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Notch signaling represents a central pathway regulating hematopoiesis, stem cell differentiation, and malignant transformation in human cancer. Activation of highly conserved Notch1 receptors results in cleavage and release of an intracellular domain (ICN1). Following translocation to the nucleus, ICN1 forms a ternary complex with the transcriptional repressor CSL (CBF-1, Suppressor of Hairless and Lag-1) bound to cognate DNA. This event triggers a repressor-to-activator switch, as an interfacial groove is formed which recruits the Mastermind-Like (MAML1) co-activator protein. Activating mutations in NOTCH1 are found in more than 50% of patients with T-Cell Acute Lymphoblastic Leukemia (T-ALL), promoting protein stability and establishing a direct link to disease pathogenesis. Pharmacologic efforts to target the Notch pathway in T-ALL have been directed at gamma secretase, a regulatory enzyme in Notch activation. Recently, the observed clinical resistance to gamma secretase inhibitors has been explained, in part, by additional mutations in the Notch-targeting ubiquitin ligase, Fbxw7, which further increases oncoprotein stability. Therefore, direct inhibitors of ICN1 function are highly desirable. Drawing upon insights afforded by the resolved crystal structure of the DNA-bound ICN1:MAML1:CSL complex, we synthesized a series of hydrocarbon stapled alpha-helical peptides targeting Notch (SAHNs) based on minimal motifs of the MAML protein predicted to engage the composite ICN1:CSL interface. Direct, high-affinity binding to purified components of the Notch complex was confirmed using surface plasmon resonance (SPR). Nuclear access of SAHN1 was confirmed using quantitative epifluorescent and confocal microscopy. Intracellular association with ICN1 and CSL was established using bidirectional affinity chromatography. Using a novel CSL-responsive reporter construct, we observed inhibition of endogenous Notch transactivation by SAHN1 in T-ALL cell lines. Furthermore, SAHN1 induces a dose-dependent knockdown of endogenous Notch1 target genes including HES1, HEY1 and cMYC in T-ALL cell lines. Remarkably, inhibition of Notch signaling by SAHN1 confers selective cytotoxicity at 48 hours in a panel of T-ALL cell lines with known mutations in NOTCH, including those resistant to gamma secretase inhibitors. Supporting an on-target mechanism of action, we have prepared a damaged analogue of SAHN1 containing a two-residue rearrangement (SAHN1D). SAHN1D possesses reduced binding affinity for the Notch complex and despite comparable intracellular access, SAHN1D lacks both transcriptional and cytotoxic effects on cultured T-ALL cell lines in vitro. Efficacy studies have also been performed in vivo using a novel murine model of T-ALL. In summary, we report here the design, biochemical characterization and translational rationale supporting the first direct inhibitor of the Notch transactivation complex in T-ALL.

Ricin is an abundant protein from the castor bean plant Ricinus communis. Because of its high toxicity and the simplicity of producing mass quantities, ricin is considered a biological terrorism agent. We have characterized ricin extensively with a view to develop Reference Materials that could be used to test and calibrate detection devices. The characterization of ricin includes: 1) purity test of a commercial batch of ricin using electrophoresis in polyacrylamide gels, 2) biological activity assay by measuring its ability to inhibit protein synthesis, 3) quantitation of protein concentration by amino acid analysis, 4) detection of ricin by an immunoassay using a flow cytometer, and 5) detection of ricin genomic DNA by polymerase chain reaction using nine different primer sets. By implementing these five methods of characterization, we are in a position to develop a reference material for ricin.

