrospray ionization tandem mass spectrometry. J. Lipid Res. 1999. 40: 126–132.

Powder coatings have attained great importance as coating materials because of their economic and environmental benefits. However, there are also some limitations which have prevented the penetration of solid paints into some promising markets up to now. A new concept of combined reactions is introduced in order to find a control mechanism for flow procedure that is dependent on the curing reaction for powder coatings. Useful combinations were found by characterization of reactivity in one-stage curing reactions in bulk using low molecular models. A two-stage reaction mechanism was proved in combined low molecular model systems as well as in polymeric powder coating basic systems consisting of binder and hardener for various combined reaction systems. Results are shown for the combined reaction system epoxide/carboxylic acid/phenolic compound.

Acute respiratory infections (ARI) are a major cause of morbidity in children worldwide, and are estimated to cause four million deaths per year, mainly in the developing world. In those countries, bacterial infection with high case fatality is common, apparently following a primary viral infection. The case management strategy has had success in controlling severe outcomes. However, its dependence on the use of antibiotics and the advantage of primary prevention support the need for vaccines. Vaccines against viruses such as respiratory syncytial and parainfluenza would prevent what is often the initial infection and vaccines against Haemophilus influenzae and S. pneumoniae the major bacterial causes of mortality. Maternal immunization may have special relevance in developing countries where protection early in life is required. The development of combination vaccines would also be especially useful, since contacts with the medical system are often difficult. The introduction and use of new vaccines in those regions will require demonstration of cost effectiveness and acceptance by policy makers.

Triple negative breast cancer (TNBC) is a heterogeneous collection of biologically diverse cancers, which contributes to variable clinical outcomes. Previously, we identified a TNBC subtype that has a luminal phenotype and expresses androgen receptor (AR+). TNBC cells derived from these luminal AR+ tumors have high frequency PIK3CA mutations. The purpose of this study was to determine if targeting PI3K alone or in combination with an AR antagonist is effective in AR+ TNBC. Methods: We determined the frequency of activating PIK3CA mutations in AR+ and AR- TNBC clinical cases. Using AR+ TNBC cell lines and xenograft models we evaluated the effectiveness of PI3K inhibitors, used alone or in combination with an AR antagonist, on tumor cell growth and viability. Results: PIK3CA kinase mutations were highly clonal, more frequent in AR+ vs. AR- TNBC (40% vs. 4%), and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR+ TNBC cells. We also analyzed the combination of bicalutamide +/- the pan-PI3K inhibitor GDC-0941 or the dual PI3K/mTOR inhibitor GDC-0980 in xenograft tumor studies and observed additive effects. Conclusions: While approximately one third of TNBC patients respond to neoadjuvant/adjuvant chemotherapy, recent studies have shown that patients with androgen receptor positive (AR+) TNBC are far less likely to benefit from the current standard of care chemotherapy regimens and novel targeted approaches need to be investigated. In this study, we show that activating PIK3CA mutations are enriched in AR+ TNBC; and, the growth and viability of AR+ TNBC cell line models is significantly reduced after treatment with PI3K inhibitors used in combination with an AR antagonist. These results provide rationale for pre-selection of TNBC patients with a biomarker (AR expression) to investigate the use of AR antagonists in combination with PI3K/mTOR inhibitors. Citation Format: Brian D Lehmann, Joshua A Bauer, Johanna M Schafer, Christopher S Pendleton, Luojia Tang, Kimberly C Johnson, Xi Chen, Justin M Balko, Henry Gomez, Carlos L Arteaga, Gordon B Mills, Melinda E Sanders, Jennifer A Pietenpol. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-04-03.

Heterogenous nucleation on small molecule crystals causes a monoclinic crystal form of bacteriorhodopsin (BR) in which trimers of this membrane protein pack differently than in native purple membranes. Analysis of single crystals by nano-electrospray ionization-mass spectrometry demonstrated a preservation of the purple membrane lipid composition in these BR crystals. The 2.9-Å x-ray structure shows a lipid-mediated stabilization of BR trimers where the glycolipid S-TGA-1 binds into the central compartment of BR trimers. The BR trimer/lipid complex provides an example of local membrane thinning as the lipid head-group boundary of the central lipid patch is shifted by 5 Å toward the membrane center. Nonbiased electron density maps reveal structural differences to previously reported BR structures, especially for the cytosolic EF loop and the proton exit pathway. The terminal proton release complex now comprises an E194-E204 dyad as a diffuse proton buffer.

