Utilizing biological experimental data and molecular dynamics for the classification of mutational hotspots through machine learning

Motivation: Benzo[a]pyrene, a notorious DNA-damaging carcinogen, belongs to the family of polycyclic aromatic hydrocarbons commonly found in tobacco smoke. Surprisingly, nucleotide excision repair (NER) machinery exhibits inefficiency in recognizing specific bulky DNA adducts including Benzo[a]pyrene Diol-Epoxide (BPDE), a Benzo[a]pyrene metabolite. While sequence context is emerging as the leading factor linking the inadequate NER response to BPDE adducts, the precise structural attributes governing these disparities remain inadequately understood. We therefore combined the domains of molecular dynamics and machine learning to conduct a comprehensive assessment of helical distortion caused by BPDE-Guanine adducts in multiple gene contexts. Specifically, we implemented a dual approach involving a random forest classification-based analysis and subsequent feature selection to identify precise topological features that may distinguish adduct sites of variable repair capacity. Our models were trained using helical data extracted from duplexes representing both BPDE hotspot and nonhotspot sites within the TP53 gene, then applied to sites within TP53, cII, and lacZ genes. Results: We show our optimized model consistently achieved exceptional performance, with accuracy, precision, and f1 scores exceeding 91%. Our feature selection approach uncovered that discernible variance in regional base pair rotation played a pivotal role in informing the decisions of our model. Notably, these disparities were highly conserved among TP53 and lacZ duplexes and appeared to be influenced by the regional GC content. As such, our findings suggest that there are indeed conserved topological features distinguishing hotspots and nonhotpot sites, highlighting regional GC content as a potential biomarker for mutation. Availability and implementation: Code for comparing machine learning classifiers and evaluating their performance is available at https://github.com/jdavies24/ML-Classifier-Comparison, and code for analysing DNA structure with Curves+ and Canal using Random Forest is available at https://github.com/jdavies24/ML-classification-of-DNA-trajectories

Cost-Effectiveness of Skin Surveillance Through a Specialized Clinic for Patients at High Risk of Melanoma

Purpose Clinical guidelines recommend that people at high risk of melanoma receive regular surveillance to improve survival through early detection. A specialized High Risk Clinic in Sydney, Australia was found to be effective for this purpose; however, wider implementation of this clinical service requires evidence of cost-effectiveness and data addressing potential overtreatment of suspicious skin lesions. Patients and Methods A decision-analytic model was built to compare the costs and benefits of specialized surveillance compared with standard care over a 10-year period, from a health system perspective. A high-risk standard care cohort was obtained using linked population data, comprising the Sax Institute’s 45 and Up cohort study, linked to Medicare Benefits Schedule claims data, the cancer registry, and hospital admissions data. Benefits were measured in quality-adjusted life-years gained. Sensitivity analyses were undertaken for all model parameters. Results Specialized surveillance through the High Risk Clinic was both less expensive and more effective than standard care. The mean saving was A$6,828 (95$5,564 to $8,092) per patient, and the mean quality-adjusted life-year gain was 0.31 (95% CI, 0.27 to 0.35). The main drivers of the differences were detection of melanoma at an earlier stage resulting in less extensive treatment and a lower annual mean excision rate for suspicious lesions in specialized surveillance (0.81; 95% CI, 0.72 to 0.91) compared with standard care (2.55; 95% CI, 2.34 to 2.76). The results were robust when tested in sensitivity analyses. Conclusion Specialized surveillance was a cost-effective strategy for the management of individuals at high risk of melanoma. There were also fewer invasive procedures in specialized surveillance compared with standard care in the community

Development of an Objective Structured Clinical Examination as a Component of Assessment for Initial Board Certification in Anesthesiology.

