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Dendritic cells (DCs) are antigen-presenting cells that provide a link between innate and adaptive immunity. Ca(2+)-dependent signaling plays a central regulatory role in DC responses to diverse antigens. DCs are a primary target of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a secosteroid hormone, that, in addition to its well-established action on Ca(2+) homeostasis, possesses immunomodulatory properties. Surprisingly, nothing is known about its effects on DC cytosolic Ca(2+) activity. The present study explored whether 1,25(OH)(2)D(3) modifies the intracellular Ca(2+) concentration ([Ca(2+)](i)) in DCs. Here we show that mouse DCs expressed K(+)-independent (NCX1-3) and K(+)-dependent (NCKX1, 3, 4, and 5) Na(+)/Ca(2+) exchangers. Acute application of LPS (100 ng/ml) to DCs increased [Ca(2+)](i), an effect significantly blunted by prior incubation with 1,25(OH)(2)D(3). 1,25(OH)(2)D(3) increased the membrane abundance of the NCKX1 protein, up-regulated the K(+)- and Na(+)-dependent Ca(2+) entry and enhanced the K(+)-dependent Na(+)/Ca(2+) exchanger currents. The NCKX blocker 3',4'-dichlorobenzamyl (DBZ) reversed the inhibitory effect of 1,25(OH)(2)D(3) on the LPS-induced increase of [Ca(2+)](i). Expression of the costimulatory molecule CD86 was down-regulated by 1,25(OH)(2)D(3), an effect reversed by DBZ. In summary, 1,25(OH)(2)D(3) blunts the LPS-induced increase in [Ca(2+)](i) by stimulation of Na(+)/Ca(2+) exchanger-dependent Ca(2+) extrusion, an effect that contributes to 1,25(OH)(2)D(3)-mediated immunosuppression. The results disclose completely novel mechanisms in the regulation of DC maturation and function.

[1] Polarimetric radar variables and ground-based raindrop size distributions (DSDs) of two convective cells in a Baiu frontal rainband over the Okinawa region were analyzed to clarify the precipitation particle distributions in convective cells with low echo top heights. One cell existed in the stratiform rain zone, and the other was in the convective rain zone of the rainband. Both cells had echo top (30 dBZ) heights of approximately 5.5 km above sea level, with large radar reflectivity (Z h ) greater than 50 dBZ in each core. For the cell in the stratiform rain zone, polarimetric variables indicated that small raindrops predominated; differential reflectivity (Z DR ) was smaller than 1.5 dB, and the correlation coefficient (ρ hv ) was greater than 0.98 with large Z h (>40 dBZ). The DSD showed high number densities of small raindrops with diameters of 1-2 mm. For the other cell, polarimetric variables indicated the presence of large raindrops; Z DR greater than 1.5 dB and ρ hv smaller than 0.98 predominated in large Z h (>40 dBZ). The DSD for this cell showed lower number densities of raindrops with diameters of 1-2 mm and higher number densities of raindrops exceeding 3 mm. The significance of these distributions was confirmed by the Z DR and ρ hv for 25 cells in the stratiform rain zone and for 28 cells in the convective rain zone. It is notable that different precipitation particle distributions in convective cells were found in the stratiform and convective rain zones of a Baiu frontal rainband with common characteristics of low echo top heights and large Z h .

The short-term prediction of hail has been investigated by a thorough analysis of high-resolution radar data. This contribution consists of two parts. Part I presents prediction models for radar parameters of hailfall intensity whereas Part II considers the prediction of the location of hailfall occurrence. The available data of 209 hail cells have been divided into two equally sized groups: one sample was used for estimates of the model coefficients whereas the second sample was used for an independent test about the performance of the prediction models. Three different statistical models for predictions of the hailfall parameters have been defined: a persistence model, an autoregressive time-series model and a more general regression model. The residual mean square of the prediction errors is about 20–30% smaller when using the regression model instead of the persistence model or the autoregressive model. A major part of the error reduction is attributed to predictor variables which characterize the height and the extent of the 50 dBZ contour. A secondary result of this study is the periodic behaviour of the maximum radar reflectivity of hail cells. A spectral analysis of the data has shown that the peaks of maximum radar reflectivity tend to appear in time intervals of about 15 min. This periodic property is attributed to a weak-evolution behaviour that is characteristic for “Swiss-type” hail cells.

Employing a multi-year radar database of precipitation in a mid-Atlantic coast region, the authors have characterized rain cell size statistics. The measurements were made with a high resolution, high power radar in which equicircle diameter contours of resolutions of 1 km and greater were identified out to ranges of 100 km from the radar. The rain cell was constructed by its core intensity isopleth and a family of enveloping contours having defined rain rate intervals in the regions between them. The isopleth statistics were extracted from a database of cores with rain level number 7 (18-24 mm/h) and greater. >

Two pituitary adenylate cyclase-activating polypeptide (PACAP)-signaling pathways linked to schizophrenia were reviewed. One pathway regulates the association between disrupted-in-schizophrenia 1 (DISC1) and DISC1-binding zinc-finger protein via PACAP, and the other inhibits stathmin1 expression via PACAP. PACAP reduces the association of the binding between DISC1 (a potential susceptibility gene for major psychiatric disease) and DISC1-binding zinc-finger protein (which binds to DISC1 near the translocation site) to induce neurite outgrowth. In addition, an association between SNPs of the PACAP or PAC1 genes and schizophrenia has been reported. On the other hand, expression of stathmin1, which induces abnormal axonal arborization, is upregulated in PACAP-knock out mice and the brains of patients with schizophrenia. Thus it is likely that, in the schizophrenic brain, the neural development depending on these two systems has been disturbed. The possibility that the regulation of these two systems could lead to new treatments for schizophrenia is also discussed.

[1] The effects of multiple scattering on larger precipitating hydrometers have an influence on measurements of the spaceborne W-band (94 GHz) CloudSat radar. This study presents initial quantitative estimates of these effects in “dry” snow using radiative transfer calculations for appropriate snowfall models. It is shown that these effects become significant (i.e., greater than approximately 1 dB) when snowfall radar reflectivity factors are greater than about 10–15 dBZ. Reflectivity enhancement due to multiple scattering can reach 4–5 dB in heavier stratiform snowfalls. Multiple scattering effects counteract signal attenuation, so the observed CloudSat reflectivity factors in snowfall could be relatively close to the values that would be observed in the case of single scattering and the absence of attenuation.