Abstract —The aim of this study was to establish the relation between noninvasive Doppler ultrasound assessments of aortic compliance, based on “foot-to-foot” aortic pulse wave velocity measurements, and presumed atherosclerotic load in patients with vascular disease and/or diabetes mellitus. One hundred ten patients with vascular disease and/or diabetes mellitus (arteriopaths) underwent measurement of in vivo aortic compliance using Doppler ultrasound. Demographic data on these subjects were recorded along with details of cardiovascular risk factors and events. Aortic compliance values were compared with data from 51 age-matched healthy, asymptomatic subjects putatively free of vascular disease (controls). Data are expressed as mean±SD. Arteriopaths were aged 64.1±8.4 years and had total cholesterol levels of 5.9±1.1 mmol/L and aortic compliance of 0.78±0.42%/10 mm Hg [1.33 kPa]. Most arteriopaths had 2 or more cardiovascular risk factors and events: diabetes (n=41), hypertension (n=45), smoking (n=86), cerebrovascular/transient ischemic event (n=13), myocardial infarction (n=44), angina (n=51), and/or peripheral vascular disease (n=33). Controls were aged 64.3±12.1 years with total cholesterol of 6.1±1.1 mmol/L and aortic compliance of 1.14±0.46%/10 mm Hg [1.33 kPa] ( P P

One trend in polymer chemistry apparent over the last few years - that knowledge about known polyreactions has been combined to produce new polymeric architectures - continued in 1997. The greater understanding of metallocenes led to the further development of catalysts and with them to new polymer combinations. Interest is still being shown in hyperbranched polymers and dendrimers. Further interest was shown in the understanding of the structures and properties of interfaces and surfaces, as well as their applications. An overview of news from polymer analysis concludes this part of the report.

By using nanoelectrospray ionization and a triple quadrupole analyzer, simplified fragment ion spectra of peptides have been recorded by combining skimmer collision-induced dissociation with precursor ion scanning or neutral loss scanning. These pseudo-MS 3 scan modes are characterized by two-stage collision-induced dissociation and have been termed sCID/precursor and sCID/neutral loss scan, respectively. By these scan modes, peptide fragment ion spectra can be generated that predominantly show signals of a single fragment ion series, such as the B or Y″ series. Skimmer collision-induced dissociation combined with scanning for neutral loss of 28 generates spectra showing B ions, whereas combination with precursor ion scanning for the Y ″ 1 ion results in spectra showing Y″ ions for tryptic peptides (Y ″ 1 = m / z 147 for C-terminal lysine, Y ″ 1 = m / z 175 for C-terminal arginine). Sequence information including the direction of the sequence is easily extracted from the simplified fragment ion spectra generated by two-stage collision-induced dissociation, because the scan mode defines the type of fragments observed. The analytical results reported are similar to those that have been achieved in MS 3 experiments using a hybrid BEQQ or a pentaquadrupole mass spectrometer (Schey, K. L.; Schwartz, J. C.; Cooks, R. G. Rapid Commun. Mass Spectrom. 1989, 3 , 305–309). The pseudo-MS 3 technique used in this study has some limitations with respect to sample purity, because there is no step of mass selection before the first stage of collisional activation; however, it has the advantage that a standard triple quadrupole instrumentation can be used.

This paper describes the methodologies used to develop a prediction model to assist health workers in developing countries in facing one of the most difficult health problems in all parts of the world: the presentation of an acutely ill young infant. Statistical approaches for developing the clinical prediction model faced at least two major difficulties. First, the number of predictor variables, especially clinical signs and symptoms, is very large, necessitating the use of data reduction techniques that are blinded to the outcome. Second, there is no uniquely accepted continuous outcome measure or final binary diagnostic criterion. For example, the diagnosis of neonatal sepsis is ill-defined. Clinical decision makers must identify infants likely to have positive cultures as well as to grade the severity of illness. In the WHO/ARI Young Infant Multicentre Study we have found an ordinal outcome scale made up of a mixture of laboratory and diagnostic markers to have several clinical advantages as well as to increase the power of tests for risk factors. Such a mixed ordinal scale does present statistical challenges because it may violate constant slope assumptions of ordinal regression models. In this paper we develop and validate an ordinal predictive model after choosing a data reduction technique. We show how ordinality of the outcome is checked against each predictor. We describe new but simple techniques for graphically examining residuals from ordinal logistic models to detect problems with variable transformations as well as to detect non-proportional odds and other lack of fit. We examine an alternative type of ordinal logistic model, the continuation ratio model, to determine if it provides a better fit. We find that it does not but that this model is easily modified to allow the regression coefficients to vary with cut-offs of the response variable. Complex terms in this extended model are penalized to allow only as much complexity as the data will support. We approximate the extended continuation ratio model with a model with fewer terms to allow us to draw a nomogram for obtaining various predictions. The model is validated for calibration and discrimination using the bootstrap. We apply much of the modelling strategy described in Harrell, Lee and Mark (Statist. Med. 15, 361-387 (1998)) for survival analysis, adapting it to ordinal logistic regression and further emphasizing penalized maximum likelihood estimation and data reduction.