The laser fluorescence method has been used to measure CO(ν=1) collisional transfer rates in several binary and ternary gas mixtures at 296°K. Excitation of the CO(ν=1) level was achieved using pulsed 4.6 μm radiation from a frequency doubled CO2 laser. The relative inertness of CO molecules towards V→T deactivation greatly facilitates the study of vibrational relaxation rates of the additive species in selected cases. In this paper, intermolecular V→V transfer rates at 296°K are reported for CO(ν=1) with N2O, OCS, SO2, CS2, C2N2, and for CO(ν=2) with CO. In addition, the additive deactivation rates were determined for the following collisional processes: N2O(001) with N2O, CO, Ar; OCS(001) with OCS, CO, Ar; CS2(001) with CS2, CO; and C2N2(00100) with C2N2 and CO.

Rate constants for the vibrational deactivation of CO in collisions with HD, D2, and He have been measured as a function of temperature using the laser excited vibrational fluorescence technique. Throughout the 109–630 °K range, CO–He and CO–HD samples exhibit a single exponential decay, dominated by V–T,R transfer, with rates increasing rapidly with temperature. Typical collision deactivation rate constants at 630 °K are 22.7 sec−1 torr−1 for He and 82.5 sec−1 torr−1 for HD, and, at 109 °K, 0.067 sec−1 torr−1 for He and 0.27 sec−1 torr−1 for HD. At low temperatures, diffusion and radiative decay become important contributions to the observed rates. In CO–D2 mixtures, double exponential decay of CO fluorescence at large D2 mole fractions is obtained, corresponding to rapid V–V transfer between the (v=1) vibrational levels of CO and D2, followed by coupled V–T,R deactivation. The V–V transfer rate (ΔE=−850 cm−1) increases from 0.26 sec−1 torr−1 at 202 °K to 69.4 sec−1 torr−1 at 633 °K. The V–T,R deactivation rate constant for excited CO by D2 is significantly slower than that by HD and H2, going from 0.089 sec−1 torr−1 at 156 °K to 3.7 sec−1 torr−1 at 450 °K, indicating the decreased importance of the rotational states of D2 in the deactivation of CO than hypothesized for H2 and HD. The deactivation of excited D2 by collisions with D2 also increases with temperature, ranging from 0.080 sec−1 torr−1 at 202 °K to 6.9 sec−1 torr−1 at 450 °K.

We report H2 V→V transfer rates to a number of simple molecules using a stimulated Raman vibrational fluorescence technique. The additive gases and respective rate constants (sec−1 torr−1) are HCl(1510±210), DCl(689±30), CO2(497±30), N2O(462±14), HBr(224±18), DBr(212±36), NO(42±17), 12CO(12.3±9.5), and 13CO(9.7±1.9). The ease of experimental data collection, even at total pressures as low as 70 torr, shows the utility and general application of this approach in the excitation of Raman active vibrations in simple systems.

Acetone extracts from a variety of rat tissues were tested for their ability to stimulate renal glucose-6-phosphate dehydrogenase (G6PD) activity at 2 min in an in-vitro cytochemical assay which is a marker of the sodium potassium-dependent adenosine triphosphatase (Na+-K+-ATPase) inhibiting activity. Extracts of the hypothalamus were the only ones found to be active in this system. Acetone extract of hypothalamus also inhibited renal Na+-K+-ATPase activity in vitro. The G6PD-stimulating activity from one hypothalamus was about 10000 to 100 000 times greater than that of 1 ml plasma. The G6PD-stimulating activity of hypothalamic extracts from rats which had been on a high sodium intake for 4 weeks were approximately 150 times more active than those obtained from rats which had been on a low sodium diet. The G6PD-stimulating activity of the corresponding plasma was sixfold more active. These findings suggest that a circulating sodium transport inhibitor(s) may be secreted from the hypothalamus.