Raindrops impacting the rough sea modify its surface and its backscattering coefficient. This roughness change essentially depends on the rain content in very large drops, which is highly variable from one drop size distribution model to another. However, it has been observed that the radar reflectivity of raindrops has a drop size dependence very similar to that of the ringwaves induced by rain on the surface. From a numerical analysis on various drop size distributions, rain rates, and frequencies from 3 to 35 GHz, a relationship between the sea surface elevation variance of ringwaves resulting from drop impact and the rain radar reflectivity Z is established. It is found to be weakly dependent on the raindrop size distribution model. This link is expected to lead to better estimates of the surface roughness, and in turn, via electromagnetic scattering models, it could improve algorithms for near nadir rain radar retrieval.

[1] Knowledge of rain cell size distribution is relevant for the modeling and design of Earth-space communication systems. Long-term rain rate time series were processed to determine the spatial structure of rain cells by applying the synthetic storm technique assuming some known value of storm translation speed. Using a 3 1/2 year record of rain rate at Sparsholt, UK, the size distributions of rain fields were determined using rain cell translation speeds derived from analysis of radar plan position indicator scans. The results were compared with distributions of rain cell sizes determined directly from 66 radar reflectivity scans performed in seven rain events and found to give cell sizes in the region of 10 km for rain cells of threshold ≥ 20 mm/h.

Disrupted-in-Schizophrenia 1 (DISC1) and its molecular cascade have been implicated in the pathophysiology of major psychoses. Previously, we identified pericentrin 2 (PCNT2) and DISC1-binding zinc finger protein (DBZ) as binding partners of DISC1; further, we observed elevated expression of PCNT2 in the postmortem brains and in the lymphocytes of bipolar disorder patients, compared to controls. Here, we examined the association of PCNT2 with schizophrenia in a case–control study of Japanese cohorts. We also examined the association of DBZ with schizophrenia and with bipolar disorder, and compared the mRNA levels of DBZ in the postmortem brains of schizophrenia, bipolar and control samples. DNA from 180 schizophrenia patients 201 controls were used for the association study of PCNT2 and DBZ with schizophrenia. Association of DBZ with bipolar disorder was examined in DNA from 238 bipolar patients and 240 age- and gender-matched controls. We observed significant allelic and genotypic associations of the PCNT2 SNPs, rs2249057, rs2268524, and rs2073380 (Ser/Arg) with schizophrenia; the association of rs2249057 (P = 0.002) withstand multiple testing correction. Several two SNP- and three SNP-haplotypes showed significant associations; the associations of haplotypes involving rs2249057 withstand multiple testing correction. No associations were observed for DBZ with schizophrenia or with bipolar disorder; further, there was no significant difference between the DBZ mRNA levels of control, schizophrenia and bipolar postmortem brains. We suggest a possible role of PCNT2 in the pathogenesis of schizophrenia. Abnormalities of PCNT2, the centrosomal protein essential for microtubule organization, may be suggested to lead to neurodevelopmental abnormalities. © 2009 Wiley-Liss, Inc.

In this study, the accuracy of reflectivity measured using vertically pointing profiling radars is investigated. Interesting, while disdrometer observations are used to absolutely calibrate profiling radars, this study quantifies that disdrometers have significantly larger random measurement uncertainty than profiling radars. Using observations from a S-band profiling radar during the Tropical Warm Pool International Cloud Experiment (TWPICE), reflectivity uncertainties of rainfall were found to be about 0.25 dBZ for 9-second dwell times and about 0.1 dBZ for 60-second dwell times. It was also found that the reflectivity uncertainty was dependent on both the signal-to-noise ratio and the number of velocity channels in the Doppler velocity power spectrum above the noise threshold. This lead to the reflectivity uncertainty for snow which has narrower velocity spectra than rain to increase to 0.4 and 0.2 dBZ for 9- and 60-second dwell times, respectively.

För att kalibrera väderradarna i Sverige finns en miniräknare med program som styr kalibreringen. Deluppgiften ”Program för kalibrering” innebär att överföra dessa program till en PC. Då ingen dokumentation finns om hur kommunikationen sker mellan radar och miniräknare, är första steget att analysera och jämföra programkoden från miniräknaren med informationen från en linjelyssnare. Därefter skrivs programmen i det grafiska programmeringsspråket Agilent Vee. Programmen läser av radarns svar på signaler med olika dämpning från en signalgenerator, beräknar en radarkonstant, skapar en kalibreringstabell, samt programmerar kalibreringstabellen i radarns signalprocessor. Datorns mätvärden och beräkningar jämförs med miniräknarens, och det kan konstateras att programmen överensstämmer med varandra. Deluppgiften ”Automatiserad kontroll av dämpsteg” innebär att med en spektrumanalysator läsa av effekten på en signal med varierande dämpning från en signalgenerator. Detta görs för att kontrollera dämpstegen, då man på Saab Aerotech upptäckt problem med signalgeneratorn. Ett program skrivs för att automatiskt styra både signalgenerator och spektrumanalysator. Den avlästa effekten vid varje dämpsteg sparas och en graf med dessa värden genereras automatiskt av programmet. I grafen återfås en linjär kurva, vilket är det förväntade utseendet vid fungerande dämpsteg. För en ytterligare kontroll läses effekten av vid varje enskild dämpare. Även dessa värden ligger inom accepterade gränser, vilket innebär att problemet ligger på annat håll i signalgeneratorn, än i dämpstegen., A calculator is used to calibrate all the weather radars in Sweden. One part of this thesis is to transfer the programs on this calculator to a PC. There is no documentation on how the calculator communicates with the radar, so the first step is to analyze and compare the code from the program with the information shown on a protocol analyzer. When the communication is known, a program is written in the language Agilent Vee. One program reads the response from the radar of a signal with different attenuation. Others calculates the radar constant, generates a calibration table and programs the table to the signal processor in the radar. By comparing the result from the programs on the PC and the corresponding results from the calculator it is verified that the programs run correctly. Saab Aerotech have found that the signal generator in not working correctly. The other part of this thesis is to automatically control the signal generator and a spectrum analyzer. The spectrum analyzer reads the power of a signal with different attenuation from the signal generator and presents the values in a graph. The curve of the graph is linear which means that there is no problem with the attenuation.

This paper extends some first steps given in merging radar and rain gauge data for a better understanding of rainfall rate spatial structure. The study has been performed analyzing spatial correlation between sites within a densely meshed rain gauge network and also with their corresponding pixels in weather radar images.