Tbe isotopomeric ions of non-isotope-enriched biomolecules generated by nanoelectrospray ionization were selectively fragmented by collision-induced dissociation in a triple-quadrupole mass spectrometer. Using this technique, the influence of heavy isotopes, such as 13 C or 18 O, on the isotopic pattern of fragment ions is significantly enhanced compared with the dissociation of an entire group of non-mass selected molecular ions. Dissociation of the +1 Da isotopomeric ions results in fragment ion doublets, allowing the determination of the number of carbon atoms in the fragment when the empirical formula of the precursor molecular ion is known. Dissociation of the + 2 Da isotopomeric ions results in fragment ion triplets. On the basis of the carbon atom number of a fragment, the ion abundances of these triplets allow the determination of a heteroelement such as oxygen, containing a stable isotope two mass units heavier than the value of its principle isotope. The technique was applied to the determination of the elemental composition of the two main fragment ions of protonated 1-alkenyl-2-acyl-phosphatidylethanolamine (plasmenyl-phosphatidylethanolamine). The results show that they are formed by a rearrangement resulting in two complementary fragment ions carrying the 1-alkenyl and 2-acyl substituent, respectively. Information on the elemental composition of fragment ions can be obtained by isotope-selective tandem electrospray mass spectrometry using sample amounts in the low picomole range.

The human multidrug resistance protein (MRP1) confers resistance of cells to a number of different cytostatic drugs and functions as an export pump for glutathione S-conjugates, glucuronides and other amphiphilic anions. The present study details for the first time MRP1-mediated ATP-dependent transport of various glutathione S-conjugates of the bifunctional alkylating agents chlorambucil and melphalan. In membrane vesicles prepared from cells expressing recombinant MRP1, the conjugates were transported at rates in the following order: monoglutathionyl chlorambucil > bisglutathionyl chlorambucil > monohydroxy monoglutathionyl chlorambucil and monoglutathionyl melphalan > monohydroxy monoglutathionyl melphalan. In addition, we show that membranes from chlorambucil-resistant GST-alpha-overexpressing CHO cells as well as from their parental cells express the hamster homologue of MRP1. With both CHO cell membrane preparations, we observed ATP-dependent transport of monoglutathionyl chlorambucil and of leukotriene C4, a glutathione S-conjugate and high-affinity substrate of MRP1. The transport rates measured in the resistant cells were only two- to three-fold higher than those measured in the control cells. These results together with cytotoxicity assays comparing MRP1-overexpressing cell pairs with the CHO cell pair indicate that, although MRP1-mediated transport is active, it may not be the rate-limiting step in chlorambucil resistance in these cell lines. Images Figure 3

Metastable fragmentation of modified peptides during matrix-assisted laser desorption/ionization (MALDI) mass spectrometry has been investigated. Fragment ions of modified peptides generated by metastable loss of modification-specific neutral fragments have been detected by MALDI mass spectrometry in the reflector mode. Peptides acetylated at their N-terminus exhibit a characteristic loss of CH2CO from the acetyl group. Serine and threonine phosphopeptides typically show metastable loss of H3PO4 and to a minor extent of HPO3 in both the continuous and delayed extraction mode. Tyrosine phosphopeptides generally show a loss of HPO3 of moderate abundance. For methionine sulfoxide containing peptides metastable loss of methanesulfenic acid is observed. The extent of this fragmentation is reduced when the analysis is performed with delayed extraction. However, delayed extraction facilitates the recognition of metastable fragment ion signals, since signals of intact molecular ions exhibit a significantly higher resolution than signals generated by metastable fragmentation. In complex mixtures precursor ion selection supports the correlation between the molecular ions of modified peptides and their characteristic fragment ions generated by metastable decomposition.

The magnetic fleld dependence of the drag current induced by beams of acoustic phonons is studied in a 2D gas of carriers, formed in a heterostructure. This drag current is related to the velocity of the center of mass of the gas. The elimination of the degrees of freedom related to the relative motion of the carriers leads to a Langevin equation for the center-of-mass position vector. From this equation one can obtain an expression for the induced current density which depends on carrier density—density correlation functions. An explicit formula for the time-integrated current density is derived taking into account all intra and inter Landau level transitions. Corresponding numerical results are in good agreement with the experimental patterns. PACS numbers: 63.20.Kr, 73.40.—c

The momentum relaxation of one-dimensional electrons scattered by acoustic phonons has been investigated in the Bloch - Gruneisen temperature range. The temperature dependence of mobility follows the same, (for deformation acoustic interaction) and (for piezoelectric interaction), power laws as known for two-dimensional and three-dimensional Fermi gases. The calculations performed estimate to be at and at low electron concentrations. The specific feature of a one-dimensional gas is an intermediate temperature region, where an exponential temperature dependence of mobility is traced.

