We derive concentration inequalities for maxima of empirical processes associated with Poisson point processes. The proofs are based on a careful application of Ledoux's entropy method. We ...demonstrate the utility of the obtained concentration inequalities by application to adaptive intensity estimation.
The cosmic-ray Sun shadow, which is caused by high-energy charged cosmic rays being blocked and deflected by the Sun and its magnetic field, has been observed by various experiments, such as ...Argo-YBJ, Tibet, HAWC, and IceCube. Most notably, the shadow’s size and depth was recently shown to correlate with the 11-year solar cycle. The interpretation of such measurements, which help to bridge the gap between solar physics and high-energy particle astrophysics, requires a solid theoretical understanding of cosmic-ray propagation in the coronal magnetic field. It is the aim of this paper to establish theoretical predictions for the cosmic-ray Sun shadow in order to identify observables that can be used to study this link in more detail. To determine the cosmic-ray Sun shadow, we numerically compute trajectories of charged cosmic rays in the energy range of 5−316 TeV for five different mass numbers. We present and analyze the resulting shadow images for protons and iron, as well as for typically measured cosmic-ray compositions. We confirm the observationally established correlation between the magnitude of the shadowing effect and both the mean sunspot number and the polarity of the magnetic field during the solar cycle. We also show that during low solar activity, the Sun’s shadow behaves similarly to that of a dipole, for which we find a non-monotonous dependence on energy. In particular, the shadow can become significantly more pronounced than the geometrical disk expected for a totally unmagnetized Sun. For times of high solar activity, we instead predict the shadow to depend monotonously on energy and to be generally weaker than the geometrical shadow for all tested energies. These effects should become visible in energy-resolved measurements of the Sun shadow, and may in the future become an independent measure for the level of disorder in the solar magnetic field.
Epidemiological evidence suggests that chronic low-intensity extremely-low-frequency magnetic-field exposure is associated with increased risk of childhood leukaemia; it is not certain the ...association is causal.
We report a national case-control study relating childhood cancer risk to the average magnetic field from high-voltage overhead power lines at the child's home address at birth during the year of birth, estimated using National Grid records. From the National Registry of Childhood Tumours, we obtained records of 28,968 children born in England and Wales during 1962-1995 and diagnosed in Britain under age 15. We selected controls from birth registers, matching individually by sex, period of birth, and birth registration district. No participation by cases or controls was required.
The estimated relative risk for each 0.2 μT increase in magnetic field was 1.14 (95% confidence interval 0.57 to 2.32) for leukaemia, 0.80 (0.43-1.51) for CNS/brain tumours, and 1.34 (0.84-2.15) for other cancers.
Although not statistically significant, the estimate for childhood leukaemia resembles results of comparable studies. Assuming causality, the estimated attributable risk is below one case per year. Magnetic-field exposure during the year of birth is unlikely to be the whole cause of the association with distance from overhead power lines that we previously reported.
Previous research suggests associations of lower alcohol intake and higher tobacco consumption with increased risks of haematological malignancy. The prospective Million Women Study provides ...sufficient power for reliable estimates of subtype-specific associations in women.
Approximately 1.3 million middle-aged women were recruited in the United Kingdom during 1996-2001 and followed for death, emigration and cancer registration until 2009 (mean 10.3 years per woman); potential risk factors were assessed by questionnaire. Adjusted relative risks were estimated by Cox regression.
During follow-up, 9162 incident cases of haematological malignancy were recorded, including 7047 lymphoid and 2072 myeloid cancers. Among predominantly moderate alcohol drinkers, higher intake was associated with lower risk of lymphoid malignancies, in particular diffuse large B-cell lymphoma (relative risk 0.85 per 10 g alcohol per day (95% confidence interval 0.75-0.96)), follicular lymphoma (0.86 (0.76-0.98)) and plasma cell neoplasms (0.86 (0.77-0.96)). Among never- and current smokers, higher cigarette consumption was associated with increased risk of Hodgkin lymphoma (1.45 per 10 cigarettes per day (1.22-1.72)), mature T-cell malignancies (1.38 (1.10-1.73)) and myeloproliferative/myelodysplastic disease (1.42 (1.31-1.55)).
These findings confirm and extend existing evidence for associations of subtypes of haematological malignancy with two common exposures in women.
Herpes virus type 1 (HSV‐1) is one of the most widespread human pathogens and accounts for more than 90% of cases of herpes simplex encephalitis (HSE) causing severe and permanent neurologic sequelae ...among surviving patients. We hypothesize such CNS deficits are due to HSV‐1 infection of neural progenitor cells (NPCs). In vivo, HSV‐1 infection was found to diminish NPC numbers in the subventricular zone. Upon culture of NPCs in conditions that stimulate their differentiation, we found HSV‐1 infection of NPCs resulted in the loss of neuronal precursors with no significant change in the percentage of astrocytes or oligodendrocytes. We propose this is due a direct effect of HSV‐1 on neuronal survival without alteration of the differentiation process. The neuronal loss was prevented by the addition of microglia or conditioned media from NPC/microglia co‐cultures. Using neutralizing antibodies and recombinant cytokines, we identified interleukin‐6 (IL‐6) as responsible for the protective effect by microglia, likely through its downstream Signal Transducer and Activator of Transcription 3 (STAT3) cascade. GLIA 2014;62:1418–1434
Main Points:
HSV‐1 infection of NPCs reduces the survival of NPC‐derived neuroblasts.
Microglia prevents the neuronal loss upon infection of NPCs.
We identified IL‐6 as a key factor for the protective effect of microglia.
Greater adiposity and height have been associated with increased risk of haematological malignancies. Associations for disease subtypes are uncertain.