[1] The layer-mean radar reflectivity e observed by CloudSat and the columnar effective particle radius Re obtained from a combined microwave-shortwave analysis are combined to investigate the joint relationships between e and Re for warm clouds. Global statistics for seasonally averaged data reveals that radar reflectivities e less than about −10 dBZ tend to relate to the effective radius via a sixth-power dependency, corresponding to a constant number concentration implying that the condensation particle growth process mainly takes place within the cloud layer for e −10 dBZ, e depends on Re through a cubic relation, corresponding to a constant mass concentration implying coagulation as the dominant particle growth process. These microphysical regimes so identified are shown to be consistent with CloudSat-inferred rainfall rate.

High-resolution 10 cm radar data from 209 severe convective cells are investigated. The areal distribution of radar reflectivity is fitted by a three-parameter power law. It is found that the exponent of the power law is on the order of two. This means, that a simplified area- Z relationship exists, which contains only two radar parameters: a maximum reflectivity parameter and a reflectivity gradient parameter. The agreement between hailfall parameters derived directly from radar measurements and computed using the two radar parameters is excellent. We conclude that the two parameters represent important aspects of the structure of hail cells and suggest that consideration be given to use of this parameterization scheme in all types of hail cell models.

A differential reflectivity radar technique for observing hailstorms is demonstrated using measurements obtained during the 13 June 1984 Denver hailstorm. The hail regions of the storm are identified with the differential reflectivity hail signal. Histograms of ZH and ZDR are generated for different heights in the hail regions and the relative variation of these parameters is also determined. It is observed that due to melting, the mean values of ZH and ZDR increase with decreasing height below the 0°C level (which is around 2.6 km above ground level). Furthermore, at the lower levels ZDR varies between −1 and +2 dB and ZH is generally greater than 50 dBZ. The value of ZH peaks at around 60 dBZ or more when ZDR is in the range −0.5 to 0 dB and 1.5 to 2 dB at 1.5 km and 2 km below the 0°C level, respectively. These and other features of ZH and ZDR are interpreted in terms of the size, shape and fall behavior of the hailstones using the dual wavelength ratio and the linear depolarization ratio rada...

[1] Analysis of the collocated rain retrievals from Tropical Rainfall Measuring Mission's precipitation radar and microwave radiometer reveals that their difference depends on the intensity and the type of rain – the radiometer-derived rain rates vary from higher to lower than the radar-derived ones as rain rate or convective fraction increases. To better understand how this difference occurs, the relations between the two leading EOFs (Empirical Orthogonal Functions) of the observed brightness temperatures and the radiometer- or radar-derived rain rates were examined for convective, mixed and non-convective rain categories. In all types of rain, the two EOFs respond to the variation of the radiometer- and radar-derived rain rates in a similar fashion in low rain rates, while they respond quite differently in high rain rates.

In this paper an approach is described to improve weather radar estimates of rainfall based on a neural network technique. Other than rain gauges which measure the rain rate R directly on the ground, the weather radar measures the reflectivity Z aloft and the rain rate has to be determined over a Z-R relationship. Besides the fact that the rain rate has to be estimated from the reflectivity many other sources of possible errors are inherent to the radar system. In other words the radar measurements contain an amount of observation noise which makes it a demanding task to train the network properly. A feed-forward neural network with Z values as input vector was trained to predict the rain rate R on the ground. The results indicate that the model is able to generalize and the determined input-output relationship is also representative for other sites nearby with similar conditions.

Divergent synthesis of multifunctional molecular probes based on caprolactam-derived dipeptidic gamma-secretase inhibitors (GSIs), Compound E (CE) and LY411575 analogue (DBZ), was efficiently accomplished by means of Cu(I)-catalyzed azide/alkyne fusion reaction. Photoaffinity labeling experiments using these derivatives coupled to photoactivatable and biotin moieties provided direct evidence that the molecular targets of CE and DBZ are the N-terminal fragment of presenilin 1 within the gamma-secretase complex. Moreover, these photoprobes directly targeted signal peptide peptidase. These data suggest that the divergent synthesis of molecular probes has been successfully applied to characterize the interaction of GSIs with their molecular targets and define the structural requirements for inhibitor binding to intramembrane-cleaving proteases.

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1;11) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To investigate how DISC1 confers susceptibility to psychiatric disorders, we previously identified fasciculation and elongation protein zeta-1 and Kendrin as DISC1-interacting molecules in a yeast two-hybrid screen of a human brain complementary DNA library. Here, we have further identified a novel DISC1-interacting protein, termed DISC1-Binding Zinc-finger protein (DBZ), which has a predicted C(2)H(2)-type zinc-finger motif and coiled-coil domains. DBZ was co-immunoprecipitated with DISC1 in lysates of PC12 cells and rat brain tissue. The domain of DISC1 interacting with DBZ was close to the translocation breakpoint in the DISC1 gene. DBZ messenger RNA (mRNA) was expressed in human brains, but not in peripheral tissues. In situ hybridization revealed high expression of DBZ mRNA in the hippocampus, olfactory tubercle, cerebral cortex and striatum in rats. Because this pattern of localization was similar to that of the pituitary adenylate cyclase (PAC(1)) receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), which has recently been implicated in neuropsychological functions, we examined whether DISC1/DBZ interaction was involved in the PACAP signaling pathway. PACAP upregulated DISC1 expression and markedly reduced the association between DISC1 and DBZ in PC12 cells. A DISC1-binding domain of DBZ reduced the neurite length in PC12 cells after PACAP stimulation and in primary cultured hippocampal neurons. The present results provide some new molecular insights into the mechanisms of neuronal development and neuropsychiatric disorders.

[1] Attenuation of radar signals in rain increases with frequency while the variability of non-attenuated reflectivity of rainfall diminishes as resonance scattering effects become more pronounced at higher radar frequencies. At mm-wavelength frequencies, attenuation often becomes the dominant factor responsible for apparent reflectivity changes in vertical. This study presents an attenuation-based method to retrieve vertical profiles of rain rate from nadir-pointing W-band (94 GHz) radars. The quantitative assessments of retrieval errors are discussed, and an illustration of the retrievals using measurements from the spaceborne 94 GHz CloudSat radar is shown. As a consistency check, the spaceborne W-band radar retrievals are compared with concurrent estimates from a ground-based weather surveillance radar.

