Annihilation of NMSSM neutralinos in the Sun and neutrino telescope limits

We investigate neutralino dark matter in the framework of NMSSM performing a scan over its parameter space and calculating neutralino capture and annihilation rates in the Sun. We discuss the prospects of searches for neutralino dark matter in neutrino experiments depending on neutralino content and its main annihilation channel. We recalculate the upper limits on neutralino-proton elastic cross sections directly from neutrino telescopes upper bounds on annihilation rates in the Sun. This procedure has advantages as compared with corresponding recalcalations from the limits on muon flux, namely, it is independent on details of the experiment and the recalculation coefficients are universal for any kind of WIMP dark matter models. We derive 90% c.l. upper limits on neutralino-proton cross sections from the results of the Baksan Underground Scintillator Telescope.Comment: 28 pages, 16 figures, accepted for publication in JCAP, references adde

Risk and promotive effects in the explanation of persistent serious delinquency in boys

Risk and promotive effects were investigated as predictors of persistent serious delinquency in male participants of the Pittsburgh Youth Study (R. Loeber, D. P. Farrington, M. Stouthamer-Loeber, & W. B. van Kammen, 1998), living in different neighborhoods. Participants were studied over ages 13–19 years for the oldest sample and 7–13 years for the youngest sample. Risk and promotive effects were studied in 6 domains: child behavior, child attitudes, school and leisure activities, peer behaviors, family functioning, and demographics. Regression models improved when promotive effects were included with risk effects in predicting persistent serious delinquency. Disadvantaged neighborhoods, compared with better neighborhoods, had a higher prevalence of risk effects and a lower prevalence of promotive effects. However, predictive relations between risk and promotive effects and persistent serious delinquency were linear and similar across neighborhood socioeconomic status. Although advances have been made in the study of predictors of serious delinquency (Hawkins et al., 1998; Lipsey & Derzon, 1998), little is known about predictors of persistent serious offend-ing, which from a societal point of view is of particular concern. Most youth commit some delinquent acts in childhood or adoles

Mitochondrial precursor proteins are imported through a hydrophilic membrane environment

We have analyzed how translocation intermediates of imported mitochondrial precursor proteins, which span contact sites, interact with the mitochondrial membranes. F1-ATPase subunit β(F1β) was trapped at contact sites by importing it into Neurospora mitochondria in the presence of low levels of nucleoside triphosphates. This F1β translocation intermediate could be extracted from the membranes by treatment with protein denaturants such as alkaline pH or urea. By performing import at low temperatures, the ADP/ATP carrier was accumulated in contact sites of Neurospora mitochondria and cytochrome b2 in contact sites of yeast mitochondria. These translocation intermediates were also extractable from the membranes at alkaline pH. Thus, translocation of precursor proteins across mitochondrial membranes seems to occur through an environment which is accessible to aqueous perturbants. We propose that proteinaceous structures are essential components of a translocation apparatus present in contact sites

Young people, crime and school exclusion: a case of some surprises

During the 1990s the number of young people being permanently excluded from schools in England and Wales increased dramatically from 2,910 (1990/91) to a peak of 12,700 (1996/97). Coinciding with this rise was a resurgence of the debate centring on lawless and delinquent youth. With the publication of Young People and Crime (Graham and Bowling 1995) and Misspent Youth (Audit Commission 1996) the 'common sense assumption' that exclusion from school inexorably promoted crime received wide support, with the school excludee portrayed as another latter day 'folk devil'. This article explores the link between school exclusion and juvenile crime, and offers some key findings from a research study undertaken with 56 young people who had experience of being excluded from school. Self-report interview questions reveal that whilst 40 of the young people had offended, 90% (36) reported that the onset of their offending commenced prior to their first exclusion. Moreover, 50 (89.2% of the total number of young people in the sample), stated that they were no more likely to offend subsequent to being excluded and 31 (55.4%) stated that they were less likely to offend during their exclusion period. Often, this was because on being excluded, they were 'grounded' by their parents

A Novel High-Throughput Assay for Islet Respiration Reveals Uncoupling of Rodent and Human Islets

The pancreatic beta cell is unique in its response to nutrient by increased fuel oxidation. Recent studies have demonstrated that oxygen consumption rate (OCR) may be a valuable predictor of islet quality and long term nutrient responsiveness. To date, high-throughput and user-friendly assays for islet respiration are lacking. The aim of this study was to develop such an assay and to examine bioenergetic efficiency of rodent and human islets.The XF24 respirometer platform was adapted to islets by the development of a 24-well plate specifically designed to confine islets. The islet plate generated data with low inter-well variability and enabled stable measurement of oxygen consumption for hours. The F1F0 ATP synthase blocker oligomycin was used to assess uncoupling while rotenone together with myxothiazol/antimycin was used to measure the level of non-mitochondrial respiration. The use of oligomycin in islets was validated by reversing its effect in the presence of the uncoupler FCCP. Respiratory leak averaged to 59% and 49% of basal OCR in islets from C57Bl6/J and FVB/N mice, respectively. In comparison, respiratory leak of INS-1 cells and C2C12 myotubes was measured to 38% and 23% respectively. Islets from a cohort of human donors showed a respiratory leak of 38%, significantly lower than mouse islets.The assay for islet respiration presented here provides a novel tool that can be used to study islet mitochondrial function in a relatively high-throughput manner. The data obtained in this study shows that rodent islets are less bioenergetically efficient than human islets as well as INS1 cells

