Cosmic ray isotope measurements with a new Cerenkov X total energy telescope

Measurements of the isotopic composition of cosmic nuclei with Z = 7-20 are reported. These measurements were made with a new version of a Cerenkov x total E telescope. Path length and uniformity corrections are made to all counters to a RMS level 1%. Since the Cerenkov counter is crucial to mass measurements using the C x E technique - special care was taken to optimize the resolution of the 2.4 cm thick Pilot 425 Cerenkov counter. This counter exhibited a beta = 1 muon equivalent LED resolution of 24%, corresponding to a total of 90 p.e. collected at the 1st dynodes of the photomultiplier tubes

Cosmic ray charge and energy spectrum measurements using a new large area Cerenkov x dE/dx telescope

In September, 1981, a new 0.5 square meter ster cosmic ray telescope was flown to study the charge composition and energy spectrum of cosmic ray nuclei between 0.3 and 4 GeV/nuc. A high resolution Cerenkov counter, and three dE/dx measuring scintillation counters, including two position scintillators were contained in the telescope used for the charge and energy spectrum measurements. The analysis procedures did not require any large charge or energy dependent corrections, and absolute fluxes could be obtained to an accuracy approximately 5%. The spectral measurements made in 1981, at a time of extreme solar modulation, could be compared with measurements with a similar telescope made by our group in 1977, at a time of minimum modulation and can be used to derive absolute intensity values for the HEAO measurements made in 1979 to 80. Using both data sets precise energy spectra and abundance ratios can be derived over the entire energy range from 0.3 to greater than 15 GeV/nuc

Dansgaard-Oeschger events: tipping points in the climate system

Dansgaard-Oeschger events are a prominent mode of variability in the records of the last glacial cycle. Various prototype models have been proposed to explain these rapid climate fluctuations, and no agreement has emerged on which may be the more correct for describing the paleoclimatic signal. In this work, we assess the bimodality of the system reconstructing the topology of the multi--dimensional attractor over which the climate system evolves. We use high-resolution ice core isotope data to investigate the statistical properties of the climate fluctuations in the period before the onset of the abrupt change. We show that Dansgaard-Oeschger events have weak early warning signals if the ensemble of events is considered. We find that the statistics are consistent with the switches between two different climate equilibrium states in response to a changing external forcing (e.g. solar, ice sheets...), either forcing directly the transition or pacing it through stochastic resonance. These findings are most consistent with a model that associates Dansgaard-Oeschger with changing boundary conditions, and with the presence of a bifurcation point.Comment: Final typeset version freely available at: Clim. Past, 9, 323-333, 2013 www.clim-past.net/9/323/2013/ doi:10.5194/cp-9-323-201

Unexplained Aspects of Anemia of Inflammation

Anemia of inflammation (AI), also known as anemia of chronic inflammation or anemia of chronic disease was described over 50 years ago as anemia in association with clinically overt inflammatory disease, and the findings of low plasma iron, decreased bone marrow sideroblasts and increased reticuloendothelial iron. Pathogenic features underlying AI include a mild shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the marrow to erythropoietin, and impaired iron metabolism mediated by inflammatory cytokines and the iron regulatory peptide, hepcidin. Despite marked recent advances in understanding AI, gaps remain, including understanding of the pathogenesis of AI associated with “noninflammatory” or mildly inflammatory diseases, the challenge of excluding iron deficiency anemia in the context of concomitant inflammation, and understanding more precisely the contributory role of hepcidin in the development of AI in human inflammatory diseases

Progress on Autosomal Dominant Polycystic Kidney Disease

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common life threatening hereditary disease of the kidney. It is a systemic disease characterized by multiple, bilateral renal cysts that result in massive renal enlargement and progressive functional impairment. This review discusses the current understanding of the epidemiology, genetics, clinical manifestations, natural history of the disease, the accuracy and reliability of diagnostic approaches, renal replacement therapy and emerging therapeutic strategies that are being evaluated in ADPKD. Review: ADPKD is a genetically heterogeneous disease with significant inter-familial and intra-familial variability. The responsible genes were localized to separate loci on chromosome 16 (PKD1 gene) accounting for the majority of ADPKD cases, and chromosome 4 (PKD2 gene) accounting for the remainder. Each child of an affected parent has a 50% chance of inheriting the mutated gene, which is completely penetrant. Clinical manifestations include renal and cyst enlargement, impaired urine concentration capacity, hematuria, nephrolithiasis, proteinuria, hypertension, polycystic liver disease, abdominal wall hernia and intracranial aneurysms. The diagnosis of ADPKD usually relies on renal imaging. Ongoing research has engendered crucial insight into the disease’s underlying genetic, cellular and pathogenetic mechanisms and made possible the design and implementation of clinical trials testing promising treatments. Renin Angiotensin Aldosterone System (RAAS) blockade, vasopressin antagonists, somatostatin, rapamycin, sirolimus and everolimus are currently being evaluated for a potential therapeutic role in the management of ADPKD. Conclusion: Current clinical trials investigating multiple therapeutic targets bring hope for treatments that may impede the progression of ADPKD. Keywords: ADPKD, autosomal dominant polycystic kidney disease, kidney failur