A statistical study of two groups of storms that occurred in the Paris area (France) during summer 2000 has been realized. The first group includes 26 high radar reflectivity (HRR) storms with radar reflectivity values exceeding 60 dBZ while the second one includes 19 moderate radar reflectivity (MRR) storms with a maximum radar reflectivity value between 50 and 55 dBZ. The radar reflectivity was provided by a C-band radar and the total lightning activity (cloud-to-ground (CG) and intra-cloud (IC) flashes) was provided by the French Météorage network and a Safir device. HRR storms seem to be characterized by a longer lifetime, and a more extended convective area. On average, they produce more CG and IC flashes than MRR storms. However, a large variability in the number, the rate, and the type of flashes is observed. The HRR storms producing the highest IC flash rates (above 100 min− 1) exhibit the lowest CG flash proportion (1.2 and 4.3%). Most of the HRR storms exhibit a peak lightning activity when the radar reflectivity is strong at low level within the cloud. However, several cases of these storms show a large time lag between the strong lightning production and the presence of high radar reflectivity values at low level. Some possible explanations of these observations, taking into account cloud dynamics, microphysics and lightning initiation, are discussed.

Radar measurements of rain intensity are of great practical importance and usually based on radar reflectivity. But this characteristic depends on type of precipitations, season, latitude etc. and that is why it is reasonable to use additional characteristics of precipitations (clouds) that may be connected with fluctuations of the radar signals scattered from meteorological objects. In this report the design and parameters of the double band radar for study of fluctuations of signals scattered by precipitations and clouds are presented. It was showed that spectrum width contains Gauss dependence in energetic area of the spectrum (>−16 dB) and power dependence in periphery of the spectrum (

A straightforward linkage between rain cell dynamics in terms of reflectivity Z (dBz) or its equivalent rain rate R (mm/h) and satellite or terrestrial radiolink attenuation can be performed. This work focuses on the presentation of an approach for assessing and characterizing rain cell dynamics based exclusively on the analysis of the radar reflectivity scans recorded in weather radar image, and without an a priori assumption on the structure of rain cells. This research has been addressed by using cellular automata. Rain cell dynamics are simulated by using probabilistic cellular automata rules and tracking vectors which indicate a global advection direction and velocity.

The main object of this paper is to emphasize that clouds—the nonprecipitating component of condensed atmospheric water—can produce a strong attenuation at operational microwave frequencies, although they present a low reflectivity preventing their radar detection. By way of a simple and realistic model, simulations of radar observations through warm precipitating targets are thus presented in order to quantify cloud attenuation. Simulations concern an airborne radar oriented downward and observing precipitation at four frequencies: 3, 10, 35, and 94 GHz. Two cases are first considered: a convective cell (vigorous cumulus congestus plus rain) and a stratiform one (nimbostratus plus drizzle) superimposed on the previous one. Other simulations are then performed on different types of cumulus (congestus, mediocris, and humilis) with various thicknesses characterized, in a microphysical sense, by their maximum liquid water content. Simulations confirm the low cumulus reflectivity ranging from −45 dBZ for the weakest cumulus (i.e., the humilis one) to −5 dBZ for the strongest one (i.e., the vigorous cumulus congestus). It reaches −35 dBZ for the nimbostratus cloud. On the other hand, cumulus attenuation [precisely path-integrated cloud attenuation (PICA)] is not negligible and, depending on the frequency, can be very strong: the higher the frequency, the stronger the PICA. At 3 GHz, the far less attenuated frequency, PICA for the vigorous cumulus congestus alone in the convective cell (embedded into the stratiform background) is on the order of 1.2 dB (1.5 dB) at 10 GHz, 16 dB (20 dB) at 35 GHz, and 80 dB (100 dB) at 94 GHz. For weaker cumulus, PICA is lower but, in certain cases, significant. All these results mean that it is necessary to be very careful about radar measurements if reliable information on precipitation—for example, the precipitation rate R—has to be deduced, particularly at high operational frequencies.

EarthCARE Phase-A study was successfully conducted in collaboration between ESA and Japan (JAXA and NICT). In this study, high sensitivity Cloud Profiling Radar (CPR) design with Doppler capability was studied and demonstrated that the CPR satisfies mission requirements, system resource and launcher constraint. As a result of the study, a nadir looking CPR at 94 GHz with a 2.5 m diameter antenna reflector is designed with sensitivity exceeding -36 dBZ of requirement at TOA with 10 km horizontal integration. The Doppler measurement is a new challenge to attain velocity accuracy less than 1 m/s in vertical direction. In parallel to the CPR system design, algorithm development efforts have been conducted through field campaign. A suite of measured quantities that are very similar combination to the EarthCARE data was collected and applied to the retrieval algorithm test.

The vicinity of KSC, where the primary ground truth site of the Tropical Rainfall Measuring Mission (TRMM) program is located, was the focal point of the Convection and Precipitation/Electrification (CaPE) experiment in Jul. and Aug. 1991. In addition to several specialized radars, local coverage was provided by the C-band (5 cm) radar at Patrick AFB. Point measurements of rain rate were provided by tipping bucket rain gage networks. Besides these ground-based activities, airborne radar measurements with X- and Ka-band nadir-looking radars on board an aircraft were also recorded. A unique combination data set of airborne radar observations with ground-based observations was obtained in the summer convective rain regime of central Florida. We present a comparison of these data intending a preliminary validation. A convective rain event was observed simultaneously by all three instrument types on the evening of 27 Jul. 1991. The high resolution aircraft radar was flown over convective cells with tops exceeding 10 km and observed reflectivities of 40 to 50 dBZ at 4 to 5 km altitude, while the low resolution surface radar observed 35 to 55 dBZ echoes and a rain gage indicated maximum surface rain rates exceeding 100 mm/hr. The height profile of reflectivity measured with the airborne radar show an attenuation of 6.5 dB/km (two way) for X-band, corresponding to a rainfall rate of 95 mm/hr.