Serum levels of mucin-like carcinoma associated antigen (MCA) were measured in 80 healthy women, 109 patients with breast cancer at presentation and in samples taken from 45 patients with active metastatic breast cancer. The MCA levels in controls had an upper limit of normal of 19.6 U ml-1 in post-menopausal and 16.4 U ml-1 in premenopausal women. The levels at presentation in stages I and II and III were not significantly different from the post-menopausal controls. Longitudinal studies over 5-9 years in 20 patients with stage I and II disease who had remained tumour-free showed a narrow MCA range for each individual patient, but the mean and range of a single measurement in a further 63 of these patients were similar to those of the normal controls. Rising MCA levels occurred in 12/14 patients who developed metastases in 2-8 years after surgery, but local recurrence was not associated with a rise of MCA. Eighty per cent of patients with active metastatic disease had MCA levels greater than 15 U ml-1. MCA levels fell during clinical responses to therapy in metastatic cancer. In the context of follow-up serum MCA levels appear to be a sensitive indicator of metastatic disease; caution is required in the interpretation of isolated measurements.

Deuterium fluoride vibrational energy transfer measurements have been performed at 198, 209, 232, 264, and 296°K using the laser excited vibrational fluorescence technique. Rate contants for the following processes have been determined: HF(v=1)+DF(v=0) →ke+k12 HF(v=0)+DF(v=1,0) ÷ΔE=1055,3962 cm−1, DF(v=1)+DF(v=0) →k222DF(v=0)+ΔE=2907 cm−1, DF(v=1)+Ar→k2mDF(v=0)+Ar+ΔE=2907 cm−1. Experimental results taken at 198, 209, and 232°K exhibited rate enhancements for increasing DF pressure which is most easily explained as HF(v=1) and DF(v=1) quenching by (DF)n. Relaxation rates in this regime were best described by the empirical equation τ−1=C exp(DPDF), where C and D are temperature dependent coefficients and PDF is the total DF pressure, [DF+(DF)n]. The variation τ−1 with exp(PDF) cannot be reconciled in terms of a monomer–dimer model only. Higher order terms (n=4 and 6) are expected to dominate the collisional quenching of HF(v=1) and DF(v=1). The characterization of (DF)n and its effect upon these studies are...

Analysis of human serum reactivities to the Schistosoma mansoni adult microsomal antigens (MAMA) showed that S. japonicum and S. haematobium infection sera, as a rule, did not react as well to MAMA as did the homologous S. mansoni infection sera. The degree of species specificity, although not absolute, was quite pronounced. Purification of the corresponding microsomal antigens from S. japonicum adults (JAMA) and subsequent assays with both homologous and heterologous infection sera show a distinct and reciprocating species specificity between S. mansoni and S. japonicum microsomal antigens. The specificities of these antigens were quantitated by k-ELISA. Qualitative analysis of active antigenic components for both JAMA and MAMA involved assay by the "Western blot" or enzyme-linked immunoelectrotransfer blot (EITB). The EITB patterns of both antigens, after resolution by SDS-PAGE, show species-specific reactive bands at the 16,000 to 35,000 m.w. region. S. japonicum-specific antigens are located at the 18,000 to 35,000 m.w. region whereas S. mansoni-specific antigens were associated with m.w. components of 16,000 to 29,000. High m.w. antigen components (greater than 40,000) of both JAMA and MAMA are recognized by both heterologous and homologous infection sera and are thus not species specific. The demonstration of the clear separation of species-specific antigen bands of JAMA and MAMA by physical size offers a unique opportunity to isolate and characterize the species specificities of antibody-antigen reactions in these parasitic infections.

This instrument measures the three-dimensional (3-D) distribution function of positive ions at the UKS. Novel electrostatic analyzers using 2600 turning angle cover all viewing angles as the spacecraft rotates. The instrument has sufficient resolution to measure the solar wind as well as giving full 3-D coverage within a spin period. The operation of the experiment and organization of the data are synchronized to the spacecraft spin. A sample of the real-time data showing magnetospheric boundary crossings is presented.