Recently, HVEE has completed a novel 3.5 MV single ended accelerator (Singletron™) for the University of Leipzig, Germany. For one of the main applications, the system will be connected to a nanobeamline to achieve submicron resolution. Because the energy stability and ripple of the beam, and beam brightness are of vital importance for the performance of a nanoprobe, special care has been taken in optimizing these parameters. The system consists of an RF source which is directly mounted on the accelerator tube, a switching magnet to bend the beam into a chamber for standard analysis purposes and an analysis magnet that directs the beam into the nanoprobe. The stability of the beam energy was measured at a terminal voltage of 1.881 MV. These measurements were taken during factory acceptance with large production equipment operational, which negatively influenced the stability of the mains. The measured stability was found to be approx. ±50 eV over 5 h, but it is anticipated that this figure will be as good as ±20 eV (i.e. ∼ 10−5) under normal laboratory conditions. The terminal voltage ripple was measured at 2.25 MV to be 25 Vpp (i.e. ∼ 1.1 × 10−5). Finally, the beam brightness of a 2.25 MeV hydrogen beam was measured by the use of two micrometer slit systems. A brightness of approx. 18 Amps · rad−2 m−2 eV−1 was obtained. In this article we will describe the considerations which have led to the layout of the present system.

A visual documentation scheme for depicting various mass analyzers, collision-induced dissociation schemes, and mass-spectrometer and tandem mass-spectrometer scan modes are proposed. The schemes, called “pictograms,” are aimed at facilitating the presentation of complex mass-spectrometry experiments on spectral outputs, figures, and schemes in research notes, presentations, and articles.

Linomide (quinoline-3-carboxamide, LS-2616), a synthetic immunomodulator, protects animals against a variety of experimental autoimmune diseases. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), linomide blocks both the clinical and histological signs of the disease, without inducing generalized immunosuppression. In the first clinical trial in patients with MS, linomide was shown to inhibit the progression of the disease. In the present study we investigated several aspects of the mechanisms of action of this immunomodulator. We found that linomide can inhibit acute EAE even when given as pretreatment, prior to induction of disease (days −10 to 0). This inhibitory effect was reversed by adoptive transfer of naive spleen cells. A short course (7 days) of linomide treatment also inhibited EAE, especially when administered immediately after disease induction. Spleen cells from linomide-treated mice failed to present myelin antigens to T-cell lines in vitro. The defective antigen presentation was normalized by anti-oxidants such as 2-mercaptoethanol. The proportion of Mac1 + cells in the spleens of linomide-treated mice was significantly reduced and macrophage growth was inhibited in long term cultures of spleen cells derived from linomide-treated animals. Our findings suggest that the effect of linomide on EAE may be attributed, at least in part, to inactivation of antigen presenting cells, possibly following a short period of over-stimulation and increased oxidant production. This mechanism may play a universal role in the regulation of autoimmune reactivity and merits further investigation.

27-Channel EEG potential map series were recorded from 12 normals with closed and open eyes. Intracerebral dipole model source locations in the frequency domain were computed. Eye opening (visual input) caused centralization (convergence and elevation) of the source locations of the seven frequency bands, indicative of generalized activity; especially, there was clear anteriorization of alpha-2 (10.5-12 Hz) and beta-2 (18.5-21 Hz) sources (alpha-2 also to the left). Complexity of the map series' trajectories in state space (assessed by Global Dimensional Complexity and Global OMEGA Complexity) increased significantly with eye opening, indicative of more independent, parallel, active processes. Contrary to PET and fMRI, these results suggest that brain activity is more distributed and independent during visual input than after eye closing (when it is more localized and more posterior).

Rat bile phosphatidylcholine was structurally characterized and quantified by electrospray mass spectrometry using a triple quadrupole instrument. All results were obtained by direct analysis of an unprocessed total lipid extract from rat bile. Structural characterization of phosphatidylcholine was achieved by collision-induced dissociation of [M + Cl] − ions observed in the negative-ion electrospray mass spectrum. Quantification of phosphatidylcholine was performed in the positive-ion mode using precursor ion scanning of m / z 184 and dimyristoyl-phosphatidylcholine as internal standard. Using this new methodology, the effect of cyclosporin A on biliary phosphatidylcholine excretion in the rat was investigated. After intravenous administration of cyclosporin A (25 mg/kg body wt) the phosphatidylcholine level in bile was reduced to about 30% of the control level. This suggests an inhibition by cyclosporin A of the translocation of phosphatidylcholine across the hepatocyte canalicular membrane which is mediated by the Mdr2 P-glycoprotein.

The influence of the immediate prestimulus EEG microstate (sub-second epoch of stable topography/map landscape) on the map landscape of visually evoked 47-channel event-related potential (ERP) microstates was examined using the frequent, non-target stimuli of a cognitive paradigm (12 volunteers). For the two most frequent prestimulus microstate classes (oriented left anterior-right posterior and right anterior-left posterior), ERP map series were selectively averaged. The post-stimulus ERP grand average map series was segmented into microstates; 10 were found. The centroid locations of positive and negative map areas were extracted as landscape descriptors. Significant differences (MANOVAs and t-tests) between the two prestimulus classes were found in four of the ten ERP microstates. The relative orientation of the two ERP microstate classes was the same as prestimulus in some ERP microstates, but reversed in others. — Thus, brain electric microstates at stimulus arrival influence the landscapes of the post-stimulus ERP maps and therefore, information processing; prestimulus microstate effects differed for different post-stimulus ERP microstates.

