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Experiments deploying large arrays of transition-edge sensors (TESs) often require a robust method to monitor gain variations with minimal loss of observing time. We propose a sensitive and non-intrusive method for monitoring variations in TES responsivity using small square waves applied to the TES bias. We construct an estimator for a TES's small-signal power response from its electrical response that is exact in the limit of strong electrothermal feedback. We discuss the application and validation of this method using flight data from SPIDER, a balloon-borne telescope that observes the polarization of the cosmic microwave background with more than 2000 TESs. This method may prove useful for future balloon- and space-based instruments, where observing time and ground control bandwidth are limited., Comment: 7 pages, 3 figures; Proceedings of the 19th International Workshop on Low Temperature Detectors (LTD19); Minor updates to match published version

We studied 2780 adults in Hong Kong who received CoronaVac inactivated virus vaccine (Sinovac) and BNT162b2 mRNA vaccine ("Comirnaty", BioNTech/Fosun Pharma). We compared rates of antibody waning over time using an enzyme-linked immunosorbent assay for spike receptor binding domain and a surrogate virus neutralization test. We found stronger and more durable antibody responses to two doses of the mRNA vaccine, and slightly stronger initial antibody responses to each vaccine in younger adults and women. The weaker and less durable responses following CoronaVac support earlier provision of third doses to persons who previously received two doses of this vaccine.

Modern CMB analysis pipelines regularly employ complex time-domain filters, beam models, masking, and other techniques during the production of sky maps and their corresponding angular power spectra. However, these processes can generate couplings between multipoles from the same spectrum and from different spectra, in addition to the typical power attenuation. Within the context of pseudo-$C_\ell$ based, MASTER-style analyses, the net effect of the time-domain filtering is commonly approximated by a multiplicative transfer function, $F_{\ell}$, that can fail to capture mode mixing and is dependent on the spectrum of the signal. To address these shortcomings, we have developed a simulation-based spectral correction approach that constructs a two-dimensional transfer matrix, $J_{\ell\ell'}$, which contains information about mode mixing in addition to mode attenuation. We demonstrate the application of this approach on data from the first flight of the SPIDER balloon-borne CMB experiment., Comment: 14 pages, 7 figures; updated to match published version

In this work we describe upgrades to the Spider balloon-borne telescope in preparation for its second flight, currently planned for December 2021. The Spider instrument is optimized to search for a primordial B-mode polarization signature in the cosmic microwave background at degree angular scales. During its first flight in 2015, Spider mapped ~10% of the sky at 95 and 150 GHz. The payload for the second Antarctic flight will incorporate three new 280 GHz receivers alongside three refurbished 95- and 150 GHz receivers from Spider's first flight. In this work we discuss the design and characterization of these new receivers, which employ over 1500 feedhorn-coupled transition-edge sensors. We describe pre-flight laboratory measurements of detector properties, and the optical performance of completed receivers. These receivers will map a wide area of the sky at 280 GHz, providing new information on polarized Galactic dust emission that will help to separate it from the cosmological signal., 13 pages, 8 figures; as published in the conference proceedings for SPIE Millimeter, Submillimeter, and Far-Infrared Detectors and Instrumentation for Astronomy X (2020)

We identified seasonal human coronaviruses, influenza viruses and rhinoviruses in exhaled breath and coughs of children and adults with acute respiratory illness. Surgical face masks significantly reduced detection of influenza virus RNA in respiratory droplets and coronavirus RNA in aerosols, with a trend toward reduced detection of coronavirus RNA in respiratory droplets. Our results indicate that surgical face masks could prevent transmission of human coronaviruses and influenza viruses from symptomatic individuals.

SuperSpec is a new technology for mm and sub-mm spectroscopy. It is an on-chip spectrometer being developed for multi-object, moderate-resolution ( R∼300 ), large bandwidth survey spectroscopy of high-redshift galaxies for the 1 mm atmospheric window. This band accesses the CO ladder in the redshift range of z= 0–4 and the [CII] 158 μ m line from redshift z= 5–9. SuperSpec employs a novel architecture in which detectors are coupled to a series of resonant filters along a single microwave feedline instead of using dispersive optics. This construction allows for the creation of a full spectrometer occupying only ∼10cm2 of silicon, a reduction in size of several orders of magnitude when compared to standard grating spectrometers. This small profile enables the production of future multi-beam spectroscopic instruments envisioned for the millimeter band to measure the redshifts of dusty galaxies efficiently. The SuperSpec collaboration is currently pushing toward the deployment of a SuperSpec demonstration instrument in fall of 2018. The progress with the latest SuperSpec prototype devices is presented; reporting increased responsivity via a reduced inductor volume (2.6 μm3 ) and the incorporation of a new broadband antenna. A detector NEP of 3–4 ×10−18 W/Hz 0.5 is obtained, sufficient for background-limited observation on mountaintop sites. In addition, beam maps and efficiency measurements of a new wide-band dual bow-tie slot antenna are shown.

Line intensity mapping (LIM) provides a unique and powerful means to probe cosmic structures by measuring the aggregate line emission from all galaxies across redshift. The method is complementary to conventional galaxy redshift surveys that are object-based and demand exquisite point-source sensitivity. The Tomographic Ionized-carbon Mapping Experiment (TIME) will measure the star formation rate (SFR) during cosmic reionization by observing the redshifted [CII] 158$\mu$m line ($6 \lesssim z \lesssim 9$) in the LIM regime. TIME will simultaneously study the abundance of molecular gas during the era of peak star formation by observing the rotational CO lines emitted by galaxies at $0.5 \lesssim z \lesssim 2$. We present the modeling framework that predicts the constraining power of TIME on a number of observables, including the line luminosity function, and the auto- and cross-correlation power spectra, including synergies with external galaxy tracers. Based on an optimized survey strategy and fiducial model parameters informed by existing observations, we forecast constraints on physical quantities relevant to reionization and galaxy evolution, such as the escape fraction of ionizing photons during reionization, the faint-end slope of the galaxy luminosity function at high redshift, and the cosmic molecular gas density at cosmic noon. We discuss how these constraints can advance our understanding of cosmological galaxy evolution at the two distinct cosmic epochs for TIME, starting in 2021, and how they could be improved in future phases of the experiment., Comment: 30 pages, 18 figures, accepted for publication in ApJ