The purified Schistosoma mansoni adult microsomal antigen, MAMA, was used in the quantitative single-tube kinetic dependent enzyme-linked immunosorbent assay (k-ELISA) to measure antibody levels of various human patient sera. The 511 serum specimens tested were from patients with both homologous and heterologous infections. Sera from U.S., Egyptian, Brazilian, and Puerto Rican patients infected with S. mansoni reacted strongly with MAMA. Chinese patients infected with S. japonicum, and Nigerians or Egyptians infected with S. haematobium produced much lower responses to this antigen than those infected with S. mansoni. Sera from patients with echinococcosis, filariasis, paragonimiasis, clonorchiasis, trichinosis, amebiasis, and hepatitis and from healthy uninfected control individuals generally contained no detectable antibodies against this antigen. The S. mansoni adult microsomal antigen, MAMA, therefore, appears to be a highly potent and specific reagent for the serodiagnosis of S. mansoni infections.

Collisional quenching of carbon monoxide by hydrogen and nitrogen has been studied in the 100–650°K temperature range using the laser excited vibrational fluorescence method. The rate constant for CO–H2 deactivation increases smoothly with temperature from 2.6±0.3 sec−1·Torr−1 at 112°K to 170±15 sec−1·Torr−1 at 623°K. The vibration‐to‐vibration energy transfer results for CO–N2 mixtures (exothermic direction) show only a slight temperature dependence from 103 to 651°K with a broad maximum of 420±30 sec−1·Torr−1 in the temperature range 300–400°K. Comparison of our rates with high temperature shock tubes results show excellent agreement for the CO–H2 V → R,T process and only fair agreement for the CO–N2 V → V exchange process. This latter discrepancy may be partially due to the uncertainties involved in extracting V → V energy transfer rates from shock tube data.

Vibrational energy transfer rates in CO2–CO mixtures have been measured from 163 to 406 °K using the laser excited vibrational fluorescence method. The near resonant V→V transfer step CO(v=1)+CO2(000)ke⇌ke′ CO(v=0)+CO2(001)+ΔE=−206 cm−1 has been measured in the endothermic direction and after detailed balancing [ke′=ke exp(−ΔE/kT)] is in excellent agreement with data taken in the exothermic direction at and above room temperature. V→R,T quenching of the CO2(001) level by CO2 and CO has also been studied. The CO2 self‐relaxation rate reverses in temperature dependence between 250–300 °K with rates becoming progressively faster as temperature decreases. The total quenching rate for CO2 deactivation in CO2–CO collisions behaves similarly to the self‐relaxation rate. It was not possible in the present analysis to separate and distinguish the pathways for V→R,T deactivation in equilibrated CO2–CO mixtures. The cross relaxation terms (CO+2–CO) and (CO+–CO 2) are both expected to be important at low temperatures.

The author describes her work at the National Health Studies Learning Resources Unit, where she provides information about audio-visual teaching support material for nurse teachers. This service is offered as part of the unit's work, the aim being to provide a focal point for the collection, translation, and dissemination of information and advice on aspects of educational technology which can be applied to nurse education: Audio-Visual Media Information for Nurse Education—AV MINE.

A systematic and quantitative search was conducted to identify and isolate a serologically pertinent antigen with high specific activity and low cross-reactivity from adult worms of Schistosoma mansoni. Adult worms of S. mansoni quickly thawed from liquid N2 temperatures were disrupted by controlled homogenization in isotonic buffered sucrose. Differential centrifugation of the homogenate yielded three particulate and one soluble fractions: the 480 x G pellet (nuclear), the 7650 x G pellet (mitochondrial), the 360,000 x G pellet (microsomal), and the 360,000 x G supernatant (cytosol). Quantitative analysis indicated a major concentration of specific antigenic activities in the microsomal fraction. Further purifications of the urea-solubilized, n-butanol-treated microsomal particles by gel filtration and ionic-exchange chromatography resulted in a microsomal antigen (MAMA) possessing high specific activity and low cross-reactivity. The final purification post-ionic exchange chromatograph showed a 30-fold increase of specific antigen activity over that of the cytosol fraction. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme-linked immunotransfer blot by the "Western blot" technique (EITB) indicated specific antigenic activities in association with several different m.w. bands (heterogeneous m.w. by extrapolation = 4.3 to 11.9 x 10(6), 2.0 x 10(5), and 2.0 x 10(4) daltons) of the MAMA fraction. When compared with other reported serologic antigens, MAMA showed substantially higher specific activity and lower cross-reactivity.