Peptides containing a monoiodo- or diiodo-tyrosine residue (monoiodo-Y, diiodo-Y) were found to generate abundant immonium ions following collision-induced dissociation at m/z 261.97 and 387.87 Da, respectively. These residue-specific marker ions are between about 140 mDa (monoiodo-Y) and 300 mDa (diiodo-Y) mass deficient relative to any other peptide fragment ions of unmodified peptides, qualifying them as highly specific marker ions for tyrosine iodination when analyzed by high resolution tandem mass spectrometry (MS/MS). Two new iodination sites (Y-364 and Y-2165) were pinpointed in bovine thyroglobulin by MS/MS using these iodotyrosine-specific marker ions and combined tryptic/chymotryptic digestion.

A 15-year-old male patient presented with mental retardation, mild motor impairment, and partial deafness. Biochemical investigations showed an abnormal urinary profile of leukotrienes. Concentration of leukotriene D4 (LTD4), which is usually not detectable, was highly increased, whereas LTE4, the major urinary metabolite in humans, was completely absent. These data suggest membrane-bound dipeptidase deficiency, a new defect in leukotriene biosynthesis on the step of LTE4 synthesis, as underlying defect. Ann Neurol 2005;58:968–970

Metastasis, the main cause of death from cancer, remains poorly understood at the molecular level.Based on a pattern of reduced expression in human prostate cancer tissues and tumor cell lines, a candidate suppressor gene (SPARCL1) was identified. We used in vitro approaches to determine whether overexpression of SPARCL1 affects cell growth, migration, and invasiveness. We then employed xenograft mouse models to analyze the impact of SPARCL1 on prostate cancer cell growth and metastasis in vivo.SPARCL1 expression did not inhibit tumor cell proliferation in vitro. By contrast, SPARCL1 did suppress tumor cell migration and invasiveness in vitro and tumor metastatic growth in vivo, conferring improved survival in xenograft mouse models.We present the first in vivo data suggesting that SPARCL1 suppresses metastasis of prostate cancer.

Wepresentadetailedtheoreticalframeworkforthecalculationofthermopower, S,intwo-dimensionalelectron gases confined in (001) AlAs quantum wells (QWs) taking into account the band anisotropy. Particular emphasis is given on the phonon-drag contribution S g that is related to the momentum exchange between acoustic phonons and electrons in the presence of a weak in-plane temperature gradient via the electron-phonon coupling. Our model is based on the semiclassical Boltzmann formalism and is a generalization of previous models that are applicable only for an isotropic energy spectrum. We find that the electron anisotropy in AlAs affects strongly the electron-acoustic phonon coupling and S g . Considerable enhancement of S g is reported in relation to isotropic GaAs QWs. More interestingly, we find that strong anisotropy in phonon-drag thermopower occurs by tuning the valley occupancy. Namely, the predicted S g and S g can differ by over a factor of 5 while a giant magnitude for S g can be achieved in a particular direction exceeding 10 mV/ Ka tT = 5 K. The diffusion thermopower is also calculated for comparison.

This document describes the technical layout and the expected performance of the Straw Tube Tracker (STT), the main tracking detector of the $\bar{P}$ANDA target spectrometer. The STT encloses a Micro-Vertex-Detector (MVD) for the inner tracking and is followed in beam direction by a set of GEM stations. The tasks of the STT are the measurement of the particle momentum from the reconstructed trajectory and the measurement of the specific energy loss for a particle identification. Dedicated simulations with full analysis studies of certain proton-antiproton reactions, identified as being benchmark tests for the whole $\bar{P}$ANDA scientific program, have been performed to test the STT layout and performance. The results are presented, and the time lines to construct the STT are described.

Reactive extrusion has been applied as a very effective and fast process for controlled chemical degradation of a commercial polyamide 6 with trimellitic anhydride in the melt. A reaction mechanism based mainly on the amide/anhydride reaction has been discussed and confirmed by measurements of the solution viscosity, end group analysis, SEC, NMR, and IR spectroscopy. The systematic loss of molecular weight of the polyamides resulting from PA chain repture and the formation of imide linkages and carboxyl end groups were investigated. The theoretical values of molecular weight and end group concentration of the obtained oligoamides predicted by the reaction mechanism are in good agreement with the experimental ones. © 1996 John Wiley & Sons, Inc.

Tle response of a 2D gas of charge carriers of mobility μ in magnetic freld to pulsed phonon beams is considered. Previously we derived a quantum Langevin equation for the centre-of-mass of the carrier gas, which allows us to calculate the time integrated drag current. This formula is studied in the weak magnetic field limit. When the ratio of the cyclotron frequency ωc to the frequency ω of phonons is small and μB < 1, the general formula coincides with the corresponding expression obtained in the frame of the Boltzmann equation with the collision integral independent of B.