International audience; We describe the construction and characterization of the 280 GHz bolometric focal plane units (FPUs) to be deployed on the second flight of the balloon-borne Spider instrument. These FPUs are vital to Spider’s primary science goal of detecting or placing an upper limit on the amplitude of the primordial gravitational wave signature in the cosmic microwave background (CMB) by constraining the B-mode contamination in the CMB from Galactic dust emission. Each 280 GHz focal plane contains a $16 \times 16$ grid of corrugated silicon feedhorns coupled to an array of aluminum–manganese transition-edge sensor (TES) bolometers fabricated on 150 mm diameter substrates. In total, the three 280 GHz FPUs contain 1530 polarization-sensitive bolometers (765 spatial pixels) optimized for the low loading environment in flight and read out by time-division SQUID multiplexing. In this paper, we describe the mechanical, thermal, and magnetic shielding architecture of the focal planes and present cryogenic measurements which characterize yield and the uniformity of several bolometer parameters. The assembled FPUs have high yields, with one array as high as 95% including defects from wiring and readout. We demonstrate high uniformity in device parameters, finding the median saturation power for each TES array to be $\sim $ 3 pW at 300 mK with a less than 6% variation across each array at $1\sigma $ . These focal planes will be deployed alongside the 95 and 150 GHz telescopes in the Spider-2 instrument, slated to fly from McMurdo Station in Antarctica in December 2018.

SuperSpec is a novel on-chip spectrometer we are developing for multi-object, moderate resolution (R = 100 - 500), large bandwidth (~1.65:1) submillimeter and millimeter survey spectroscopy of high-redshift galaxies. The spectrometer employs a filter bank architecture, and consists of a series of half-wave resonators formed by lithographically-patterned superconducting transmission lines. The signal power admitted by each resonator is detected by a lumped element titanium nitride (TiN) kinetic inductance detector (KID) operating at 100 - 200 MHz. We have tested a new prototype device that achieves the targeted R = 100 resolving power, and has better detector sensitivity and optical efficiency than previous devices. We employ a new method for measuring photon noise using both coherent and thermal sources of radiation to cleanly separate the contributions of shot and wave noise. We report an upper limit to the detector NEP of $1.4\times10^{-17}$ W Hz$^{-1/2}$, within 10% of the photon noise limited NEP for a ground-based R=100 spectrometer., 8 pages, 4 embedded figures, accepted for publication in the Journal of Low Temperature Physics

We are developing a series of close-packed modular detector arrays for TIME-Pilot, a new mm-wavelength grating spectrometer array that will map the intensity fluctuations of the redshifted 157.7 μm emission line of singly ionized carbon ([CII]) from redshift z∼5 to 9. TIME-Pilot’s two banks of 16 parallel-plate waveguide spectrometers (one bank per polarization) will have a spectral range of 183–326 GHz and a resolving power of R∼100. The spectrometers use a curved diffraction grating to disperse and focus the light on a series of output arcs, each sampled by 60 transition edge sensor (TES) bolometers with gold micro-mesh absorbers. These low-noise detectors will be operated from a 250 mK base temperature and are designed to have a background-limited NEP of ∼10^(−17) W/Hz^(1/2). This proceeding presents an overview of the detector design in the context of the TIME-Pilot instrument. Additionally, a prototype detector module produced at the Microdevices Laboratory at JPL is shown.

SuperSpec is a new technology for millimeter and submillimeter spectroscopy. It is an on-chip spectrometer being developed for multi-object, moderate resolution (R = ~300), large bandwidth survey spectroscopy of high-redshift galaxies for the 1 mm atmospheric window. SuperSpec targets the CO ladder in the redshift range of z = 0 to 4, the [CII] 158 um line from z = 5 to 9, and the [NII] 205 um line from z = 4-7. All together these lines offer complete redshift coverage from z = 0 to 9. SuperSpec employs a novel architecture in which detectors are coupled to a series of resonant filters along a single microwave feedline instead of using dispersive optics. This construction allows for the creation of a full spectrometer occupying only 20 cm squared of silicon, a reduction in size of several orders of magnitude when compared to standard grating spectrometers. This small profile enables the production of future multi-object spectroscopic instruments required as the millimeter-wave spectroscopy field matures. SuperSpec uses a lens-coupled antenna to deliver astrophysical radiation to a microstrip transmission line. The radiation then propagates down this transmission line where upon proximity coupled half wavelength microstrip resonators pick off specific frequencies of radiation. Careful tuning of the proximity of the resonators to the feedline dials in the desired resolving power of the SuperSpec filterbank by tuning the coupling quality factor. The half wavelength resonators are then in turn coupled to the inductive meander of kinetic inductance detectors (KIDs), which serve as the power detectors for the SuperSpec filterbank. Each SuperSpec filter bank contains hundreds of titanium nitride TiN KIDs and the natural multiplexibility of these detectors allow for readout of the large numbers of required detectors. The unique coupling scheme employed by SuperSpec allows for the creation of incredibly low volume (2.6 cubic microns), high responsivity, TiN KIDs. Since responsivity is proportional to the inverse of quasiparticle-occupied volume, this allows SuperSpec to reach the low NEPs required by moderate resolution spectroscopy to be photon limited from the best ground-based observing sites. We will present the latest results from SuperSpec devices. In particular, detector NEPs, measured filter bank efficiency (including transmission line losses), and spectral profiles for a full ~ 300-channel filterbank. Finally, we will report on our system end to end efficiency and total system NEP.

