Evolution of coordinated mutagenesis and somatic hypermutation in VH5

The VH5 human antibody gene was analyzed using a computer program (mfg) which simulates transcription, to better understand transcription-driven mutagenesis events that occur during phase 1 of somatic hypermutation. Results show that the great majority of mutations in the non-transcribed strand occur within loops of two predicted high-stability stem-loop structures, termed SLSs 14.9 and 13.9. In fact, 89% of the 2505 mutations reported are within the encoded complementarity-determining region (CDR) and occur in loops of these high-stability structures. In vitro studies were also done and verified the existence of SLS 14.9. Following the formation of SLSs 14.9 and 13.9, a sustained period of transcriptional activity occurs within a window size of 60-70 nucleotides. During this period, the stability of these two SLSs does not change, and may provide the substrate for base exchanges and mutagenesis. The data suggest that many mutable bases are exposed simultaneously at pause sites, allowing for coordinated mutagenesis

The roles of transcription and genotoxins underlying p53 mutagenesis in vivo

Transcription drives supercoiling which forms and stabilizes single-stranded (ss) DNA secondary structures with loops exposing G and C bases that are intrinsically mutable and vulnerable to non-enzymatic hydrolytic reactions. Since many studies in prokaryotes have shown direct correlations between the frequencies of transcription and mutation, we conducted in silico analyses using the computer program, mfg, which simulates transcription and predicts the location of known mutable bases in loops of high-stability secondary structures. Mfg analyses of the p53 tumor suppressor gene predicted the location of mutable bases and mutation frequencies correlated with the extent to which these mutable bases were exposed in secondary structures. In vitro analyses have now confirmed that the 12 most mutable bases in p53 are in fact located in predicted ssDNA loops of these structures. Data show that genotoxins have two independent effects on mutagenesis and the incidence of cancer: Firstly, they activate p53 transcription, which increases the number of exposed mutable bases and also increases mutation frequency. Secondly, genotoxins increase the frequency of G-to-T transversions resulting in a decrease in G-to-A and C mutations. This precise compensatory shift in the \u27fate\u27 of G mutations has no impact on mutation frequency. Moreover, it is consistent with our proposed mechanism of mutagenesis in which the frequency of G exposure in ssDNA via transcription is rate limiting for mutation frequency in vivo

Summary of the High Ice Water Content (HIWC) RADAR Flight Campaigns

NASA and the FAA conducted two flight campaigns to quantify onboard weather radar measurements with in-situ measurements of high concentrations of ice crystals found in deep convective storms. The ultimate goal of this research was to improve the understanding and develop onboard weather radar processing to detect regions of high ice water content ahead of an aircraft and enable tactical avoidance of the potentially hazardous conditions. Both High Ice Water Content (HIWC) RADAR campaigns utilized the NASA DC-8 Airborne Science Laboratory which was equipped with a Honeywell RDR-4000 weather radar and icing instruments to characterize the ice crystal clouds. The purpose of this paper is to summarize how these campaigns were conducted and highlight key results

Infrared cameras overestimate skin temperature during rewarming from cold exposure

This is an accepted manuscript of an article published by Elsevier in Journal of Thermal Biology on 03/05/2020, available online: https://doi.org/10.1016/j.jtherbio.2020.102614 The accepted version of the publication may differ from the final published version.Objective The primary aim of this study was to assess the accuracy of an infrared camera and that of a skin thermistor, both commercially available. The study aimed to assess the agreement over a wide range of skin temperatures following cold exposure. Methods Fifty-two males placed their right hand in a thin plastic bag and immersed it in 8 °C water for 30 min whilst seated in an air temperature of 30 °C. Following hand immersion, participants removed the bag and rested their hand at heart level for 10 min. Index finger skin temperature (Tsk) was measured with a thermistor, affixed to the finger pad, and an infrared camera measured 1 cm distally to the thermistor. Agreement between the infrared camera and thermistor was assessed by mean difference (infrared camera minus thermistor) and 95% limits of agreement analysis, accounting for the repeated measures over time. The clinically significant threshold for Tsk differences was set at ±0.5 °C and limits of agreement ±1 °C. Results As an average across all time points, the infrared camera recorded Tsk 1.80 (SD 1.16) °C warmer than the thermistor, with 95% limits of agreement ranging from −0.46 °C to 4.07 °C. Conclusion Collectively, the results show the infrared camera overestimated Tsk at every time point following local cooling. Further, measurement of finger Tsk from the infrared camera consistently fell outside the acceptable level of agreement (i.e. mean difference exceeding ±0.5 °C). Considering these results, infrared cameras may overestimate peripheral Tsk following cold exposure and clinicians and practitioners should, therefore, adjust their risk/withdrawal criteria accordingly.Published versio

Eff ect of a congregation-based intervention on uptake of HIV testing and linkage to care in pregnant women in Nigeria (Baby Shower): a cluster randomised trial

