The interpretation of the spectrum of energetic cosmic rays

One of the most prominent and well established features in the primary energy spectrum of cosmic rays observed at the Earth is the change of slope occurring at several 10(^15) eV. A comprehensive survey of experimental EAS data is used to establish the integral size spectrum for electrons and muons at sea level and for electrons at mountain altitudes. A model for the diffusion of protons in the Galaxy is developed based on experimental observations of the structure of hydrogen in the interstellar medium and of the magnetic field strengths and their orientations in galactic space. A numerical treatment of the diffusion problem is adopted. A pre-diction is made of the primary cosmic ray proton energy spectrum at the top of the atmosphere. A survey of the data on cosmic ray primaries with energies below ~10(^11) eV obtained by balloon and satellite experiments, was used to establish the relative abundances of all cosmic rays. By assuming that the cosmic ray composition remains the same at EAS energies the primary spectrum representing diffusion of cosmic rays with mixed composition is derived. Comparison of the theory with experiment was made by converting the integral primary energy spectrum representing diffusion to the integral size spectrum by using results of EAS simulations through the atmosphere. Excellent agreement of theory with experiment is obtained provided that the primary cosmic radiation is protonic. The problems encountered with ensuring isotropy of cosmic rays at the Earth are dealt with in great detail and are shown to create little problem over the part of the spectrum considered provided the solar system lies in the centre of the spiral arm. Finally, a model is proposed as an alternative to that of diffusion which provides a qualitative but adequate explanation for the origin of the 'knee'

Evaluating the impacts of urban freight traffic: application of micro-simulation at a large establishment

Heavy Goods Vehicles, HGV, and Light Goods Vehicles, LGV, are a significant contributor to air pollution problems in urban areas. This paper quantifies the contribution to the environment of the deliveries to a single, large city employer addressing a research gap in the literature. Analysis of data from comprehensive surveys carried out over two years demonstrated that freight delivery traffic generated by an urban establishment with multiple properties in a compact urban setting, is characterised by a high proportion of LGV consistent with recent national and international trends. Also, despite freight traffic is only 10% of local traffic, more than 50% serves the single establishment, suggesting a different approach to policy making driven by the employer should be explored. The modelling results showed, relatively, the largest contribution to total emissions comes from HGVs in the AM peak, 13.8%, 43.7%, 9.2% for CO2, NOx and PM respectively. LGV contribute less, with 5.5%, 3.8%, 6% for CO2, NOx and PM respectively but more responsible for local congestion due to their numbers. This research is the first known study of its type and with the unique combination of measurement and traffic microsimulation allowed consideration of more effective traffic management strategies as well as providing evidence to support a consolidation centre for deliveries outside the city with fewer electric or low emissions last mile vehicles reducing substantially the environmental impact. The research outputs are relevant to many other similar cases in UK and Europe. The paper contributes to the ongoing development of research and policy looking to achieve sustainable urban logistics through receiver and purchasing led initiatives

Fc receptor modulation in mononuclear phagocytes maintained on immobilized immune complexes occurs by diffusion of the receptor molecule

We describe a method for synchronously assembling antigen-antibody complexes underneath macrophages adherent to an antigen-coated surface. We have used this method to study the mechanism of Fc receptor (FcR) disappearance that occurs when resident and thioglycollate-elicited mouse macrophages are cultured on immune complex-coated surfaces. Erythrocytes opsonized with IgG (E(IgG) and a monoclonal antibody (2.4G2 IgG) directed against the trypsin-resistant FcR (FcRII) were used as indicators of the presence and distribution of FcRII molecules on the macrophage plasma membrane. Inhibitors of aerobic (NaCN) and anerobic (2-deoxyglucose, NaF) glycolysis and pinocytosis, of protein biosynthesis (cycloheximide), and of cytoskeletal function (cytochalasin B and D, colchicine, podophyllotoxin, taxol) did not reduce the rate or extent of FcRII modulation. Moreover, treatment of the macrophages with 0.1-0.5% formaldehyde did not reduce the extent of FcRII modulation as measured by the disappearance of E(IgG) binding sites. FcRII modulation was markedly slowed when the temperature was decreased to 2-4 degrees C. These results prove that FcRII modulation is governed by diffusion of the receptor in the plasma membrane. From the speed of FcRII disappearance from the macrophage's upper surface we calculate that the receptor has a diffusion coefficient at 37 degrees C of 2.5 X 10(-9) cm2/s. This finding indicates that FcRII, in its unligated form, is not linked to the macrophage's cytoskeleton, and that the receptor is capable of accommodating spatially to any distribution of ligands on a particle's surface