OBJECTIVE While the effects of age on the growth hormone/insulin-like growth factor (IGF) axis are well documented, the influence of ethnic background is unknown. The differences in IGF and IGF binding proteins (IGFBPs) were investigated in two ethnic groups. DESIGN A cross-sectional study of an age-selected cohort of healthy, normoglycaemic, non-obese Caucasian (C) and Asian (A) subjects. PATIENTS Fifty-three (27 C, 26 A) subjects with a mean age (±SD) of 20.6±0.8 years were studied. MEASUREMENTS Fasting measurements of glucose, insulin, IGF-I, IGF-II, IGFBP-1 and IGFBP-3. Western ligand blotting and immunoblotting with IGFBP-2 and IGFBP-3 of serum samples. RESULTS There were no significant differences in IGF-I levels between Caucasian and Asian subjects (C 218±55 vs A 229±40μg/l; P=0.44). IGF-II (C 707±110 vs A 583±75μg/l; P

The kinetic description of the response of two-dimensional gases of carriers in a weak magnetic field to pulsed beams of bulk long-wavelength acoustic phonons is presented. It is assumed that a surface element with radius vector r filled with this gas has an elongated form characterized by the unit vector . The component of the time-integrated current density is calculated. This quantity depends on a time characterizing the elastic scattering of carriers by defects and on the cyclotron frequency via dimensionless parameter . Using the obtained formula for the component of time-integrated current density, we calculate suitable response patterns and compare them with results of our experiments for a gas of holes.

The Dubin-Johnson syndrome (DJS) is characterized by a hereditary conjugated hyperbilirubinemia and a typical dark pigment accumulation in liver parenchymal cells. In the present study the renal excretion of leukotrienes in five patients with histologically established DJS and five age- and sex-matched healthy subjects was investigated. Endogenous urinary leukotrienes were separated by high-performance liquid chromatography and subsequently quantified by immunoassays and gas chromatography-mass spectrometry. Patients with DJS excreted significantly (P < 0.01) greater amounts of cysteinyl leukotriene, LTE4 (8-fold), the omega-oxidation product omega-carboxy-LTE4 (15-fold) and the beta-oxidation metabolite omega-carboxy-tetranor-LTE3 (26-fold) into urine than healthy controls. These results imply that in DJS leukotriene elimination into bile is defective, leading to a compensatory renal leukotriene elimination and a typical excretion pattern of urinary leukotriene metabolites. Analysis of endogenous urinary leukotrienes seems to be a new approach to the noninvasive diagnosis of this disease.

Proteins were digested in normal and highly 18O-enriched water using proteases commonly employed for protein sequencing. The extent of 18O incorporation into the resulting peptide fragments was characterized by electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The endoproteinases trypsin, Lys-C and Glu-C incorporate two atoms of 18O, resulting in a mass shift of +4 D for the peptide fragments. This indicates that, following proteolytic cleavage, peptide products continue to interact with these proteases and undergo repeated binding/hydrolysis cycles, resulting in complete equilibration of both oxygens in the carboxy terminus of the fragments with oxygen from solvent water. In contrast, chymotrypsin and Asp-N incorporate only one atom of 18O, resulting in a mass shift of +2 D, indicating that after the cleavage step these proteases do not accept the peptides as substrates. In addition, it was found that the proteases trypsin, Glu-C, and Lys-C exhibit minor or nontypical sequence specificities, resulting in unexpected peptide fragments. These fragments incorporate only one 18O atom, indicating that they do not undergo further binding/hydrolysis cycles with the enzyme. Thus, it is possible to discriminate between enzyme-typical peptide fragments with mass shifts of +4 D and nontypical fragments with mass shifts of only +2 D. Based on these observations, protein digest strategies are described for the generation of 1:1 ion doublets spaced either by 2 or 4 D. In addition, the C-terminus of a protein can be identified by the absence of an ion doublet in the corresponding peptide fragment. In protein sequencing by mass spectrometry, digest protocols generating ion doublets provide the most clear-cut analytical results for the recognition of ion series in ESI-MS/MS and MALDI post-source decay (PSD) product ion spectra. Only the mass spectrometric fragment ions of a C-terminal series show ion doublets spaced either by 2 or 4 D, whereas the fragment ions belonging to an N-terminal series remain unshifted. This assignment unequivocally reveals the direction of the identified sequence.