Background Few eff ective community-based interventions exist to increase HIV testing and uptake of antiretroviral therapy (ART) in pregnant women in hard-to-reach resource-limited settings. We assessed whether delivery of an intervention through churches, the Healthy Beginning Initiative, would increase uptake of HIV testing in pregnant women compared with standard health facility referral. Methods In this cluster randomised trial, we enrolled self-identifi ed pregnant women aged 18 years and older who attended churches in southeast Nigeria. We randomised churches (clusters) to intervention or control groups, stratifi ed by mean annual number of infant baptisms (<80 vs ≥80). The Healthy Beginning Initiative intervention included health education and on-site laboratory testing implemented during baby showers in intervention group churches, whereas participants in control group churches were referred to health facilities as standard. Participants and investigators were aware of church allocation. The primary outcome was confi rmed HIV testing. This trial is registered with ClinicalTrials.gov, identifi er number NCT 01795261. Findings Between Jan 20, 2013, and Aug 31, 2014, we enrolled 3002 participants at 40 churches (20 per group). 1309 (79%) of 1647 women attended antenatal care in the intervention group compared with 1080 (80%) of 1355 in the control group. 1514 women (92%) in the intervention group had an HIV test compared with 740 (55%) controls (adjusted odds ratio 11·2, 95% CI 8·77–14·25; p<0·0001). Interpretation Culturally adapted, community-based programmes such as the Healthy Beginning Initiative can be eff ective in increasing HIV screening in pregnant women in resource-limited settings

Dynamical Friction in a Gas: The Subsonic Case

We study the force of dynamical friction acting on a gravitating point mass that travels through an extended, isothermal gas. This force is well established in the hypersonic limit, but remains less understood in the subsonic regime. Using perturbation theory, we analyze the changes in gas velocity and density far from the mass. We show analytically that the steady-state friction force is Mdot*V, where Mdot is the mass accretion rate onto an object moving at speed V. It follows that the speed of an object experiencing no other forces declines as the inverse square of its mass. Using a modified version of the classic Bondi-Hoyle interpolation formula for Mdot as a function of V, we derive an analytic expression for the friction force. This expression also holds when mass accretion is thwarted, e.g. by a wind, as long as the wind-cloud interaction is sufficiently confined spatially. Our result should find application in a number of astrophysical settings, such as the motion of galaxies through intracluster gas.Comment: To appear in MNRAS, 26 pages, 7 figures, single column v2 - Small changes to reflect published version, fixed y-axis scaling on Figure

Summary of the High Ice Water Content (HIWC) RADAR Flight Campaigns

NASA and the FAA (Federal Aviation Administration) conducted two flight campaigns to quantify onboard weather radar measurements with in-situ measurements of high concentrations of ice crystals found in deep convective storms. The ultimate goal of this research was to improve the understanding and develop onboard weather radar processing to detect regions of high ice water content ahead of an aircraft and enable tactical avoidance of the potentially hazardous conditions. Both High Ice Water Content (HIWC) RADAR campaigns utilized the NASA DC-8 Airborne Science Laboratory which was equipped with a Honeywell RDR-4000 weather radar and icing instruments to characterize the ice crystal clouds. The purpose of this paper is to summarize how these campaigns were conducted and highlight key results

Primary brain T-cell lymphoma of the lymphoblastic type presenting as altered mental status

The authors present a case of a 56-year-old man with altered mental status. Magnetic resonance imaging (MRI) of the brain revealed non-enhancing abnormalities on T2 and FLAIR imaging in the brainstem, cerebellum, and cerebrum. Immunohistochemisty demonstrated precursor T-cell lymphoblastic lymphoma. After treatment with methotrexate, he improved clinically without focal sensorimotor deficits and with improving orientation. MRI showed almost complete resolution of brainstem and cerebral lesions. To the authors’ knowledge, there are only five previous reports of primary central nervous system T-cell lymphoblastic lymphoma. Since treatable, it deserves consideration in patients with altered mental status and imaging abnormalities that include diffuse, non-enhancing changes with increased signal on T2-weighted images

Summary of the High Ice Water Content (HIWC) RADAR Flight Campaigns

NASA and the FAA conducted two flight campaigns to quantify onboard weather radar measurements with in-situ measurements of high concentrations of ice crystals found in deep convective storms. The ultimate goal of this research was to improve the understanding and develop onboard weather radar processing to detect regions of high ice water content ahead of an aircraft and enable tactical avoidance of the potentially hazardous conditions. Both High Ice Water Content (HIWC) RADAR campaigns utilized the NASA DC-8 Airborne Science Laboratory which was equipped with a Honeywell RDR-4000 weather radar and icing instruments to characterize the ice crystals clouds. The purpose of this paper is to summarize how these campaigns were conducted and highlight key results