[1] Serial reflectivity measurements from paired instruments are examined during two field campaigns in order to examine the precision of the measurements. The instruments studied are two collocated Joss-Waldvogel disdrometers (JWD) at Wallops Island, VA and two collocated profilers deployed at Ji-Parana, Brazil during Tropical Rainfall Measuring Mission (TRMM) Large-Scale Biosphere-Atmosphere Experiment. Differencing the measured reflectivity from the instrument pairs eliminated most of the temporal and large-scale precipitation variability, reducing the error fluctuations to those of the instrument precision plus fluctuations due to precipitation variability over the small differences in sample volume and distances between the instruments. For both pairs of calibrated instruments we found that the observed time-series of one-minute dBZ differences were not autocorrelated and exhibited a Gaussian-like distribution. Consequently, the difference time-series could be meaningfully characterized by their standard statistics, including the rms difference or standard deviation, and the standard error about the mean. While the disdrometer pair exhibited an rms difference of 2.1 dBZ, a standard error about the mean of less than 0.1 dBZ for the 12-hour rain event was achieved. The profiler pair exhibited an rms difference of 0.4 dBZ, with a standard error of only 0.05 dBZ for the 90-minute stratiform rain event. Since it is currently difficult to routinely calibrate radars in an absolute sense to better than 1–3 dBZ, the precisions of a few tenths of a dBZ obtained here suggest the potential for substantially improving these calibrations, and open the door to examination of subtle sampling and stability effects.

It is anticipated that gamma-secretase inhibitors (gamma-Sec-I) that modulate Notch processing will alter differentiation in tissues whose architecture is governed by Notch signaling. To explore this hypothesis, Han Wistar rats were dosed for up to 5 days with 10-100 micromol/kg b.i.d. gamma-Sec-I from three chemical series that inhibit Notch processing in vitro at various potencies (Notch IC(50)). These included an arylsulfonamide (AS) (142 nM), a dibenzazepine (DBZ) (1.7 nM), and a benzodiazepine (BZ) (2.2 nM). The DBZ and BZ caused dose-dependent intestinal goblet cell metaplasia. In contrast, the AS produced no detectable in vivo toxicity, despite higher exposure to free drug. In a time course using BZ, small intestinal crypt cell and large intestinal glandular cell epithelial apoptosis was observed on days 1-5, followed by goblet cell metaplasia on days 2-5 and crypt epithelial and glandular epithelial regenerative hyperplasia on days 4-5. Gene expression profiling of duodenal samples from BZ-dosed animals revealed significant time-dependent deregulation of mRNAs for various panendocrine, hormonal, and transcription factor genes. Somatostatin, secretin, mucin, CCK, and gastrin mRNAs were elevated twofold or more by day 2, and a number of candidate "early-predictive" genes were altered on days 1-2, remaining changed for 4-5 days; these included Delta1, NeuroD, Hes1-regulated adipsin, and the Hes-regulated transcriptional activator of gut secretory lineage differentiation, the rat homolog of Drosophila atonal, Rath1. Western blotting of fecal protein from BZ-and DBZ-dosed animals exhibited increased levels of both anti-Rath1 reactive protein and anti-adipsin reactive proteins, confirming their potential value as noninvasive biomarkers of intestinal goblet metaplasia.

[1] An assessment on the performance of a dual-wavelength (13.6/35.0 GHz) precipitation radar to observe snow and rain from space is drawn based on a simplified model, so-called noncoalescence and nonbreakup model, for falling hydrometeors. The simulation, first, generates vertical profiles of dual-wavelength radar integral parameters using raindrop size distribution (DSD) data measured at ground. The simulation results are then compared with some typical observations. Despite many uncertainties and assumptions, the simulated reflectivity profiles have shown some degrees of consistency with observations. The results based on statistical analysis of the simulated effective reflectivity factors (Zes) at 13.6 (Ze14) and 35 (Ze35) GHz radar frequencies indicate that: (1) rain and dry snow signatures are separable, if Ze14 is above ∼10 dBZ, (2) separation of rain and wet snow signatures is feasible, only if Ze14 is between ∼25 and ∼45 dBZ, while above ∼45 dBZ (Ze14) rain and wet snow signatures are poorly separable, and (3) separation of Ze signatures for dry and wet snow is rarely feasible. Moreover, from the analysis of the maximum allowable fluctuation in the standard deviations in Zes for rain and snow (dry and wet), this study proposes “rain/snow discrimination thresholds”. The rain/snow separation aspect is also studied with different distributions of snow density. Also, this study proposes conventional type Ze14-R relationships for snowfall rate retrieval for dry and wet snow regions.

[1] This paper presents the results and analyses of Doppler radar measurements taken as part of a long-term campaign conducted in Singapore. Eight months of data taken in the zenith-pointing mode have been analyzed, in order to examine the validity of the assumptions underlying the retrieval algorithm proposed for the precipitation radar on board the TRMM satellite. Stratiform and convective events were analyzed separately. The former exhibits a clear melting layer in the 4–5 km height region, defined by an enhancement in the radar reflectivity, an increase in the mean fall velocity from 1–2 m/s in the snow region just above the melting layer to over 8 m/s in the rain region just below it. The corresponding width increases from less than 1 m/s to greater than 1 m/s. The variation in all three parameters can be accurately represented by the Noncoalescence-Nonbreakup melting layer model used for the satellite radar retrieval algorithms. Also examined was the monthly variation of the reflectivity-height profiles. In the rain region below the melting layer, a consistent decrease in the radar reflectivity with decreasing height is seen, indicating that the drop size distribution (DSD) cannot be assumed constant over all heights. However, if only the parameter N0 of the DSD is assumed constant, then good agreement is obtained between the mean velocity estimated from the reflectivity data and the measured velocity throughout the height profile. The agreement is also obtained in the spectrum width profile in the rain region. Convective precipitation on the other hand, does not exhibit a melting layer, and its averaged dBZ and velocity profiles cannot be characterized even under the constant N0 assumption. Its averaged reflectivity-height profiles show more variability than stratiform precipitation. For such cases, factors such as up and down drafts and nonstandard atmosphere need to be taken into account. The implication for the so-called N0 adjustment method is that while it can be applied to stratiform precipitation, the convective events need additional information, such as dual-frequency radar measurements, in order to improve the accuracy of the rainfall estimates.

This study establishes new relations between the microstructure and the dynamics of rain and Doppler-polarimetric parameters of the radar signal. The rain rate and intensity of turbulence in rain can be retrieved on this basis.

Using a data clustering method, monthly statistics are calculated from rain rate estimates of the TRMM Precipitation Radar. The statistics show how the following variables change with the size of a rain event: convective rain rate, total rain rate, and convective rain fraction. On average, the convective rain fraction is found to be greatest for small mesoscale events covering 10/sup 3/ km/sup 2/, while rain rate increases monotonically with the size of the rain event.