The Prolactin-inducible-protein (PIP)/Gross Cystic Disease Fluid Protein-15 (GCDFP-15) gene is highly expressed in salivary, lacrimal and sweat glands and the protein abundantly found in the secretions that originate from these glands; saliva, tears and sweat. PIP is thus considered to be strategically located at sites viewed as the first port of entry for invading organisms. PIP is also found over-expressed under abnormal and pathological conditions of the breast and prostate. The function of PIP has yet to be defined but it has been implicated to play a role in immunity, with respect to bacterial and viral infection, cancer and fertility. Despite such predictive functions, there is still no clear demonstration of an immunoregulatory role for PIP. In this review we will focus on accumulating evidence that suggests a role for PIP in both innate and adaptive immunity. Moreover, we will discuss recent evidence that defines a modulatory role for PIP with regards to a CD4+ T cell immune response, identifying for the first time, a critical role for PIP in effective cell-mediated immunity against an intracellular pathogen.

The propensity for breast cancers to elicit immune responses in patients is well established. The accumulation of tumor infiltrating lymphocytes within the primary breast tumor has been linked to better prognosis and better response to therapy. The prolactin-inducible protein (PIP) is a 15 kD protein that is expressed under physiological conditions of the breast and is regarded as a marker of mammary differentiation. While highly expressed under pathological conditions of the mammary gland, including breast cancers, PIP is expressed in very few other cancers. Although the function of PIP is not well elucidated, numerous studies suggest that its primary role may be related to host defense and immune modulation. However, evidence to show a direct link between PIP and the immune response has been lacking. In this review, we discuss our recent work with Pip-deficient mice, linking PIP not only to a role in innate immunity but for the first time, providing evidence for a role in cell-mediated immunity. These functional studies in Pip null mice lend new insight into the role of PIP in immunity and suggest that PIP may play a similar immune-regulatory role in breast cancer.

SuperSpec is a new spectrometer-on-a-chip technology for submm/mm-wave spectroscopy. SuperSpec stands out from other direct-detection submm spectrometer technologies in that the detectors are coupled to a series of resonant filters along a single microwave feedline instead of using dispersive optics. SuperSpec makes use of kinetic inductance detectors (KIDs) to detect radiation in this filter bank. The small profile of this design makes SuperSpec a natural choice to produce a multi-object spectrometer for tomographic mapping or galaxy redshift surveys. We have recently fabricated a device that is a 50 channel subset of a full 280 channel filter bank, which would cover the 190 - 310 GHz range at R = 275. Analysis of the data from this device informs us of the potential design modifications to enable a high-yield background-limited SuperSpec spectrometer. The results indicate that this subset filter bank can scale up to a full filter bank with only a few collisions in readout space and less than 20% variation in responsivity for the detectors. Additionally, the characterization of this and other prototype devices suggests that the noise performance is limited by generation-recombination noise. Finally, we find that the detectors are sufficiently sensitive for ground-based spectroscopy at R = 100, appropriate for tomographic mapping experiments. Further modifications are required to reach the background limit for R = 400, ideal for spectroscopy of individual galaxies.

The performance of electromagnetic calorimeter modules made of proton-irradiated PbWO4 crystals has been studied in beam tests. The modules, similar to those used in the Endcaps of the CMS electromagnetic calorimeter (ECAL), were formed from 5×5 matrices of PbWO4 crystals, which had previously been exposed to 24 GeV protons up to integrated fluences between 2.1 × 1013 and 1.3 × 1014 cm-2. These correspond to the predicted charged-hadron fluences in the ECAL Endcaps at pseudorapidity η = 2.6 after about 500 fb-1 and 3000 fb-1 respectively, corresponding to the end of the LHC and High Luminosity LHC operation periods. The irradiated crystals have a lower light transmission for wavelengths corresponding to the scintillation light, and a correspondingly reduced light output. A comparison with four crystals irradiated in situ in CMS showed no significant rate dependence of hadron-induced damage. A degradation of the energy resolution and a non-linear response to electron showers are observed in damaged crystals. Direct measurements of the light output from the crystals show the amplitude decreasing and pulse becoming faster as the fluence increases. The latter is interpreted, through comparison with simulation, as a side-effect of the degradation in light transmission. The experimental results obtained can be used to estimate the long term performance of the CMS ECAL. © CERN 2016.

The human prolactin-inducible protein / gross cystic disease fluid protein-15 (hPIP/GCDFP-15) is a secretory glycoprotein found primarily in apocrine tissues including the breast and salivary glands. With largely unknown functions, PIP has been implicated in breast cancer and metastasis, host defense processes and T lymphocyte apoptosis. To begin to address PIP function in vivo, we generated the PIP null mouse (Pip−/−mouse). Additionally, to determine the effect of the loss of PIP on gene expression and to gain insight into some of the molecular mechanisms underlying PIP function, microarray analysis of the submandibular gland was also undertaken. Pip−/−mice developed normally with no overt differences in behaviour or gross morphology and were fertile. However, histological examination of 3-month-old Pip−/−mice sometimes showed enlarged submandibular lymph nodes, lymphocytic aggregations within the prostate lobes, and enlarged medulla in the thymus. Functional analysis of gene expression revealed sets of multiple differentially expressed genes associated with cell death and survival, lipid metabolism, inflammation, immune disease, and cancer, as a consequence of mPIP abrogation. Taken together, these studies lend support to an immunomodulatory role for PIP in vivo and provide further insights into potentially novel signaling pathways and regulatory networks for PIP.

Elevated production of proprotein convertases (PCs), proteolytic enzymes that posttranslationally modify the biological activities of diverse groups of cellular proteins, is a common occurrence in human breast carcinomas. A transgenic mouse model was developed to gain insight into the significance of PC production in breast development and neoplasia. Mammary epithelium-specific and early expression of PC1 was targeted by the use of the mouse mammary tumor virus promoter/enhancer. Whole-mount examinations revealed that the mammary glands of 83-day-old virgin PC1 transgenic mice exhibited an accelerated lobuloalveolar development compared with that of age-matched wild-type mice (p < 0.001). This phenotypic change was accompanied by extensive alterations in gene expression assessed by gene expression microarray analyses. Pathway analysis of PC1-induced alterations in gene expression has revealed possible mechanism of action of PC1 in the mammary gland. PC1 expression alone, however, did not promote spontaneous mammary tumorigenesis in the transgenic mice. PC1 transgene expression resulted in a significantly higher incidence (p = 0.008) and accelerated growth (p = 0.023) of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary adenocarcinomas. The present study therefore shows that PC1 expression can promote normal and neoplastic mammary development and growth and suggests that proprotein convertases may be important etiological factors in human breast neoplasia.

