The Van Allen Probes Electric Fields and Waves (EFW) instrument provided measurements of electric fields and spacecraft floating potentials over a wide dynamic range from DC to 6.5 kHz near the ...equatorial plane of the inner magnetosphere between 600 km altitude and 5.8 Re geocentric distance from October 2012 to November 2019. The two identical instruments provided data to investigate the quasi-static and low frequency fields that drive large-scale convection, waves induced by interplanetary shock impacts that result in rapid relativistic particle energization, ultra-low frequency (ULF) MHD waves which can drive radial diffusion, and higher frequency wave fields and time domain structures that provide particle pitch angle scattering and energization. In addition, measurements of the spacecraft potential provided a density estimate in cold plasmas (
<
20
eV
) from 10 to
3000
cm
−
3
. The EFW instrument provided analog electric field signals to EMFISIS for wave analysis, and it received 3d analog signals from the EMFISIS search coil sensors for inclusion in high time resolution waveform data.
The electric fields and potentials were measured by current-biased spherical sensors deployed at the end of four 50 m booms in the spacecraft spin plane (spin period
∼
11
sec
) and a pair of stacer booms with a total tip-tip separation of 15 m along the spin axis. Survey waveform measurements at 16 and/or 32 S/sec (with a nominal uncertainty of 0.3 mV/m over the prime mission) were available continuously while burst waveform captures at up to 16,384 S/sec provided high frequency waveforms.
This post-mission paper provides the reader with information useful for accessing, understanding and using EFW data. Selected science results are discussed and used to highlight instrument capabilities. Science quantities, data quality and error sources, and analysis routines are documented.
The immunosuppressant azathioprine is used to prevent graft rejection after organ transplantation. To investigate whether azathioprine-associated mutagenesis contributes to the high incidence of skin ...tumours in organ transplant recipients (OTRs), we analysed PTCH gene mutations in 60 basal cell carcinomas (BCC); 39 from OTRs receiving azathioprine and 21 from individuals never exposed to azathioprine. PTCH was mutated in 55% of all tumours, independent of azathioprine treatment. In both the azathioprine and non-azathioprine groups, transitions at dipyrimidine sequences, considered to indicate mutation by ultraviolet-B radiation, occurred frequently in tumours from chronically sun-exposed skin. In BCC from non-sun-exposed skin of azathioprine-treated patients, there was an over-representation of unusual G:C to A:T transitions at non-dipyrimidine sites. These were exclusive to the azathioprine-exposed group and all in the same TGTC sequence context at different positions within PTCH. Meta-analysis of 247 BCCs from published studies indicated that these mutations are rare in sporadic BCC and had never previously been reported in this specific sequence context. This study of post-transplant BCC provides the first indication that azathioprine exposure may be associated with PTCH mutations, particularly in tumours from non-sun-exposed skin.
We report on quasi-parallel whistler emissions detected by the near-earth satellites of the THEMIS mission before, during, and after local dipolarization. These emissions are associated with an ...electron temperature anisotropy α=T⊥e/T||e>1 consistent with the linear theory of whistler mode anisotropy instability. When the whistler mode emissions are observed the measured electron anisotropy varies inversely with β||e (the ratio of the electron parallel pressure to the magnetic pressure) as predicted by Gary and Wang (1996). Narrow band whistler emissions correspond to the small α existing before dipolarization whereas the broad band emissions correspond to large α observed during and after dipolarization. The energy in the whistler mode is leaving the current sheet and is propagating along the background magnetic field, towards the Earth. A simple time-independent description based on the Liouville's theorem indicates that the electron temperature anisotropy decreases with the distance along the magnetic field from the equator. Once this variation of α is taken into account, the linear theory predicts an equatorial origin for the whistler mode. The linear theory is also consistent with the observed bandwidth of wave emissions. Yet, the anisotropy required to be fully consistent with the observations is somewhat larger than the measured one. Although the discrepancy remains within the instrumental error bars, this could be due to time-dependent effects which have been neglected. The possible role of the whistler waves in the substorm process is discussed.