Polarimetric radar has been successful in characterizing cloud and precipitation. Polarization parameters such as radar reflectivity (Z), differential reflectivity (Z DR ), linear reflectivity difference (Z DP ), and specific differential propagation phase shift (K DP ) provide more information about precipitation and allow better characterization of hydrometeors, accurate rain rate estimation, and retrieval of rain drop size distribution (DSD). In the past, rain rate (R) estimation from S-Pol was based on empirical models such as Z-R, R (Z, Z DR ) and R (K DP ) relations, which were derived from regression analyses of radar and rain gauge measurements or numerical simulations, and are prone to errors. In this paper, we derive various rain estimators using a physically-based raindrop size distribution (DSD) model: constrained Gamma DSD. The constrain condition, the shape-slope relation in Gamma DSD, is derived from video-disdrometer observations and has been shown to represent a physical nature of rain and useful in rain DSD retrievals from remote measurements. The relation is then used to retrieve rain DSDs from two remote measurements and t derive rain estimators from polarimetric radar measurements. The derived rain estimators are then used to retrieve rain parameters from S-pol measurements. The results are also verified and compared with ground measurements.

A technique for the identification of the microphysical characteristics of stratiform precipitation is presented. It allows to estimate the attenuation at microwave frequencies from radar measurements of reflectivity.

Multiparameter polarimetric radar measurements have been made during passage of a mesoscale convective system (MCS) through Oklahoma on June 9, 1993. Joint analysis of radar reflectivity, differential reflectivity, and specific differential phase in the squall line reveals hail aloft and an excess of large raindrops with ice cores that originated from melting hail. The evolution of the melting layer in the stratiform part of the MCS, i.e., its depth and intensity, is investigated as well. >

The authors have performed radar backscattering measurements with a scatterometer in a wind-wave tank under different wind and rain conditions. The aim of these experiments was to gain further insight into those mechanisms which are responsible for the combined rain- and wind-induced modifications of the water-surface roughness and, thus, of the radar backscatter. The results from their measurements imply that the ratios of the co-polarization and cross-polarization backscatter may help to estimate rain rates, and therefore enable the authors to interpret radar images of rain cells more quantitatively.

This paper describes the results of preliminary analysis of the TRMM standard algorithm 2A25 which estimates the instantaneous vertical profile of rain from Precipitation Radar (PR) data. It first estimates the attenuation-corrected radar reflectivity factor from the measured reflectivity factor. The attenuation-corrected radar reflectivity factor (Z) is then converted to the rainfall rate (R) at each radar resolution cell. The major challenge of the algorithm lies in the attenuation correction that also takes into account the non-uniform beam filling effect. The attenuation correction is carried out with the combination of the Hitschfeld-Bordan method and the surface reference method. The bias in the attenuation estimate to the surface caused by the non-uniform distribution of rain is estimated from the spatial variations of the estimated total attenuations from the top of rain to the surface in the vicinity of the radar beam concerned. The Z-R relationship is also modified by the non-uniformity of rain distribution as well as rain type and height. The performance of the algorithm is analyzed with data in the initial phase of the mission. Results from such analysis are described.

Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease in the elderly. Activation of Notch1 pathway plays a critical role in the development of AAA, but the underlying mechanisms remain poorly understood. In the present study, we explored the mechanisms by which Notch1 activation regulates angiotensin II (Ang II)-induced AAA formation and evaluated the therapeutic potential of a new Notch γ-secretase inhibitor, dibenzazepine (DBZ), for the treatment of AAA. Apolipoprotein E knockout (Apo E(-/-)) mice infused for 4 weeks with Ang II (1000 ng/kg/min, IP) using osmotic mini-pumps were received an intraperitoneal injection of either vehicle or 1 mg/kg/d DBZ. Notch1 signaling was activated in AAA tissue from both Ang II-infused Apo E(-/-) mice and human undergoing AAA repair in vivo, with increased expression of Notch intracellular domain (NICD) and its target gene Hes1, and this effect was effectively blocked by DBZ. Moreover, infusion of Ang II markedly increased the incidence and severity of AAA in Apo E(-/-) mice. In contrast, inhibition of Notch activation by DBZ prevented AAA formation in vivo. Furthermore, DBZ markedly prevented Ang II-stimulated accumulation of macrophages and CD4(+) T cells, and ERK-mediated angiogenesis, simultaneously reversed Th2 response, in vivo. In conclusion, these findings provide new insight into the multiple mechanisms of Notch signaling involved in AAA formation and suggest that γ-secretase inhibitor DBZ might be a novel therapeutic drug for treating AAAS.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that accounts for 15% of childhood and 25% of adult ALLs. Constitutive activation of NOTCH signaling as result of activating mutations in the NOTCH1 gene is a hallmark of this disease and small molecule gamma-secretase inhibitors, which effectively block activation of the NOTCH1 receptor, have been proposed as targeted therapy. However, the progress of NOTCH1-blocking agents such as in the clinic has been limited. Here we hypothesized that detailed transcriptional profiling of T-ALL lymphoblasts upon inhibition of NOTCH1 signaling would uncover major effector pathways downstream of NOTCH1. Moreover, we proposed that these signatures would facilitate the identification of new drugs and drug combinations for the treatment of T-ALL. Gene expression profiling of NOTCH1 induced leukemias treated with DBZ, a highly active gamma-secretase inhibitor, identified numerous genes regulated by NOTCH1 in human leukemia. Notably these signatures were enriched in NOTCH1 direct target genes such as Hes1 and revealed a prominent role of NOTCH signaling in the control of cellular metabolic pathways. Following on these results we performed Connectiviy map analysis to identify drugs whose transcriptional effects could antagonize those of oncogenic NOTCH1 in human leukemia. This analysis identified HDAC inhibitors, anti-psychotic agents, anti-malarials and compounds targeting the PI3K and NFKB signaling pathways. Detailed analysis of the effects of these drugs alone and in combination with DBZ demonstrated strong antileukemic activity and strong synergism when combined with inhibition of NOTCH signaling with a gamma-secretase inhibitor. Moreover, biochemical and transcriptional profiling of these drugs identifies agents with unique and related mechanisms of action. Overall these results identify new antileukemic drugs with strongly synergistic activity in combination with NOTCH1 inhibition for the treatment of T-ALL Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A226. Citation Format: Marta Sanchez Martin, Alberto Ambesi, Daniel Herranz, Adolfo Ferrando. Identification of new synergistic compounds for the treatment of NOTCH-driven T-ALL. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A226.