An electrically initiated pulsed HF chemical laser has been used to measure vibrational relaxation of HF ( \upsilon = 1 ), CO ( \upsilon = 1 ), and NO ( \upsilon = 1 ) at 295 ± 2 K. The self-relaxation rate of HF highly dilute in argon is (8.7 \pm 0.1) \times 10^{4} s^{-1} torr-1and is independent of rotational level excitation over laser transitions P_{1 \rightarrow 0}(2) - P_{1 \rightarrow 0}(9) . The rates at which O 2 , CO, and NO quench HF( \upsilon = 1 ) have been found to be 350 \pm 25, (2.5 \pm 0.2) \times 10^{3} and (6.2 \pm 0.3) \times 10^{3} s-1torr-1, respectively. There is indirect evidence of transfer from HF( \upsilon = 1 ) to the ( \upsilon = 2 ) levels of NO and O 2 . Through the use of HF ( \upsilon = 1 ) as a collisional pumping source we have measured the deactivation rates of CO ( \upsilon = 1 ) by HF (V → R, T) and N 2 (V → V) to be 480 ± 25 s-1torr-1and 130 ± 15 s-1torr-1. Similarly, HF ( \upsilon = 1 ) has been used to pump NO ( \upsilon = 1 ) and the NO self-relaxation rate has been measured to be (2.7 \pm 0.2) \times 10^{3} s-1torr-1; this rate is about a factor of 5 faster than would be predicted by the kinetic spectroscopy results of Billingsley and Callear [43].

The laser‐excited vibrational fluorescence method has been used to obtain room temperature (294±2°K) vibrational relaxation rates for pure HF and in HF‐additive mixtures. Measurement of the quenching of HF(v=1) fluorescence in HF–HF and HF‐additive collisions has yielded the following total deactivation rates: HF†Ar

The rates at which vibrationally excited HF is deactivated by CH4, C2H6, C3H8, C4H10, C3H6, and ClF3 have been measured to be (5.3 ± 0.8) × 104; (1.10 ± 0.16) × 105; (1.35 ± 0.2) × 105; (1.7 ± 0.25) × 105; (3.2 ± 0.5) × 105 and (1.13 ± 0.17) × 105 sec−1 · torr−1, respectively, using the laser‐excited vibrational fluorescence technique. It was found that the cross‐section for HF deactivation by the lower alkanes, Cn H2n+2, varied linearly with n. The deactivation rate measured for HF–ClF3 is orders of magnitude greater than has been observed for HF deactivation by other fluorine sources. The importance of the above rate measurements in the understanding and analysis of pulsed HF lasers is discussed in detail.

4C MPERIALISM is no word for scholars." I quote my own printed Words of ten years ago.' The bewildering changes of content and color of that chameleon word throughout the brief century of its existence are now being explored by R. F. Koebner of the University of Jerusalem.2 Here indeed is a fit task for scholars-to take a key word such as imperialism or despotism, to trace the history of its usage and abusage, to fit it into its true context of ideology, propaganda, and political warfare throughout successive historical phases. What a scholar can NOT do with these emotionally reverberant words is to make them reliable instruments of scientific exploration and explanation. Rather belatedly, I have begun to doubt the reliability of the words that I have chosen as title to my own paper. Agenda is good enough, for it is my purpose to emphasize not the little knowledge that we have but the larger knowledge that we hope to gain. But the words "imperial economy" go awkwardly together throughout the earlier and longer part of the period I propose to explore; indeed, it was a main object of theory and practice in free-trade Britain to force the adjective and the noun apart. Great Britain was the imperial metropolis of a far-flung polity; she was the commercial metropolis of a fartherflung economy. Why confuse the economy with the polity? In the age of Cobden and Gladstone their separateness was not merely a point of theory but an article of faith. What it amounted to in practice we can quickly see by recalling some familiar figures of trade, investment