Although the primary response to Adriamycin (doxorubicin) in p53 mutant MDA-MB231 and p53 null MCF-7/E6 breast tumor cells is apoptotic cell death, the residual surviving population appears to be in a state of senescence, based on cell morphology, beta galactosidase staining, induction of p21(waf1/cip1) and down regulation of cdc2/cdk1. Suppression of apoptosis in MDA-MB231 and MCF-7/E6 cells treated with Adriamycin using the broad spectrum caspase inhibitor, zvad-Fmk, results in substantial induction of autophagy. Overall sensitivity to Adriamycin, measured by clonogenic survival, is not altered in the cells undergoing autophagy, consistent with autophagy contributing to cell death in response to Adriamycin. The free radical scavengers, glutathione and N-acetyl cysteine attenuate the accelerated senescence response to Adriamycin in MCF-7 cells as well as in MDA-MB231 and MCF-7/E6 cells, but protect primarily the MCF-7 cells, indicating that reactive oxygen is unlikely to be directly responsible for Adriamycin toxicity in breast tumor cells. Expression of caspase 3 or induced expression of c-myc in MCF-7 cells fails to abrogate accelerated senescence induced by Adriamycin. Taken together, these studies suggest that accelerated senescence induced by Adriamycin is similar in cells with wild type p53 and in cells lacking functional p53 with regard to the upregulation of p21(waf1/cip1), down regulation of cdc2 and the involvement of reactive oxygen species. Furthermore, accelerated senescence, autophagy and apoptosis all appear to be effective in suppressing self-renewal capacity in breast tumor cells exposed to Adriamycin.

The material response of the constrained microcrystalline cellulose particles during the manufacture of bilayer tablets has been investigated. This work exploits the ability of a non-contact optical profilometer to elucidate both the intricate roughness detail and the inherent form of a compacted sample surface within one measurement. Thus the effects of the imposed non-uniform stress pattern that develops during the two sequential compaction cycles have been determined. The indirect measurement procedure has been able to infer the degree of particle deformation and hence the relative local porosity can be determined. The application of two compaction cycles has shown to exasperate the inhomogeneity of the localised regions of stored elastic strain energy and this is highlighted by the non-uniform and complex ejected tablet geometry. The localised stored energy release by volume expansion in the radial direction is thought to be responsible for the fracture of tablets during the ejection phase of the manufacturing process. When the magnitude of the final layer compaction stress is greater than the initial layer compaction stress the radial volume expansion can even result in the rupture of junctions between particles in the adjacent layers at the periphery of the interfacial zone. Thus the energy dissipation by volume expansion is a possible explanation for the stress concentrating crack commonly present at interfacial boundary zone within the bilayer formulations.

Metallothioneins (MTs) are low-molecular-weight proteins whose physiologic roles are the regulation of essential metals Cu and Zn, sequestration of heavy metals, and free radical scavenging. Induced production of MTs in a wide variety of organisms exposed to heavy metals has made them popular exposure indicators. While it has been postulated that the three different isoforms of MT play different physiologic roles, methods to discern induction separately have not been available. The development of real-time polymerase chain reaction (real-time PCR) primers and TaqMan probes to measure the two MT isoforms found in salmonid fish are described. Assuming a high degree of homology between the isoforms and within different groups of salmonids, the sequences for MT-I and MT-II from rainbow trout were used to develop primers and probes for lake trout using the Primer3 program. Two sections of each isoform that varied by only a few nucleotides were targeted. SYBR Green validated the primer specificity, and melt curve analysis further ensured that only one product was amplified. Analysis of archived samples from fish captured in unmanipulated reference lakes or from lakes experimentally treated with cadmium or ethynylestradiol (EE2) afforded an examination of seasonal and contaminant influences on MT-I and MT-II mRNA expression.

A voltage-mode first-order allpass filter using one differential difference current conveyor (DDCC), one grounded capacitor and one floating resistor is presented. No passive component matching constraints are required. Because the output impedance of the proposed allpass filter is low, the output terminal can be directly connected to the next stage. Using the proposed first-order allpass filter as a basic building block, a new quadrature oscillator and even-phase sinusoidal oscillators can be obtained. The simulation results confirm the theoretical analysis.

Internet shopping is overwhelmingly predicted to grow although opinion differs on the pace of growth. Growth is anticipated particularly for those countries with a large number of Internet users. One reason for this prediction of growth is the assertion that the Internet is an internationalised product or idea that appeals to a cross-national consumer segment who possess common personal characteristics and exhibit similar Internet shopping behaviour. This article explores this assertion. The article integrates the two conventional approaches to Internet consumer research, i.e. within-country analysis and between-country analysis, to search for a cross-national consumer segment group. Britain and Taiwan are selected for conducting this cross-national study. National survey data sets collected for each of the two countries are used. Intra-country analysis shows that demographic structures of Internet shoppers respectively in Britain and Taiwan are quite different. Internet shoppers can be segmented more cle...