A phase I/IIa trial using CD19-targeted third-generation CAR T cells for lymphoma and leukemia

Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19þ B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy. Patients and Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array. Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14þCD33þHLADR) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2. Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers

Limits on the high-energy gamma and neutrino fluxes from the SGR 1806-20 giant flare of December 27th, 2004 with the AMANDA-II detector

On December 27th 2004, a giant gamma flare from the Soft Gamma-ray Repeater 1806-20 saturated many satellite gamma-ray detectors. This event was by more than two orders of magnitude the brightest cosmic transient ever observed. If the gamma emission extends up to TeV energies with a hard power law energy spectrum, photo-produced muons could be observed in surface and underground arrays. Moreover, high-energy neutrinos could have been produced during the SGR giant flare if there were substantial baryonic outflow from the magnetar. These high-energy neutrinos would have also produced muons in an underground array. AMANDA-II was used to search for downgoing muons indicative of high-energy gammas and/or neutrinos. The data revealed no significant signal. The upper limit on the gamma flux at 90% CL is dN/dE < 0.05 (0.5) TeV^-1 m^-2 s^-1 for gamma=-1.47 (-2). Similarly, we set limits on the normalization constant of the high-energy neutrino emission of 0.4 (6.1) TeV^-1 m^-2 s^-1 for gamma=-1.47 (-2).Comment: 14 pages, 3 figure

Widespread horizontal transfer of mitochondrial genes in flowering plants

Horizontal gene transfer - the exchange of genes across mating barriers - is recognized as a major force in bacterial evolution(1,2). However, in eukaryotes it is prevalent only in certain phagotrophic protists and limited largely to the ancient acquisition of bacterial genes(3-5). Although the human genome was initially reported(6) to contain over 100 genes acquired during vertebrate evolution from bacteria, this claim was immediately and repeatedly rebutted(7,8). Moreover, horizontal transfer is unknown within the evolution of animals, plants and fungi except in the special context of mobile genetic elements(9-12). Here we show, however, that standard mitochondrial genes, encoding ribosomal and respiratory proteins, are subject to evolutionarily frequent horizontal transfer between distantly related flowering plants. These transfers have created a variety of genomic outcomes, including gene duplication, recapture of genes lost through transfer to the nucleus, and chimaeric, half-monocot, half-dicot genes. These results imply the existence of mechanisms for the delivery of DNA between unrelated plants, indicate that horizontal transfer is also a force in plant nuclear genomes, and are discussed in the contexts of plant molecular phylogeny and genetically modified plants.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62688/1/nature01743.pd

Mitochondrial Networking Protects β-Cells From Nutrient-Induced Apoptosis

OBJECTIVE: Previous studies have reported that β-cell mitochondria exist as discrete organelles that exhibit heterogeneous bioenergetic capacity. To date, networking activity, and its role in mediating β-cell mitochondrial morphology and function, remains unclear. In this article, we investigate β-cell mitochondrial fusion and fission in detail and report alterations in response to various combinations of nutrients. RESEARCH DESIGN AND METHODS: Using matrix-targeted photoactivatable green fluorescent protein, mitochondria were tagged and tracked in β-cells within intact islets, as isolated cells and as cell lines, revealing frequent fusion and fission events. Manipulations of key mitochondrial dynamics proteins OPA1, DRP1, and Fis1 were tested for their role in β-cell mitochondrial morphology. The combined effects of free fatty acid and glucose on β-cell survival, function, and mitochondrial morphology were explored with relation to alterations in fusion and fission capacity. RESULTS: β-Cell mitochondria are constantly involved in fusion and fission activity that underlies the overall morphology of the organelle. We find that networking activity among mitochondria is capable of distributing a localized green fluorescent protein signal throughout an isolated β-cell, a β-cell within an islet, and an INS1 cell. Under noxious conditions, we find that β-cell mitochondria become fragmented and lose their ability to undergo fusion. Interestingly, manipulations that shift the dynamic balance to favor fusion are able to prevent mitochondrial fragmentation, maintain mitochondrial dynamics, and prevent apoptosis. CONCLUSIONS: These data suggest that alterations in mitochondrial fusion and fission play a critical role in nutrient-induced β-cell apoptosis and may be involved in the pathophysiology of type 2 diabetes.National Institutes of Health (R01HL071629-03, R01DK074778, 5T32DK007201