Laser‐induced fluorescence studies of CO collisional relaxation have been carried out using the output of a frequency‐doubled, pulsed CO2 laser as a direct source of CO(ν = 1) excitation. Energy transfer cross sections at 298 °K are reported for CO in collisions with He, Ar, H2, D2, N2, O2, Cl2, NO, CH4, CF4, and SF6. The D2–D2 self‐relaxation rate was also obtained from the analysis of CO–D2 mixtures.

The reactions of hydrogen atoms with 2-methyl ethylenimine and azacyclobutane have been investigated at various temperatures. Between 100 and 300 °C both reactions have been found to be rapid and complete, so that the maximum disappearance of either cyclic imine under these conditions may be regarded as a satisfactory measure of atomic hydrogen flow rates. At 300 °C ethane has been found to be a major product, and it has been inferred from this and other results at this temperature that the other major product of both reactions is cyanogen, which could not be isolated since it appears to form compounds with both cyclic imines.

THE FRACTIONS OF LOWER MOLECULAR WEIGHT WERE ISOLATED FROM THREE COMMERCIAL ROAD-BUILDING ASPHALTS. THE FIRST STEP WAS PRECIPITATION OF THE ASPHALTENES WITH N-PENTANE. PENTANE SOLUTIONS OF THE PETROLENES WERE THEN TREATED TWICE WITH 85% SULFURIC ACID, FOLLOWED BY CHROMATOGRAPHY OF THE SULFURIC ACID-INSOLUBLE MATERIAL ON FLORISIL. FINALLY THE PRODUCT ELUTED FROM THE FLORISIL BY N-PENTANE WAS SEPARATED INTO TEN FRACTIONS BY THERMAL DIFFUSION. THE RESULTING 30 THERMAL DIFFUSION FRACTIONS WERE INVESTIGATED BY PHYSICAL CONSTANT- STRUCTURE CORRELATION PROCEDURES AND BY ULTRAVIOLET, INFRARED, AND NUCLEAR MAGNETIC RESONANCE SPECTRAL METHODS. OF THESE PROCEDURES, NUCLEAR MAGNETIC RESONANCE SPECTROMETRY OFFERS THE MOST PROMISING APPROACH TO THE TYPE OF MATERIALS ENCOUNTERED. THE FRACTIONS OBTAINED FROM A SOLVENT-REFINED ASPHALT WERE SOMEWHAT MORE AROMATIC THAN FROM THOSE PRODUCED SOLELY BY DISTILLATION. HYPOTHETICAL MOLECULAR STRUCTURES ARE PRESENTED FOR SOME OF THE LOW MOLECULAR WEIGHT HYDROCARBONS PRESENT IN THE THREE ASPHALTS. /AUTHOR/

The high‐field rotational Zeeman effect has been observed in formyl fluoride (CHFO), vinyl fluoride (CH2CHF), trifluoroethylene (CF2CHF), ethyl fluoride (CH3CH2F), and 1, 1‐difluoroethane (CH3CHF2). The signs and magnitudes of the magnetic susceptibility anisotropies [(2χaa − χbb − χcc) and (2χbb − χaa − χcc)] and the magnitudes of the molecular g values (gaa, gbb, and gcc) were obtained and are listed. Although only the relative signs of the g values could be obtained by experiment, the signs were determined through analysis of molecular quadrupole moments and the second moments of the electronic charge distribution. The molecular quadrupole moments (Qaa, Qbb, and Qcc) are also given. Using the magnetic susceptibility anisotropies, g values, the known structures, and the bulk susceptibilities, the diagonal elements of the paramagnetic, diamagnetic, and total susceptibility tensors were calculated along with the second moments of the electronic charge distribution.