OBJECTIVES To investigate the public's knowledge and attitudes about cardiopulmonary resuscitation in Hong Kong. DESIGN Cross-sectional telephone survey. SETTING Hong Kong. PARTICIPANTS Hong Kong residents aged 15 to 64 years. MAIN OUTCOME MEASURES The knowledge and attitudes towards cardiopulmonary resuscitation. RESULTS Among the 1013 respondents, only 214 (21%) reported that they had received cardiopulmonary resuscitation training. The majority (72%) of these trained respondents had had their latest training more than 2 years earlier. The main reasons for not being involved in cardiopulmonary resuscitation training included lack of time or interest, and "not necessary". People with full-time jobs and higher levels of education were more likely to have such training. Respondents stating they had received cardiopulmonary resuscitation training were more willing to try it if needed at home (odds ratio=3.3; 95% confidence interval, 2.4-4.6; P

Variations in the mechanical strength of aggregates with aggregate cross-sectional area have been modelled in this work. The fractal structures of aggregates were considered in conjunction with fundamental mechanisms of aggregate formation and rupture during the modelling. A quantitative expression of aggregate porosity and characteristic length in terms of aggregate fractal dimensions was derived from fractal dimensional analysis. Predictions from this expression and the Rumpf's equation demonstrated that tensile strengths of aggregates decreased with increasing aggregate cross-sectional area. An experimentally determined function was introduced into the model to account for the effect of fractal characteristic length on aggregate strengths, enabling one to predict the compression strength of aggregates. The predictions of compression strength agree well with the experimental data measured for latex aggregates when compressed between two parallel plates.

Estradiol is known to play an important role in the growth and differentiation of rat uterine stromal cells into decidual cells. In particular, this hormone with progesterone is necessary for blastocyst implantation and subsequent decidualization in the rat. Although binding experiments have demonstrated the presence of estrogenbinding sites, no evidence exists as to whether the rat decidua expresses both isoforms of the estrogen receptor (ER), a and b. In this investigation, we analyzed the expression of decidual ERa and ERb, studied their regulation by PRL and steroid hormones and examined the ability of decidual ERb to transduce the estradiol signal to the progesterone receptor. Immunocytochemistry, RT-PCR, and Northern blot analysis showed that both ER species are coexpressed in the decidua during pseudopregnancy. Interestingly, these genes were preferentially found in a cell population localized in the antimesometrial site of the uterus where blastocyst implantation takes place. Using decidual cells in primary culture obtained from pseudopregnant rats and a decidua-derived cell line (GG-AD), we show a differential regulation of ERa and ERb by PRL and ovarian steroid hormones. Whereas PRL, estradiol, and progesterone all increased ERb messenger RNA (mRNA) expression in a dose-dependent manner, only PRL up-regulated the mRNA levels of ERa. Estradiol had no effect on ERa expression, whereas progesterone markedly decreased its mRNA levels. Interestingly, progesterone, which up-regulates the ability of PRL to signal to a PRL-regulated gene in mammary-gland derived cells, prevented PRL stimulation of decidual ERa and had no synergistic effect on ERb expression. The use of GG-AD cells, which express only ERb, allowed us to demonstrate that this receptor subtype is functional and transduces estradiol signal to the progesterone receptor. In summary, the results of this investigation have revealed that ERb is expressed in addition to ERa in the rat decidua, and that the expression of both ERs are cell specific and differentially regulated by PRL and steroids. One salient finding of this investigation is that progesterone down-regulates ERa, but concomitantly increases the expression of a functional ERb that mediates estradiol up-regulation of the decidual progesterone receptor. (Endocrinology 141: 3842‐3851, 2000)

Protein kinase C (PKC) delta is dramatically upregulated in the corpus luteum in the second half of pregnancy in the rat. To gain insight into the hormonal regulation of PKC delta expression, studies were undertaken to analyze the regulation of PKC delta expression in a luteinized rat granulosa cell model. PKC delta protein expression was evaluated in luteinized granulosa cells, isolated from human (h)CG-treated immature female rats 7 h after the injection of an ovulatory dose of hCG and cultured up to 12 days. Cytochrome P450 cholesterol side chain cleavage enzyme expression was observed throughout the culture period, and a majority of the cells expressed steroidogenic acute regulatory protein and responded to rat placental lactogen (rPL)-1 by exhibiting hypertrophy, consistent with maintenance of the luteal phenotype. Both PKC delta protein and mRNA expression increased 3.5-4-fold with time of culture, and PKC delta mRNA expression could be eliminated by treatment of cells with the PKC inhibitor GF109203X. E(2) caused a specific dose- and time-dependent increase in expression of PKC delta protein of twofold, whereas PKC delta mRNA was unaffected by E(2) over a 12-day culture period. Treatment of cells with 500 ng/ml rPL-1 for the final 4 days of a 12-day culture in the absence of E(2) had no effect on PKC delta protein or mRNA expression, while treatment with 500 or 3000 ng/ml rPL-1 in the presence of E(2) significantly enhanced both PKC delta protein and mRNA expression (up to threefold). These results show that two of the major regulators of luteal function in the second half of pregnancy in the rat, E(2) and rPL-1, cooperate to regulate PKC delta expression in luteinized granulosa cells.

The ability of PRL or rat placental lactogen (rPL)-1 to induce relaxin mRNA expression was analyzed in a luteinized rat granulosa cell culture model. PRL receptor activation induced relaxin mRNA expression in a concentration- and time-dependent manner. High concentrations of PRL receptor agonist, equivalent to those of the second half of pregnancy in rats, were required to elicit relaxin mRNA expression. A 40-fold induction of relaxin mRNA was observed in cells treated 24 h with 1 microg/ml of rPL-1. Estrogen enhanced relaxin expression induced by PRL but did not affect relaxin expression on its own. PRL/rPL-1 induction of relaxin expression was independent of the extracellular regulated kinase (ERK) members of the mitogen-activated protein kinase (MAPK) pathway, based on the inability of the ERK kinase inhibitor PD98059 to block induction of relaxin expression. PRL/rPL-1 induction of relaxin expression required protein kinase C (PKC) delta, based on the ability of the preferential PKC delta inhibitor rottlerin to abolish induction of relaxin expression. Direct activation of PKC by phorbol myristate acetate, however, was not sufficient to promote induction of relaxin mRNA expression. Stats (signal transducers and activators of transcription) 3 and 5 DNA binding activities were induced by PRL/rPL-1 treatment of luteinized granulosa cells but only Stat 3 DNA binding was reduced by rottlerin. PRL/rPL-1 treatment of luteinized granulosa cells resulted in increased phosphorylation on tyrosine-705 and serine-727 of Stat 3, and these responses were reduced and blocked, respectively, by rottlerin. Tyrosine and serine phosphorylations of Stat 3 in the corpus luteum were also increased in the second half of pregnancy when PL levels are highest. Stat 3, but not Stat 1 or 5, coimmunoprecipitated with luteal PKC delta during pregnancy; Stat 3 transiently coimmunoprecipitated with PKC delta from luteinized granulosa cells in response to PRL receptor activation; and Stat 3/PKC delta complex formation required PKC delta kinase activity. Taken together, these results show that PKC delta is obligatory for PRL/rPL-1-dependent relaxin expression, that PKC delta complexes with Stat 3 in response to PRL receptor activation, and that PKC delta is involved in the regulation of Stat 3 phosphorylation downstream of the PRL receptor. These results demonstrate that PRL/rPL-1 promotes relaxin expression in luteal cells and that this event is mediated, at least in part, via PKC delta.