The Rutherford Appleton Laboratory (RAL) is engaged in an experimental program to characterise precipitation in the tropics. We have developed and built a 3 GHz vertically pointing pulsed Doppler radar capable of measuring the co-polar reflectivity (Z), cross-polar reflectivity (LDR) and the full Doppler spectrum. The system has been installed at the University of Technology (Unitech) at Lae, Papua New Guinea. The radar system began a measurement campaign in December 1995. Unitech operates a receiver for the 12.75 GHz beacon of the Australian OPTUS-B satellite. The elevation angle of the satellite receiver is 72.8/spl deg/. The experiment yields valuable data on the slant path attenuation for comparison with radar predictions. The three principal parameters which are to be extracted from the radar data are the rainfall rate, the rain height and the rain drop-size distribution. The drop-size distribution is also being measured on the ground with a Jess distrometer. The rain events recorded with the radar can generally be classified into i) those which exhibit a clear, well defined bright band caused by the presence of the melting layer in stratiform precipitation, and ii) those which are convective with rain at heights often above 10 km and the Doppler data showing severe updrafts. The linear de-polarisation ratio (LDR) parameter is an excellent indicator of the melting layer which is an effective method of determining the top of the rain.

Background/Aim: The intestinal epithelium is a rapidly renewed tissue, requiring continual replenishment by intestinal stem cells (ISCs) in order to sustain life. The crypt base columnar cell (CBC) is an actively dividing ISC population marked by the expression of Lgr5, Ascl2, and Olfm4. Our recent studies show that Notch signaling regulates epithelial cell homeostasis by directing differentiated cell fate and promoting stem cell maintenance. In this study we examined Notch regulation of CBCs by characterizing Olfm4 expression and function. Methods: Gamma-secretase inhibitors (GSIs) were used to block Notch signaling in C57BL/ 6 mice (30μmol/kg dibenzazepine; DBZ) or in the human colon cancer cell line LS174T (40μM DAPT). Tissue was analyzed at various time points for progenitor and differentiated marker expression and epithelial proliferation by histological staining and qRT-PCR. LS174T cells were used to investigate the mechanism of Notch regulation of Olfm4 expression. Genetically engineered Olfm4-deficient mouse intestine was studied to examine the function of this CBC marker for intestinal epithelial cell homeostasis. Results: Chronic Notch inhibition for 6 days resulted in marked secretory cell hyperplasia, decreased cellular proliferation, and a striking decrease in Olfm4 mRNA, showing that Notch is critical for many different aspects of cellular renewal. Surprisingly, acute block of Notch with a single dose of DBZ was sufficient to cause a rapid and transient loss of Olfm4, in addition to a delayed, yet sustained surge in secretory cells and cellular proliferation. This surge in proliferation was in stark contrast to the loss of proliferation observed with chronic DBZ treatment. The acute DBZ model revealed exquisite Olfm4 regulation: mice treated with one dose showed a significant decrease in Olfm4 mRNA within 12 hours, but recovery to baseline within 2 days. Similarly, LS174T colon cancer cells showed decreased Olfm4 mRNA 4 hours after DAPT administration. To test whether changes in Olfm4 expression may mediate Notch effects in the intestine we examinedOlfm4-/mice. This analysis showed normal proliferation, cell fate, and CBC marker gene expression patterns, demonstrating that Olfm4 is not required for CBC function. However, we observed expression of other Olfactomedin family members in intestine, suggesting functional redundancy.Conclusions:Olfm4 is dynamically regulated by Notch signaling, with rapid loss of transcripts observed upon acute Notch inhibition. Thus this CBC marker is a sensitive read out of Notch activity in the intestine. Olfm4-/mice did not exhibit an intestinal phenotype, although related family members may play a compensatory role, suggesting compound mouse mutants may be needed to understand the function of Notch regulation of Olfm4 in the CBC.

Background/Aim: The intestinal epithelium is a rapidly renewed tissue, requiring continual replenishment by intestinal stem cells (ISCs) in order to sustain life. The crypt base columnar cell (CBC) is an actively dividing ISC population marked by the expression of Lgr5, Ascl2, and Olfm4. Our recent studies show that Notch signaling regulates epithelial cell homeostasis by directing differentiated cell fate and promoting stem cell maintenance. In this study we examined Notch regulation of CBCs by characterizing Olfm4 expression and function. Methods: Gamma-secretase inhibitors (GSIs) were used to block Notch signaling in C57BL/ 6 mice (30μmol/kg dibenzazepine; DBZ) or in the human colon cancer cell line LS174T (40μM DAPT). Tissue was analyzed at various time points for progenitor and differentiated marker expression and epithelial proliferation by histological staining and qRT-PCR. LS174T cells were used to investigate the mechanism of Notch regulation of Olfm4 expression. Genetically engineered Olfm4-deficient mouse intestine was studied to examine the function of this CBC marker for intestinal epithelial cell homeostasis. Results: Chronic Notch inhibition for 6 days resulted in marked secretory cell hyperplasia, decreased cellular proliferation, and a striking decrease in Olfm4 mRNA, showing that Notch is critical for many different aspects of cellular renewal. Surprisingly, acute block of Notch with a single dose of DBZ was sufficient to cause a rapid and transient loss of Olfm4, in addition to a delayed, yet sustained surge in secretory cells and cellular proliferation. This surge in proliferation was in stark contrast to the loss of proliferation observed with chronic DBZ treatment. The acute DBZ model revealed exquisite Olfm4 regulation: mice treated with one dose showed a significant decrease in Olfm4 mRNA within 12 hours, but recovery to baseline within 2 days. Similarly, LS174T colon cancer cells showed decreased Olfm4 mRNA 4 hours after DAPT administration. To test whether changes in Olfm4 expression may mediate Notch effects in the intestine we examinedOlfm4-/mice. This analysis showed normal proliferation, cell fate, and CBC marker gene expression patterns, demonstrating that Olfm4 is not required for CBC function. However, we observed expression of other Olfactomedin family members in intestine, suggesting functional redundancy.Conclusions:Olfm4 is dynamically regulated by Notch signaling, with rapid loss of transcripts observed upon acute Notch inhibition. Thus this CBC marker is a sensitive read out of Notch activity in the intestine. Olfm4-/mice did not exhibit an intestinal phenotype, although related family members may play a compensatory role, suggesting compound mouse mutants may be needed to understand the function of Notch regulation of Olfm4 in the CBC.