Atomistic Theory of Coherent Spin Transfer between Molecularly Bridged Quantum Dots

Time-resolved Faradary rotation experiments have demonstrated coherent transfer of electron spin between CdSe colloidal quantum dots coupled by conjugated molecules. We employ here a Green's function approach, using semi-empirical tight-binding to treat the nanocrystal Hamiltonian and Extended Huckel theory to treat the linking molecule Hamiltonian, to obtain the coherent transfer probabilities from atomistic calculations, without the introduction of any new parameters. Calculations on 1,4-dithiolbenzene and 1,4-dithiolcyclohexane linked nanocrystals agree qualitatively with experiment and provide support for a previous transfer Hamiltonian model. We find a striking dependence on the transfer probabilities as a function of nanocrystal surface site attachment and linking molecule conformation. Additionally, we predict quantum interference effects in the coherent transfer probabilities for 2,7-dithiolnaphthalene and 2,6-dithiolnaphthalene linking molecules. We suggest possible experiments based on these results that would test the coherent, through-molecule transfer mechanism.Comment: 12 pages, 9 figures. Submitted Phys. Rev.

Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents.

HIV latency in resting CD4+ T cell represents a key barrier preventing cure of the infection with antiretroviral drugs alone. Latency reversing agents (LRAs) can activate HIV expression in latently infected cells, potentially leading to their elimination through virus-mediated cytopathic effects, host immune responses, and/or therapeutic strategies targeting cells actively expressing virus. We have recently described several structurally simplified analogs of the PKC modulator LRA bryostatin (termed bryologs) designed to improve synthetic accessibility, tolerability in vivo, and efficacy in inducing HIV latency reversal. Here we report the comparative performance of lead bryologs, including their effects in reducing cell surface expression of HIV entry receptors, inducing proinflammatory cytokines, inhibiting short-term HIV replication, and synergizing with histone deacetylase inhibitors to reverse HIV latency. These data provide unique insights into structure-function relationships between A- and B-ring bryolog modifications and activities in primary cells, and suggest that bryologs represent promising leads for preclinical advancement

Synergistic Communication between CD4+ T Cells and Monocytes Impacts the Cytokine Environment

Physiological cytokine environments arise from factors produced by diverse cell types in coordinated concert. Understanding the contributions of each cell type in the context of cell-cell communication is important for effectively designing disease modifying interventions. Here, we present multi-plexed measurement of 48 cytokines from a coculture system of primary human CD4+ T cells and monocytes across a spectrum of stimuli and for a range of relative T cell/monocyte compositions, coupled with corresponding measurements from PBMCs and plasma from the same donors. Computational analysis of the resulting data-sets elucidated communication-independent and communication-dependent contributions, including both positive and negative synergies. We find that cytokines in cell supernatants were uncorrelated to those found in plasma. Additionally, as an example of positive synergy, production levels of CXCR3 cytokines IP-10 and MIG, depend non-linearly on both IFNγ and TNFα levels in cross-talk between T cells and monocytes. Overall, this work demonstrates that communication between cell types can significantly impact the consequent cytokine environment, emphasizing the value of mixed cell population studies.United States. National Institutes of Health (DP3 DK097681)Institute for Collaborative Biotechnologies (W911NF-09-0001)David H. Koch Institute for Integrative Cancer Research at MITNational Science Foundation (U.S.

Subsynovial connective tissue development in the rabbit carpal tunnel

The carpal tunnel contains the digital flexor tendons and the median nerve, which are embedded in a unique network of fibrovascular interconnected subsynovial connective tissue (SSCT). Fibrous hypertrophy of the SSCT and subsequent adaptations in mechanical response are found in patients with carpal tunnel syndrome (CTS), but not much is known about the development of the SSCT. This observational study describes the morphological development of SSCT using histology and ultramicroscopy in an animal model at four time points between late-term fetuses through adulthood. A transition