The prolactin-inducible protein (PIP/GCPD15) is believed to originate from a limited set of tissues, including breast and salivary glands, and has been applied as a clinical marker for the diagnosis of metastatic tumours of unknown origin. We have investigated the potential role of PIP mRNA as a marker of human breast cancer metastasis. Using reverse transcription polymerase chain reaction and Southern or dot blot analysis, PIP mRNA was detected in 4/6 breast cell lines, independent of oestrogen receptor (ER) status. In breast primary tumours (n = 97), analysed from histologically characterized sections, PIP mRNA was detected in most cases. Higher PIP mRNA levels correlated with ER+ (P = 0.0004), progesterone receptor positive (PR+) (P = 0.0167), low-grade (P = 0.0195) tumours, and also PIP protein levels assessed by immunohistochemistry (n = 19, P = 0.0319). PIP mRNA expression was also detectable in 11/16 (69%) of axillary node metastases. PIP mRNA expression, however, was also detected in normal breast duct epithelium, skin, salivary gland and peripheral blood leucocyte samples from normal individuals. We conclude that PIP mRNA is frequently expressed in both primary human breast tumours and nodal metastases. However, the presence of PIP expression in skin creates a potential source of contamination in venepuncture samples that should be considered in its application as a marker for breast tumour micrometastases. © 1999 Cancer Research Campaign

A micromanipulation method is described for measuring the bursting forces of bacteria and relating them to cell size. At a compression speed of 6.2 μm s−1, bursting forces of three samples of rapidly growing Staphylococcus epidermis from a batch culture varied from 3 to 34 μN with an average value of 13.8 μN (standard error 0.8 μN). Escherichia coli grown in continuous culture at a specific growth rate of 0.5 h−1 had bursting forces varying from 1 to 9 μN with an average value of 3.6 μN (standard error 0.4 μN). In squeeze-hold experiments, force relaxation was observed, which was attributed to water loss from the cells, or viscoelasticity, or both. At high compression speed, such as 6.2 μm s−1, this relaxation could be neglected. Micromanipulation strength measurements might be used in studies of cell mechanical disruption and of the dependence of cell strength on cell physiology.

As a first step towards elucidating the role that pro-protein convertases play in the growth regulation of breast cancer, we studied the gene expression of 6 known human convertase members (PC1/PC3, PC2, furin/PACE, PACE4, PC5/PC6 and PC7/LPC) in human breast cancer tumors and cell lines. PC1, furin, PACE4 and PC7 mRNAs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) amplification in all 7 human breast cancer cell lines and 30 breast tumor tissues tested. PC5 expression was detected in 2/30 tumor tissues. PC2 mRNA, however, was not detected. In situ hybridization localized furin mRNA to the tumor cells; adjacent fibrous stroma and blood vessel elements were negative for furin gene expression. Thirty breast tumors with varying quantities of estrogen and progesterone receptors were assayed for furin, PACE4 and PC1 mRNAs by quantitative RT-PCR, and 22 tumors were assayed for PC7 mRNA. An apparent association was observed only between PACE4 and estrogen receptors. No statistically significant correlation was found between the levels of steroid receptors and the expression of human furin, PC1 and PC7 genes. Convertase mRNA levels appeared similar in both the estrogen-responsive and -unresponsive breast cancer cell lines. Also, pro-protein convertase mRNAs were not detected in 9 histologically normal human breast tissues. These results suggest that elevated expression of some members of the pro-protein convertase gene family is a characteristic of human breast cancer, an event which may be important for human breast tumorigenesis.Int. J. Cancer 71: 966-971, 1997. © 1997 Wiley-Liss Inc.

The rat placenta expresses two rat placental lactogen-I (rPL-I) proteins: the normal rPL-I in the first half of pregnancy and a variant (rPL-Iv) in the second half of pregnancy. They are 70% identical at the amino acid level but arise from different cell types: rPL-I from giant cells and rPL-Iv from cytotrophoblasts. To assess whether rPL-Iv originates from alternative splicing of the rPL-I gene or is the product of a separate gene, genomic clones of rPL-I and rPL-Iv were isolated from a lambda EMBL-3 rat genomic library. Restriction enzyme analysis of the 14-kilobase full-length genomic clones of rPL-I and rPL-Iv indicated that the two genes are distinct. To assess the biological activity of the variant protein relative to other members of the rat PL/PRL/GH family, two expression systems were chosen to obtain the purified recombinant protein: 1) a secreted form of rPL-Iv was obtained from Chinese hamster ovary (CHO) cells transfected with rPL-Iv-complementary DNA; and 2) a rPL-Iv fusion protein (Bac-rPL-Iv) was obtained from Spodoptera frugiperda (Sf9) insect cells that had been infected with a recombinant baculovirus generated from rPL-Iv complementary DNA. An antibody was generated to the purified Bac-rPL-Iv fusion protein and used for affinity chromatography to purify recombinant rPL-Iv from the CHO cell media. The mitogenic activity of rPL-Iv was monitored in the Nb2 lymphoma cell bioassay. The relative potency of rPL-Iv compared with other members of the PL/PRL/GH family follows: ovine PRL 100, rPL-I 200, rPL-II 160, rPRL 40, CHO-rPL-Iv 0.7, and Bac rPL-Iv 0.4. Iodinated CHO-rPL-Iv showed minimal binding to Nb2 lymphoma cells, but at a 500-fold protein concentration rPL-I was able to displace [125I]rPL-I from the lymphoma cell PRL receptor. Using recombinant CHO-derived rPL-Iv as standard and antisera against the Bac-rPL-Iv fusion protein, a RIA was developed for rPL-Iv. In pregnant rats rPL-Iv appeared in the serum at day 14, rising to a peak of 2080 +/- 440 ng/ml at day 18, followed by a slight decline. These values reflect the levels of messenger RNA for rPL-Iv in rat placenta noted previously. In summary, rPL-Iv arises from a gene different from rPL-I and the rPL-I protein displays minimal binding and mitogenic activity in the Nb2 lymphoma cells.