RUNX-mediated growth arrest and senescence are attenuated by diverse mechanisms in cells expressing RUNX1 fusion oncoproteins

RUNX gene over-expression inhibits growth of primary cells but transforms cells with tumor suppressor defects, consistent with reported associations with tumor progression. In contrast, chromosomal translocations involving RUNX1 are detectable in utero, suggesting an initiating role in leukemias. How do cells expressing RUNX1 fusion oncoproteins evade RUNX-mediated growth suppression? Previous studies showed that the TEL-RUNX1 fusion from t(12;21) B-ALLs is unable to induce senescence-like growth arrest (SLGA) in primary fibroblasts while potent activity is displayed by the RUNX1-ETO fusion found in t(8;21) AMLs. We now show that SLGA potential is suppressed in TEL-RUNX1 but reactivated by deletion of the TEL HLH domain or mutation of a key residue (K99R). Attenuation of SLGA activity is also a feature of RUNX1-ETO9a, a minor product of t(8;21) translocations with increased leukemogenicity. Finally, while RUNX1-ETO induces SLGA it also drives a potent senescence-associated secretory phenotype (SASP), and promotes the immortalisation of rare cells that escape SLGA. Moreover, the RUNX1-ETO SASP is not strictly linked to growth arrest as it is largely suppressed by RUNX1 and partially activated by RUNX1-ETO9a. These findings underline the heterogeneous nature of premature senescence and the multiple mechanisms by which this failsafe process is subverted in cells expressing RUNX1 oncoproteins

Processes to manage analyses and publications in a phase III multicenter randomized clinical trial

Background: The timely publication of findings in peer-reviewed journals is a primary goal of clinical research. In clinical trials, the processes leading to publication can be complex from choice and prioritization of analytic topics through to journal submission and revisions. As little literature exists on the publication process for multicenter trials, we describe the development, implementation, and effectiveness of such a process in a multicenter trial. Methods: The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial included a data coordinating center (DCC) and clinical centers that recruited and followed more than 1,000 patients. Publication guidelines were approved by the steering committee, and the publications committee monitored the publication process from selection of topics to publication. Results: A total of 73 manuscripts were published in 23 peer-reviewed journals. When manuscripts were closely tracked, the median time for analyses and drafting of manuscripts was 8 months. The median time for data analyses was 5 months and the median time for manuscript drafting was 3 months. The median time for publications committee review, submission, and journal acceptance was 7 months, and the median time from analytic start to journal acceptance was 18 months. Conclusions: Effective publication guidelines must be comprehensive, implemented early in a trial, and require active management by study investigators. Successful collaboration, such as in the HALT-C trial, can serve as a model for others involved in multidisciplinary and multicenter research programs. Trial registration The HALT-C Trial was registered with clinicaltrials.gov (NCT00006164)

Addiction to Runx1 is partially attenuated by loss of p53 in the Eμ-Myc lymphoma model

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt’s lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ- Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status

Working with Children with Learning Disabilities and/or who Communicate Non-verbally: Research experiences and their implications for social work education, increased participation and social inclusion

Social exclusion, although much debated in the UK, frequently focuses on children as a key 'at risk' group. However, some groups, such as disabled children, receive less consideration. Similarly, despite both UK and international policy and guidance encouraging the involvement of disabled children and their right to participate in decision-making arenas, they are frequently denied this right. UK based evidence suggests that disabled children's participation lags behind that of their non-disabled peers, often due to social work practitioners' lack of skills, expertise and knowledge on how to facilitate participation. The exclusion of disabled children from decision-making in social care processes echoes their exclusion from participation in society. This paper seeks to begin to address this situation, and to provide some examples of tools that social work educators can introduce into pre- and post-qualifying training programmes, as well as in-service training. The paper draws on the experiences of researchers using non-traditional qualitative research methods, especially non-verbal methods, and describes two research projects, focusing on the methods employed to communicate with and involve disabled children, the barriers encountered and lessons learnt. Some of the ways in which these methods of communication can inform social work education are explored alongside wider issues of how and if increased communication can facilitate greater social inclusion