The synthesis of pharmaceutical products frequently involves the use of reactive reagents and the formation of intermediates and by-products. Low levels of some of these may be present in the final ...drug substance and drug product as impurities. Such chemically reactive impurities may have at the same time the potential for unwanted toxicities including genotoxicity and carcinogenicity and hence can have an impact on product risk assessment. This paper outlines a procedure for testing, classification, qualification, toxicological risk assessment, and control of impurities possessing genotoxic potential in pharmaceutical products. Referencing accepted principles of cancer risk assessment, this document proposes a
staged threshold of toxicological concern (TTC) approach for the intake of genotoxic impurities over various periods of exposure. This staged TTC is based on knowledge about tumorigenic potency of a wide range of genotoxic carcinogens and can be used for genotoxic compounds, for which cancer data are limited or not available. The delineated acceptable daily intake values of between ∼1.5
μg/day for ∼ lifetime intake and ∼120
μg/day for ⩽1 month are virtually safe doses. Based on sound scientific reasoning, these virtually safe intake values do not pose an unacceptable risk to either human volunteers or patients at any stage of clinical development and marketing of a pharmaceutical product. The intake levels are estimated to give an excess cancer risk of 1 in 100,000 to 1 in a million over a lifetime, and are extremely conservative given the current lifetime cancer risk in the population of over 1 in 4 (
http://seer.cancer.gov/statfacts/html/all.html). The proposals in this document apply to all clinical routes of administration and to compounds at all stages of clinical development. It is important to note that certain types of products, such as those for life-threatening indications for which there are no safer alternatives, allow for special considerations using adaptations of the principles outlined in this paper.
Several procedures have been proposed to assess structural and functional characteristics of cryopreserved ram semen but none so far have yielded consistent relationships with
in vivo fertility. The ...objectives of this study were to evaluate several sperm function tests as potential markers of
in vivo ram fertility (determined by pregnancy rate in ewes) using frozen-thawed semen. In experiment 1, frozen-thawed straws (
n
=
3 per ram) of semen from three high and three low fertility rams were assessed using fluorescent microscopy for (1) progressive motility, (2) viability and, (3) acrosomal status. In experiment 2, frozen-thawed straws (
n
=
3 per ram) of semen from 18 rams of known fertility were analysed using either computer-assisted sperm analysis (CASA) for eight motion characteristics or flow cytometric staining for: (1) viability and acrosomal status, (2) plasma membrane status and capacitation-like changes, and (3) live cells following an osmotic resistance test (ORT). In experiment 3, platelet-activating factor (PAF) was isolated from straws (
n
=
2 per ram) of semen using high-pressure liquid chromatography (HPLC) and quantified using HPLC–tandem mass spectrometry for 18 rams. In experiment 1, no association was found between motility, viability (% live) or acrosomal status (% damaged, % intact and % reacted) and
in vivo fertility. In experiment 2, no correlation was found between motility (CASA), viability (% live), acrosomal status (% live, % live intact and % reacted), capacitation status (% capacitated, % non-capacitated), plasma membrane stability (% dead) and % live cells following ORT and ram
in vivo fertility. In experiment 3, there was no relationship between PAF content in spermatozoa and ram fertility. In conclusion, we were unable to relate the
in vivo fertility of rams with
in vitro functional tests of their frozen-thawed semen and suggest that the fertility of a given semen sample cannot easily be quantified using available
in vitro tests.
The association of fitness with cancer risk is not clear.
We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, ...endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method.
After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O
⋅min
⋅kg
total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73-0.89), colorectal (0.94, 0.90-0.99), and breast cancer (0.96, 0.92-0.99). In MR analyses, a 0.5 SD increase in genetically predicted O
⋅min
⋅kg
fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86-0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated.
Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.
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