The possible role of the conceptus in stimulating the onset of maternal behavior through its secretion of placental lactogens and their passage into the brain was investigated in female rats. In the first study, significant mitogenic activity in the Nb2 lymphoma cell bioassay was detected in cerebrospinal fluid (CSF) samples collected by push-pull perfusion from rats on days 12–21 of pregnancy, coincident with the establishment of placental function. In contrast, mitogenic activity was absent from CSF in lactating and gonadectomized, virgin females. In a second study the mitogenic activity in day 12 pregnant samples was neutralized 71% with antibodies to rat placental lactogen-I (rPL-I) and > 90% with a combination of antibodies to rPL-I plus rPL-II. In contrast, activity on day 21 of pregnancy, 1 day prepartum, was reduced by antibodies to rPL-II (>85%), but not by antibodies to rPL-I, indicating that the predominant lactogen in the CSF prepartum is rPL-II. The behavioral actions of placental secretions were assessed in the third experiment by infusing recombinant rPL-I and purified rPL-II directly into the medial preoptic area of the brain of steroid-primed, nulliparous rats. Latencies to respond maternally to foster young were significantly reduced in rPL-I- and rPL-II-treated rats (2- to 3-day latencies) when compared with latencies in control females (5- to 6-day latencies). Thus, the conceptus through its secretion of rPLs which apparently gain access to the CSF helps to prime the pregnant female’s brain to respond maternally at the end of gestation. This endocrine communication between the developing conceptus and pregnant female appears to be an important part of the biological system which helps to establish successful maternal care.

This paper presents the decentralized fault-tolerant tracker based on the model predictive control (MPC) for a class of unknown interconnected large-scale sampled-data nonlinear systems. Due to the computational requirements of MPC and the system information is unknown, the observer/Kalman filter identification (OKID) method is utilized to determine decentralized appropriate (low-) order discrete-time linear models. Then, to overcome the effect of modeling error on the identified linear model of each subsystem, the improved observers with the high-gain property based on the digital redesign approach will be presented. Once fault is detected in each decentralized controller, one of the backup control configurations in each decentralized subsystem is switched to using the soft switching approach. Thus, the decentralized fault-tolerant control with the closed-loop decoupling property can be achieved through the above approach with high-gain property decentralized observer/tracker.

The secretion of peptide 23 by rat pituitary cells is stimulated by growth hormone-releasing hormone and inhibited by somatostatin. Recent cloning of the cognate cDNA for peptide 23 revealed that it is identical to pancreatitis-associated protein (PAP). In the present study, the clearance and tissue uptake of recombinant peptide 23/PAP in normal adult male rats was assessed. The plasma half-life of recombinant peptide 23/PAP was 4·8 ±1·4 (s.d.) min. Maximal accumulation of radiolabelled peptide 23/PAP was observed in the kidney, stomach, small intestine and pancreas whereas negligible uptake was seen in the liver, lung or heart. Peptide 23/PAP was detected in a variety of tissue extracts using a radioimmunoassay. Extracts of ileum contained the highest concentrations of peptide 23/PAP. In situ hybridization analysis showed that peptide 23/PAP mRNA was highly expressed in the columnar epithelial cells of ileum, jejunum and duodenum. These observations demonstrate that peptide 23/PAP, a protein previously thought to be of pituitary origin, is widely expressed in the gastrointestinal tract and that it is rapidly removed from the circulation by the kidney and by tissues which express peptide 23/PAP. Journal of Endocrinology (1995) 145, 461–469

Peptide 23 was first identified in pituitary cell conditioned medium as a secreted protein which was regulated in a similar fashion to growth hormone. It was subsequently found to be a member of the C-type lectin gene superfamily and identical to pancreatis associated protein (PAP). It is widely expressed in the gastrointestinal tract. Our present study demonstrates that peptide 23 gene is also expressed in the uterus. Peptide 23/PAP mRNA was at highest levels during estrus and was not detectable in the immature rat uterus. A single injection of 17 beta-estradiol resulted in a transient induction of peptide 23/PAP mRNA in ovariectomized rats whereas a sustained induction was seen with diethylstilbestrol implants. In situ hybridization localized peptide 23/PAP mRNA to the luminal epithelial cells. During gestation, peptide 23/PAP mRNA was detected only in the uterine samples from day 12 to 18 of pregnancy with maximal expression on day 12. Peptide 23 expression was confined to the uterus itself and not expressed in either the decidua or the fetal tissues. PSP/reg, another closely related member of the C-lectin gene family was not expressed in any of these uterine tissues. These results indicate that estrogen may act as a physiological regulator of peptide 23 in the uterus and suggests that this protein may have some role in estrogen action.

Two-dimensional lattices of chiral nanoholes in a plasmonic film with lattice constants being slightly larger than light wavelength are proposed for effective control of polarization and spatial properties of light beams. Effective polarization conversion and strong circular dichroism in non-zero diffraction orders in these chiral metafilms are demonstrated by electromagnetic simulations. These interesting effects are found to result from interplay between radiation pattern of single chiral nanohole and diffraction pattern of the planar lattice, and can be manipulated by varying wavelength and polarization of incoming light as well as period of metastructure and refractive indexes of substrate and overlayer. Therefore, this work offers a novel paradigm for developing planar chiral metafilm-based optical devices with controllable polarization state, spatial orientation and intensity of outgoing light.

