The balloon-borne Cosmic Ray Energetics And Mass (CREAM) experiment launched five times from Antarctica has achieved a cumulative flight duration of about 156 days above 99.5% of the atmosphere. The instrument is configured with complementary and redundant particle detectors designed to extend direct measurements of cosmic-ray composition to the highest energies practical with balloon flights. All elements from protons to iron nuclei are separated with excellent charge resolution. Here we report results from the first two flights of ~70 days, which indicate hardening of the elemental spectra above ~200GeV/nucleon and a spectral difference between the two most abundant species, protons and helium nuclei. These results challenge the view that cosmic-ray spectra are simple power laws below the so-called -knee‖ at ~10 15 eV. This discrepant hardening may result from a relatively nearby source, or it could represent spectral concavity caused by interactions of cosmic rays with the accelerating shock. Other possible explanations should also be investigated.

Cosmic-ray proton and helium spectra have been measured with the balloon-borne Cosmic Ray Energetics And Mass experiment flown for 42 days in Antarctica in the 2004-2005 austral summer season. High-energy cosmic-ray data were collected at an average altitude of ∼38.5 km with an average atmospheric overburden of ∼3.9 g cm −2 . Individual elements are clearly separated with a charge resolution of ∼0.15 e (in charge units) and ∼0.2 e for protons and helium nuclei, respectively. The measured spectra at the top of the atmosphere are represented by power laws with a spectral index of −2.66 ± 0.02 for protons from 2.5 TeV to 250 TeV and -2.58 ± 0.02 for helium nuclei from 630 GeV nucleon −1 to 63 TeV nucleon −1 . They are harder than previous measurements

We report here a mitochondria-targetable pH-sensitive probe that allows for a quantitative measurement of mitochondrial pH changes, as well as the real-time monitoring of pH-related physiological effects in live cells. This system consists of a piperazine-linked naphthalimide as a fluorescence off–on signaling unit, a cationic triphenylphosphonium group for mitochondrial targeting, and a reactive benzyl chloride subunit for mitochondrial fixation. It operates well in a mitochondrial environment within whole cells and displays a desirable off–on fluorescence response to mitochondrial acidification. Moreover, this probe allows for the monitoring of impaired mitochondria undergoing mitophagic elimination as the result of nutrient starvation. It thus allows for the monitoring of the organelle-specific dynamics associated with the conversion between physiological and pathological states.

.12 e (in charge units) and ∼0.14 e for protons and helium nuclei, respectively, using two layers of silicon charge detectors. The measured proton and helium energy spectra at the top of the atmosphere are harder than other existing measurements at a few tens of GeV. The relative abundance of protons to helium nuclei is 9.53 ± 0.03 for the range of 1 TeV/n to 63 TeV/n. The ratio is considerably smaller than other measurements at a few tens of GeV/n. The spectra become softer above ∼20 TeV. However, our statistical uncertainties are large at these energies and more data are needed.

Presented here is a multicomponent synthetic strategy that allows for the direct, fluorescence-based monitoring of the targeted cellular uptake and release of a conjugated therapeutic agent. Specifically, we report here the design, synthesis, spectroscopic characterization, and preliminary in vitro biological evaluation of a RGD peptide-appended naphthalimide pro-CPT (compound 1). Compound 1 is a multifunctional molecule composed of a disulfide bond as a cleavable linker, a naphthalimide moiety as a fluorescent reporter, an RGD cyclic peptide as a cancer-targeting unit, and camptothecin (CPT) as a model active agent. Upon reaction with free thiols in aqueous media at pH 7.4, disulfide cleavage occurs. This leads to release of the free CPT active agent, as well as the production of a red-shifted fluorescence emission (λ(max) = 535 nm). Confocal microscopic experiments reveal that 1 is preferentially taken up by U87 cells over C6 cells. On the basis of competition experiments involving okadaic acid, an inhibitor of endocytosis, it is concluded that uptake takes place via RGD-dependent endocytosis mechanisms. In U87 cells, the active CPT payload is released within the endoplasmic reticulum, as inferred from fluorescence-based colocalization studies using a known endoplasmic reticulum-selective dye. The present drug delivery system (DDS) could represent a new approach to so-called theragnostic agent development, wherein both a therapeutic effect and drug uptake-related imaging information are produced and can be readily monitored at the subcellular level. In due course, the strategy embodied in conjugate 1 could allow for more precise monitoring of dosage levels, as well as an improved understanding of cellular uptake and release mechanisms.

We present the design, synthesis, spectroscopic properties, and biological evaluation of a single galactose-appended naphthalimide (1). Probe 1 is a multifunctional molecule that incorporates a thiol-specific cleavable disulfide bond, a masked phthalamide fluorophore, and a single galactose moiety as a hepatocyte-targeting unit. It constitutes a new type of targetable ligand for hepatic thiol imaging in living cells and animals. Confocal microscopic imaging experiments reveal that 1, but not the galactose-free control system 2, is preferentially taken up by HepG2 cells through galactose-targeted, ASGP-R-mediated endocytosis. Probe 1 displays a fluorescence emission feature at 540 nm that is induced by exposure to free endogenous thiols, most notably GSH. The liver-specificity of 1 was confirmed in vivo via use of a rat model. The potential utility of this probe in indicating pathogenic states and as a possible screening tool for agents that can manipulate oxidative stress was demonstrated in experiments wherein palmitate was used to induce lipotoxicity in HepG2 cells.

We present here, the design, synthesis, spectroscopic characterization, and in vitro biological assessment of a gemcitabine-coumarin-biotin conjugate (5). Probe 5 is a multifunctional molecule composed of a thiol-specific cleavable disulfide bond, a coumarin moiety as a fluorescent reporter, gemcitabine (GMC) as a model active drug, and biotin as a cancer-targeting unit. Upon addition of free thiols that are relatively abundant in tumor cells, disulfide bond cleavage occurs as well as active drug GMC release and concomitantly fluorescence intensity increases. Confocal microscopic experiments reveal that 5 is preferentially taken up by A549 cells rather than WI38 cells. Fluorescence-based colocalization studies using lysosome- and endoplasmic reticulum-selective dyes suggest that thiol-induced disulfide cleavage of 5 occur in the lysosome possibly via receptor-mediated endocytosis. The present drug delivery system is a new theranostic agent, wherein both a therapeutic effect and drug uptake can be readily monitored at the subcellular level by two photon fluorescence imaging.

We present new measurements of the energy spectra of cosmic-ray (CR) nuclei from the second flight of the balloon-borne experiment Cosmic Ray Energetics And Mass (CREAM). The instrument included different particle detectors to provide redundant charge identification and measure the energy of CRs up to several hundred TeV. The measured individual energy spectra of C, O, Ne, Mg, Si, and Fe are presented up to ∼ 10 14 eV. The spectral shape looks nearly the same for these primary elements and it can be fitted to an E −2.66±0.04 power law in energy. Moreover, a new measurement of the absolute intensity of nitrogen in the 100-800 GeV/n energy range with smaller errors than previous observations, clearly indicates a hardening of the spectrum at high energy. The relative abundance of N/O at the top of the atmosphere is measured to be 0.080 ± 0.025 (stat.) ±0.025 (sys.) at ∼ 800 GeV/n, in good agreement with a recent result from the first CREAM flight.