A cohort of 1.3 million middle-aged U.K. women ...was recruited in 1996-2001 and followed for 10 years on average. Potential risk factors were assessed by questionnaire. Death, emigration, and incident cancer were ascertained by linkage to national registers. Adjusted relative risks were estimated by Cox regression.
During follow-up, 9162 participants were diagnosed with lymphatic or haematopoietic cancers. Each 10 kg m(-2) increase in body mass index was associated with relative risk of 1.20 (95% confidence interval: 1.13-1.28) for lymphoid and 1.37 (1.22-1.53) for myeloid malignancy (P=0.06 for heterogeneity); similarly, Hodgkin lymphoma 1.64 (1.21-2.21), diffuse large B-cell lymphoma 1.36 (1.17-1.58), plasma cell neoplasms 1.21 (1.06-1.39), acute myeloid leukaemia 1.47 (1.19-1.81), and myeloproliferative/myelodysplastic syndromes 1.32 (1.15-1.52). Each 10 cm increase in height was associated with relative risk of 1.21 (1.16-1.27) for lymphoid and 1.11 (1.02-1.21) for myeloid malignancy (P=0.07 for heterogeneity); similarly, mature T-cell malignancies 1.36 (1.03-1.79), diffuse large B-cell lymphoma 1.28 (1.14-1.43), follicular lymphoma 1.28 (1.13-1.44), plasma cell neoplasms 1.12 (1.01-1.24), chronic lymphocytic leukaemia/small lymphocytic lymphoma 1.23 (1.08-1.40), and acute myeloid leukaemia 1.22 (1.04-1.42). There was no significant heterogeneity between subtypes.
In middle-aged women, greater body mass index and height were associated with modestly increased risks of many subtypes of haematological malignancy.
Record-based studies have generally reported association of higher childhood leukaemia incidence with higher socioeconomic status (SES), but recent findings are less consistent.
We examined records ...from the National Registry of Childhood Tumours for evidence of this association in England and Wales during 1976-2005. All eligible leukaemia registrations (N=11940) were grouped by year of diagnosis in decades centred on census years 1981, 1991 and 2001 (N=3748, 3922, 4270, respectively). Using data from the census appropriate to the decade, SES for each case was measured by the child-population-weighted quintile of the Carstairs deprivation index of the census ward containing the address at diagnosis.
In each decade, the age-standardised leukaemia rate in the poorest quintile was ∼90% of the rate in the most affluent. Using Poisson regression, the age-adjusted rate ratio per quintile decrease in SES was 0.96 (95% confidence interval 0.94-0.98; P<0.001 for trend) in 1976-1985, 0.97 (0.95-0.99; P=0.008) in 1986-1995 and 0.97 (0.95-0.99; P=0.009) in 1996-2005. Similar association was evident for lymphoid leukaemia, the major subgroup (N=9588 in total), but not for acute myeloid (N=1868) or other/unspecified leukaemia (N=484).
Reported childhood leukaemia incidence in England and Wales continues to be higher in relatively affluent communities. Possible explanations include under-diagnosis of leukaemia in children from poorer communities, and/or association of higher SES with hypothesised risk factors, such as population mixing and delayed exposure to infection.
To alleviate the problems in the receptor-based design of metalloprotein ligands due to inadequacies in the force-field description of coordination bonds, a four-tier approach was devised. ...Representative ligand−metalloprotein interaction energies are obtained by subsequent application of (1) docking with metal-binding-guided selection of modes, (2) optimization of the ligand−metalloprotein complex geometry by combined quantum mechanics and molecular mechanics (QM/MM) methods, (3) conformational sampling of the complex with constrained metal bonds by force-field-based molecular dynamics (MD), and (4) a single point QM/MM energy calculation for the time-averaged structures. The QM/MM interaction energies are, in a linear combination with the desolvation-characterizing changes in the solvent-accessible surface areas, correlated with experimental data. The approach was applied to structural correlation of published binding free energies of a diverse set of 28 hydroxamate inhibitors to zinc-dependent matrix metalloproteinase 9 (MMP-9). Inclusion of steps 3 and 4 significantly improved both correlation and prediction. The two descriptors explained 90% of variance in inhibition constants of all 28 inhibitors, ranging from 0.08 to 349 nM, with the average unassigned error of 0.318 log units. The structural and energetic information obtained from the time-averaged MD simulation results helped understand the differences in binding modes of related compounds.
Inclusion in clinical trials is generally viewed as best practice for most newly diagnosed childhood cancers, but the impact on population-based survival has rarely been examined.
The ...population-based data were analysed for 25853 children (66% of all registered childhood cancers) diagnosed in Britain during 1978–2005 with acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), Hodgkin lymphoma, non-Hodgkin lymphoma, medulloblastoma, neuroblastoma, Wilms tumour, hepatoblastoma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and germ-cell tumours. The Kaplan–Meier survival curves were compared by log-rank tests. Time trends were analysed by Cox regression. Separate analyses were done for children with ALL, medulloblastoma and neuroblastoma according to clinically relevant age thresholds.
Survival increased significantly during 1978–2005 for every diagnostic category; the annual reduction in risk of death ranged from 2.7% (rhabdomyosarcoma) to 12.0% (gonadal germ-cell tumours). Survival increased steadily between trial eras for ALL (age 1–14years) and neuroblastoma (age 1–14years), but changed little since the mid-1980s for medulloblastoma (age 0–2years), osteosarcoma or Ewing sarcoma.
Changes in survival between trial eras parallel those reported by the relevant clinical trials. The increasing level of participation in trials, facilitated by the organisation of specialist care, has underpinned the substantial improvements in survival seen at the population level.
Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes ...(biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the "Golden Age" of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a "lexicon", not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic.
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