expression of OLFM4, Muc1, Muc2 and IL8 was measured by quantitative RT-PCR in 200 ileal and colonic biopsies of patients with active/inactive IBD and controls. OLFM4 immunostaining was performed in formalin fixed or carnoy-fixed and paraffin-embedded tissue. The mRNA levels of the major antimicrobial peptides in mice (Cryptidin-1, mBD1, mBD2), as well as mMuc1 and mMuc2 were measured in OLFM4 knock-out mice compared to wild type controls. The effect of bacterial stimulation with different apathogenic bacteria on OLFM4 expression was determined using the mucin producing colon carcinoma cell line LS174T in the presence and absence of DBZ, a gamma-secretase inhibitor blocking the Notch pathway.Results:As expected, IL8 expressionwas significantly augmented in inflamed biopsies with comparable levels in the active IBD subgroups. OLFM4 mRNAwas significantly induced in colonic inflamed vs. noninflamed Crohn′s disease (CD, 3.6-fold, p 0.0001) and colonic (2.3-fold, p

Notch and Wnt/β-catenin pathways play essential roles in intestinal development, homeostasis and neoplasia. Citrobacter rodentium (CR) induces transmissible murine colonic hyperplasia (TMCH) and variable degrees of inflammation and necrosis depending upon the genetic background. In the current study, we investigated functional cross-talk between the Notch and Wnt pathways and how they regulate colonic crypt hyperplasia and/or colitis in response to CR infection. Infection of NIH:Swiss outbred mice with CR induced gross thickening and rigidity of the distal colon and crypt hyperplasia which peaked by day 12, persisted until day 27 before declining by day 34. Nuclear staining for Notch target Hes-1 increased at days 6-27 before declining at day 34. Acute (5 days) treatment with Notch blocker dibenzazepine (DBZ; @10μmol/Kg) beginning on the 1st day of CR infection followed by euthanasia at day 6 blocked both Notch and Wnt signaling and induced goblet cells hyperplasia; acute DBZ treatment beginning on the 7th day of CR infection followed by euthanasia at day 12 inhibited Notch signaling without blocking the components of the Wnt pathway: both β-catenin and its downstream target Jagged-1, a Notch ligand, increased significantly at day 12 leading to crypt hyperplasia. Chronic (10 days) DBZ treatment beginning on the 1st day of CR infection followed by euthanasia at day 12 blocked both Notch and Wnt signaling, increased epithelial permeability and induced colitis. To directly establish that the disruption of mucus gel layer overlying the gut epithelium by DBZ may be the cause of colitis in CR infected animals, we utilized mice lacking Core 3 beta1,3-N-acetylglucosaminyltransferase, an enzyme important in synthesis of Core 3-derived O-glycans, the primary component of the intestinal mucins. The Core-3−/− mice are susceptible to experimental triggers of colitis. Infection of Core-3−/− mice with CR destroyed the intestinal barrier and induced colitis which was exacerbated following DBZ treatment. The changes accrued were not due to loss of colonic stemness as DBZ did not alter putative stem cell marker DCAMKL-1 expression in either strain. Dietary bael extract (4%) and curcumin (4%) restored the Notch/Wnt cross-talk and promoted crypt regeneration/hyperplasia in CR-infected/DBZ-treated SW mice. Thus, 1. TMCH exhibits active Notch and Wnt signaling. 2. Blocking Notch signaling early induces goblet cells hyperplasia but no colitis. 3. Acute but late stage blocking of Notch signaling does not abrogate Wnt/β-catenin-induced crypt hyperplasia. 4. Chronic defect in Notch signaling also blocks Wnt pathway and induces colitis in response to CR infection due to loss of barrier function and lack of crypt regeneration despite lack of alterations in colonic stemness. Thus, both Wnt and Notch cross-talk and epithelial barrier regulate hyperplasia and/or colitis in response to CR infection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2833. doi:10.1158/1538-7445.AM2011-2833

A method to estimate rainrate profiles from a nadir-looking rain radar operating at a rain attenuating frequency is described. The method takes the various phases of the hydrometeors into account such as ice, melting layer and temperature variation in the rain region. It uses a numerical method to retrieve attenuation-corrected radar reflectivity and estimates the drop size distribution in rain by using a constraint for the total path attenuation derived from sea-surface echoes. The method is tested using airbome radar measurements made at 10 GHz and 35 GHz over a typhoon event. Retrieved profiles of rain intensity are derived at each of the two frequencies separately and compared with each other. Results show very good agreement for stratiform rain with moderate rainrates. For a convective cell, however, the Ka-band signal loses its surface echo signal due to high rain attenuation, thus emphasising that 35 GHz is too high a frequency for measuring intense tropical storms.

Gamma-secretase inhibitors (GSIs), which block the activation of the NOTCH1 receptor, are currently being tested in the treatment of T-cell lymphoblastic leukemias (T-ALL) with activating mutations in the NOTCH1 gene. However, inhibition of NOTCH1 signaling induces only a delayed cytostatic antileukemic effect with little or no apoptosis and GSI treatment is associated with severe gastrointestinal toxicity, which limits the clinical application of these molecularly targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids reverses glucocorticoid resistance and is highly effective against T-ALL. Inhibition of NOTCH1 signaling with CompE, a highly active GSI, in combination with dexamethasone, induced apoptotic cell death in glucocorticoid-resistant T-ALL cell lines. The synergistic antileukemic effect of GSIs and glucocorticoids was effectively rescued by forced expression of ICN1, an intracellular form of NOTCH1 that does not require gamma-secretase processing; or by treatment with the glucocorticoid receptor antagonist RU486. Reversal of glucocorticoid resistance by CompE treatment was mediated by transcriptional upregulation of BIM, a BH3-only proapototic factor previously involved in glucocorticoid induced cell death. Thus, shRNA knock down of BIM effectively impaired the ability of CompE plus dexamethasone to induce programmed cell death in leukemic lymphoblasts. Using a mouse xenograft model of glucocorticoid-resistant T-ALL we demonstrated that the combination of DBZ, a GSI with well established activity in vivo, and dexamethasone is highly effective against glucocorticoid resistant T-ALL in vivo. All animals treated with DBZ plus dexamethasone showed complete clearance of leukemic lymphoblasts and improved survival, while mice treated with vehicle or dexamethasone alone died because of disease progression (P

Interpretation of radar observations of clouds employing millimetre waves may be confused by the presence of super-large drops in clouds. In the Letter, the effect of these drops on cloud attenuation (dB) and reflectivity (dBZ) is assessed, and the implications for radar system design discussed.