The functional and structural interactions of two androgen receptor-binding sites in the 5'-flanking DNA of the rat probasin gene were determined. Deletion mapping and DNase I footprinting analysis had previously identified two androgen receptor-binding sites (ARBS) necessary for androgen induction of the probasin gene: ARBS-1, which resembled a glucocorticoid-responsive element, and ARBS-2, which had a unique sequence. In this study, maximal androgen induction in transient transfection studies only occurred when both sites were present. Neither binding site functioned independently, and deletion of the DNA sequence between the sites resulted in a 60% loss of androgen inducibility. Moreover, point mutations in either ARBS-1 or ARBS-2 led to > 90% loss in activity. Scatchard analysis indicated that ARBS-1 and ARBS-2 bound a synthetic androgen receptor, AR2, with Kd values of 20.0 and 6.7 nM, respectively. Consistent with the higher affinity, ARBS-2 bound AR2 at half the threshold concentration (200 ng) of that required in reciprocal DNase I footprinting experiments with ARBS-1. By comparison, protection occurred at a much lower threshold concentration of AR2 (60 ng) and to the same extent over each site when both sites were present, suggesting a cooperative interaction between the two sites. The cooperative effect was further substantiated when a point mutation in ARBS-1 blocked AR2 binding not only to ARBS-1, but also to ARBS-2. Similarly, a point mutation in ARBS-2 also prevented receptor binding to both sites. Androgen-specific regulation of probasin gene transcription therefore required an androgen-responsive region (positions -286 and +28) containing two androgen receptor-binding sites, where the binding of the androgen receptor to both sites occurred in a cooperative, mutually dependent manner.

A vision-based control of SMA-actuated polymer gripper with force sensing is implemented and tested. The gripper system consists of PU (polyurethane) mechanism of gripper with force sensing arm, SMA actuator, and visual-based position and force sensing system. The information of gripper motion is tracked by utilizing computer-vision method through extended Regional Edge Statistics (ERES) algorithm. The position information of gripper tips together with the deflection of force sensing arm is utilized for sensing force. Closed-loop control including PI, PI-FF (PI with feedforward), and FE-PI (fuzzy expert PI) controller are implemented and tested. FE-PI controller is employed for testing the performance of sensing gripping force in grasping of 38μm metal rod.

To clarify the roles of the rat placental lactogens in embryogenesis and fetal development, we measured the concentrations of rat placental lactogen-II (rPL-II) in fetal rat serum and examined the distribution and expression of rPL-I- and rPL-II-binding sites in rat uteroplacental and fetal tissues. The concentration of rPL-II in fetal rat serum on day 20 of gestation was 28.3 +/- 0.8 ng/ml (mean +/- SEM; n = 6), approximately 1/14th its concentration in maternal serum (398.3 +/- 45.3 ng/ml; n = 6). In the midgestational uterus and placenta, rat PL-I bound specifically to mesometrial decidua and to a capsular layer of stroma overlying the antimesometrial decidua. The binding of radiolabeled rPL-I to these tissues was inhibited by unlabeled rat PRL and human (h) GH, but not by rat GH, suggesting that the rPL-I-binding sites are lactogenic in nature. In the late gestational fetus, rat PL-II bound specifically to fetal adrenal, kidney, small intestine, liver, and pancreas; its binding, like that of rPL-I, was inhibited by rPRL, but not by rGH. rPL-II-binding sites in fetal adrenal were detected as early as day 16, whereas rPL-II-binding sites in fetal kidney and small intestine were not demonstrable until day 18. Lactogenic binding sites in fetal liver and pancreas did not appear until days 19-20. The relative amounts of specific binding of rPL-II to fetal tissues correlated positively with tissue levels of expression of the 4.2- and 1.8-kilobase PRL receptor mRNA transcripts. Radiolabeled hGH, which interacts with somatogenic receptors as well as lactogenic receptors, bound specifically to mesometrial decidua, fetal adrenal, kidney, small intestine, liver, and pancreas. In addition, radiolabeled hGH bound specifically, but with low intensity, to fetal brain. In mesometrial decidua and fetal adrenal, kidney, and small intestine, the binding of hGH was blocked by rPL-II and rPRL, but not by rGH or ovine GH, suggesting the predominance of lactogenic receptors. In contrast, in fetal brain, the binding of hGH was inhibited by rGH, but not by rPL-II, suggesting that the fetal brain contains somatogenic receptors. The presence of rPL-I-binding sites in maternal decidua suggests a paracrine role for the hormone in decidual function at midgestation. The presence of rPL-II in fetal serum and the widespread distribution of rPL-II-binding sites in fetal tissues indicate a role for rPL-II in fetal development.

BACKGROUND Amplification of the c-myc gene (also known as MYC) occurs in up to 20%-30% of breast cancers and has been associated with poor prognosis. PURPOSE The purpose of this study was to define the relationship between c-myc amplification and breast cancer progression in order to better understand the biological significance of c-myc amplification. METHODS We identified invasive tumors with grossly detectable c-myc amplification by using Southern blot analysis to examine frozen tissue from 135 breast carcinomas and polymerase chain reaction (PCR) analysis to examine archival paraffin-embedded tissue from an additional 19 invasive tumors. These 19 tumors were selected on the basis of histologically identifiable in situ and invasive components within the primary tumor and associated lymph node metastases. Amplification of c-myc in these areas was then assessed by quantitative PCR assay. RESULTS We detected gross c-myc amplification in 10 of the tumors examined--eight of the 135 frozen tissue specimens and two of the 19 archival specimens. We selected five of these 10 invasive tumors for further regional analysis. In all four cases where an in situ component was present, amplification of c-myc was present in both the in situ and the invasive components. However, c-myc amplification was present in the corresponding nodal metastases in only two of the four cases where this could be examined. CONCLUSION These results suggest that c-myc amplification can occur at an early stage in tumor progression and that amplification does not always persist in the nodal metastasis.