Prostate cancer is the second most commonly diagnosed cancer in men, and approximately one-third of those diagnosed succumb to the disease. The development of prostate cancer from small regions of hyperplasia to invasive tumors requires genetic and epigenetic alterations of critical cellular components to aid in the development of cells more adapted for aberrant growth. The p53 transcription factor is a critical element in the cell’s ability to regulate the cell cycle and its response to DNA damage. Mutations within the DNA-binding domain of p53 are common and allow the formation of tetramers; however, these alterations prevent this protein complex from associating with target gene promoters. In the present study, we examined the effects of p53 functionality in prostate cancer cells that harbored wild-type (WT) or mutant forms of the protein in response to commonly used chemotherapeutic drugs. The androgen receptor positive 22Rv-1 and LNCaP prostate cancer cell lines carry WT p53 and were demonstrated to have a decrease in chemotherapeutic drug sensitivity when transfected with a dominant-negative (DN) p53. Conversely, expression of the WT p53 in the p53-mutated and more advanced DU145 prostate cancer cell line significantly increased its overall sensitivity to anti-neoplastic drugs. Furthermore, analysis of colony formation in soft agar revealed that the functional status of p53 in each cell line altered the cell’s ability to proliferate in an anchorage-independent fashion. Prostate cancer colony growth was more prevalent when p53 transcriptional activity was decreased, whereas growth was more limited in the presence of functional p53. These results demonstrate that the functional status of the tumor suppressor p53 is important in the progression of prostate cancer and dictates the overall effectiveness a given drug would have on disease treatment.

ERK is a member of the MAPK pathway with essential functions in cell proliferation, differentiation, and survival. Complete ERK activation by the kinase MEK requires dual phosphorylation at T and Y within the activation motif TEY. We show that exposure of primary mouse hepatocytes to hepatocyte growth factor (HGF) results in phosphorylation at the activation motif, but not of other residues nearby. To determine the relative abundances of unphosphorylated ERK and the three ERK phospho-forms pT, pY, and pTpY, we employed an extended one-source peptide/phosphopeptide standard method in combination with nanoUPLC-MS. This method enabled us to determine the abundances of phospho-forms with a relative variability of ≤5% (SD). We observed a switch-like preference of ERK phospho-form abundances toward the active, doubly phosphorylated and the inactive, unphosphorylated form. Interestingly, ERK phospho-form profiles were similar upon growth factor and cytokine stimulation. A screening of several murine and human cell systems revealed that the balance between TY- and pTpY-ERK is conserved while the abundances of pT- and pY-ERK are more variable within cell types. We show that the phospho-form profiles do not change by blocking MEK activity suggesting that cellular phosphatases determine the ERK phospho-form distribution. This study provides novel quantitative insights into multisite phosphorylation.

Infants in Papua New Guinea (PNG) are at a high risk of invasive pneumococcal disease, and a substantial burden of this falls on children less than six months old. PNG is planning to introduce a pneumococcal conjugate vaccine for infants in the near future, but to make the maximum impact neonatal immunization will have to be considered. To provide evidence on safety and immunogenicity for neonatal and early infant immunization, we undertook an open randomized controlled trial of 7-valent pneumococcal conjugate vaccine (7vPCV). 318 children received 7vPCV at ages 0, 1 and 2 months or at 1, 2 and 3 months or not at all. All children received 23-valent pneumococcal polysaccharide vaccine at age 9 months. This was a large and complex trial: village reporters visited participants weekly during the first year and fortnightly for a further 6 months and nurses monitored self-reported morbidity and collected many thousands of biological samples. The study team was remarkably successful in achieving the study aims, with 18-month follow-up completed on 77% of enrolled children and over 80% of scheduled samples collected. While the results of the trial will be reported elsewhere, this paper discusses the design of the study and dissects out some of the main reasons for its successful completion. Strong community engagement was an essential factor in success and the principles of equitable partnership and service provision led to a strong research partnership. A two-stage consent process, comprising primary assent followed by later informed consent, led to a high drop-out before initial enrolment, but an outstanding retention of those enrolled in the study. We conclude that factors such as strong community participation, reciprocity and a good relationship between the study team and participants are just as important as the technical elements of laboratory testing and data handling in ensuring the success of a vaccine trial in PNG.

The aim of this study was to assess the interaction of a series of well characterised nano-objects with the Gram negative bacterium Salmonella typhimurium, and how such an interaction may relate to the potential mutagenicity of nano-objects. Transmission electron microscopy showed that nano-objects (Au-PMA-ATTO NPs, CeO₂ NPs, SWCNTs and MWCNTs), as well as CAFs entered S. typhimurium. Only DEPs did not penetrate/enter the bacteria, however, were the only particle stimulus to induce any significant mutagenicity through the Ames test. Comparison with a sophisticated 3D in vitro cell model showed CAFs, DEPs, SWCNTs and MWCNTs to cause a significant increase in mammalian cell proliferation, whilst both the Au-PMA-ATTO NPs and CeO₂ NPs had not significant adverse effects. In conclusion, these results indicate that various of different nano-objects are able to penetrate the double-lipid bilayer of Gram negative bacteria, although the Ames test may not be a good indicator for nano-object mutagenicity.

1. Non-invasive aortic compliance measurements have been used previously to assess the distensibility of the aorta in several pathological conditions associated with increased cardiovascular risk. We set out to establish whether aortic compliance is abnormal in patients with stroke. 2. Pulse wave velocity measurements of thoracoabdominal aortic compliance were made in 20 stroke patients and 25 age- and sex-matched hospitalized, non-stroke control subjects putatively free of cardiovascular disease. Since compliance varies with non-chronic changes in blood pressure, a blood pressure corrected index of aortic distensibility, Cp, was calculated. 3. Aortic compliance was significantly reduced in patients with stroke compared with non-stroke control subjects (0.46 ± 0.27 versus 0.86 ± 0.34%/10 mmHg, P < 0.0002), corresponding with higher values for pulse wave velocity. Stroke patients also had significantly higher systolic and diastolic blood pressures (P < 0.02 and P < 0.002 respectively) and total cholesterol levels (P < 0.004) than the control subjects. Calculation of Cp did not alter the observation of stiffer aortas in the stroke cohort (P < 0.0007). 4. In both stroke patient and control cohorts, as expected, inverse trends were observed between aortic compliance and blood pressure. Also as expected, in the control group Cp values did not show a relationship with blood pressure (r = 0.02, P = 0.092, not significant). However, in the stroke cohort a marked dependence of Cp on blood pressure was observed (r = −0.48, P = 0.03). 5. Transoesophageal echocardiographic studies have recently identified advanced atherosclerosis in the ascending aorta as a possible source of cerebral emboli and an independent risk factor for ischaemic stroke. Our observations of significantly stiffer thoracoabdominal aortas in patients with stroke lead us to hypothesize that a totally non-invasive assessment of aortic compliance may potentially prove a useful surrogate marker of such atherosclerotic risk. 6. Blood pressure-corrected indices of arterial elastic properties based on normotensive models are widely applied in the literature. Our observation that these indices exhibit a considerable blood pressure dependence leads us to urge caution in the use of such corrections, especially in hypertensive patients.

Triple-negative breast cancer (TNBC) is a heterogeneous disease that can be classified into distinct molecular subtypes by gene expression profiling. Considered a difficult-to-treat cancer, a fraction of TNBC patients benefit significantly from neoadjuvant chemotherapy and have far better overall survival. Outside of BRCA1/2 mutation status, biomarkers do not exist to identify patients most likely to respond to current chemotherapy; and, to date, no FDA-approved targeted therapies are available for TNBC patients. Previously, we developed an approach to identify six molecular subtypes TNBC (TNBCtype), with each subtype displaying unique ontologies and differential response to standard-of-care chemotherapy. Given the complexity of the varying histological landscape of tumor specimens, we used histopathological quantification and laser-capture microdissection to determine that transcripts in the previously described immunomodulatory (IM) and mesenchymal stem-like (MSL) subtypes were contributed from infiltrating lymphocytes and tumor-associated stromal cells, respectively. Therefore, we refined TNBC molecular subtypes from six (TNBCtype) into four (TNBCtype-4) tumor-specific subtypes (BL1, BL2, M and LAR) and demonstrate differences in diagnosis age, grade, local and distant disease progression and histopathology. Using five publicly available, neoadjuvant chemotherapy breast cancer gene expression datasets, we retrospectively evaluated chemotherapy response of over 300 TNBC patients from pretreatment biopsies subtyped using either the intrinsic (PAM50) or TNBCtype approaches. Combined analysis of TNBC patients demonstrated that TNBC subtypes significantly differ in response to similar neoadjuvant chemotherapy with 41% of BL1 patients achieving a pathological complete response compared to 18% for BL2 and 29% for LAR with 95% confidence intervals (CIs; [33, 51], [9, 28], [17, 41], respectively). Collectively, we provide pre-clinical data that could inform clinical trials designed to test the hypothesis that improved outcomes can be achieved for TNBC patients, if selection and combination of existing chemotherapies is directed by knowledge of molecular TNBC subtypes.

The main particle identification detector of the PANDA experiment will be of the DIRC type. For various reasons the favored sensors are micro-channel plate photo multipliers (MCP-PMTs). Despite many advantageous properties MCP-PMTs until recently had serious problems with aging issues at high photon rates. In this paper we present a simultaneous aging measurement for the latest MCP-PMTs of BINP, Hamamatsu (R10754X) and PHOTONIS (XP85112). In these devices specific countermeasures have been applied to reduce the loss of quantum efficiency (QE) of the photo cathode (PC) with increasing anode charge, which is the main feature of aging. We find that the new techniques show a significantly increased lifetime of the concerning MCP-PMTs. With several surface scans across the active area of the MCP-PMTs we find evidence that the loss of QE develops from the rims and corners of the PC. In addition, the spectral QE of the MCP-PMTs is given as a function of the integrated anode charge revealing that for the R10754X the QE drops faster for long wavelenghts than for short ones. At this point of the ongoing measurements the XP85112 does not show any significant aging signs after 5.6 C/cm2 which is a more than an order of magnitude improvement compared to former MCP-PMTs and corresponds to more than 10 years of running time for the PANDA Barrel DIRC. In this PMT the micro-channels are coated by an atomic layer deposition (ALD) technique which currently appears to be the most promising countermeasure against the aging of MCP-PMTs.