With its first administration of an Objective Structured Clinical Examination (OSCE) in 2018, the American Board of Anesthesiology (ABA) became the first US medical specialty certifying board to incorporate this type of assessment into its high-stakes certification examination system. The fundamental rationale for the ABA's introduction of the OSCE is to include an assessment that allows candidates for board certification to demonstrate what they actually "do" in domains relevant to clinical practice. Inherent in this rationale is that the OSCE will capture competencies not well assessed in the current written and oral examinations-competencies that will allow the ABA to judge whether a candidate meets the standards expected for board certification more properly. This special article describes the ABA's journey from initial conceptualization through first administration of the OSCE, including the format of the OSCE, the process for scenario development, the standardized patient program that supports OSCE administration, examiner training, scoring, and future assessment of reliability, validity, and impact of the OSCE. This information will be beneficial to both those involved in the initial certification process, such as residency graduate candidates and program directors, and others contemplating the use of high-stakes summative OSCE assessments

Optimisation of energetic and reproductive gains explains behavioural responses to environmental variation across seasons and years

Animals switch between inactive and active states, simultaneously impacting their energy intake, energy expenditure and predation risk, and collectively defining how they engage with environmental variation and trophic interactions. We assess daily activity responses to long‐term variation in temperature, resources and mating opportunities to examine whether individuals choose to be active or inactive according to an optimisation of the relative energetic and reproductive gains each state offers. We show that this simplified behavioural decision approach predicts most activity variation (R2 = 0.83) expressed by free‐ranging red squirrels over 4 years, as quantified through accelerometer recordings (489 deployments; 5066 squirrel‐days). Recognising activity as a determinant of energetic status, the predictability of activity variation aggregated at a daily scale, and the clear signal that behaviour is environmentally forced through optimisation of gain, provides an integrated approach to examine behavioural variation as an intermediary between environmental variation and energetic, life‐history and ecological outcomes.By assessing daily activity responses to long‐term variation in temperature, resources, and mating opportunities, we examine whether individuals choose to be active or inactive according to an optimization of energetic and reproductive gains. This simplified behavioural decision approach predicts most daily activity variation (R2 = 0.83) expressed by free‐ranging red squirrels over four years, as quantified through accelerometer recordings. Here we provide an integrated approach to examine behavioural variation as an intermediary between environmental variation and energetic, life‐history, and ecological outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154889/1/ele13494_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154889/2/ele13494.pd

Spitzer Space Telescope spectral observations of AGB stars in the Fornax dwarf spheroidal galaxy

We have observed five carbon-rich AGB stars in the Fornax dwarf spheroidal (dSph) galaxy, using the Infrared Spectrometer on board the Spitzer Space Telescope. The stars were selected from a near-infrared survey of Fornax and include the three reddest stars, with presumably the highest mass-loss rates, in that galaxy. Such carbon stars probably belong to the intermediate-age population (2-8 Gyr old and metallicity of [Fe/H] -1) of Fornax. The primary aim of this paper is to investigate mass-loss rate, as a function of luminosity and metallicity, by comparing AGB stars in several galaxies with different metallicities. The spectra of three stars are fitted with a radiative transfer model. We find that mass-loss rates of these three stars are 4-7x10^-6 Msun yr-1. The other two stars have mass-loss rates below 1.3x10^-6 Msun yr-1. We find no evidence that these rates depend on metallicity, although we do suggest that the gas-to-dust ratio could be higher than at solar metallicity, in the range 240 to 800. The C2H2 bands are stronger at lower metallicity because of the higher C/O ratio. In contrast, the SiC fraction is reduced at low metallicity, due to low silicon abundance. The total mass-loss rate from all known carbon-rich AGB stars into the interstellar medium of this galaxy is of the order of 2x10^-5 Msun yr-1. This is much lower than that of the dwarf irregular galaxy WLM, which has a similar visual luminosity and metallicity. The difference is attributed to the younger stellar population of WLM. The suppressed gas-return rate to the ISM accentuates the difference between the relatively gas-rich dwarf irregular and the gas-poor dwarf spheroidal galaxies. Our study will be useful to constrain gas and dust recycling processes in low metallicity galaxies.Comment: MNRAS accepte

Distance Scale Zero Points from Galactic RR Lyrae Star Parallaxes

We present new absolute trigonometric parallaxes and proper motions for seven Population II variable stars—five RR Lyr variables: RZ Cep, XZ Cyg, SU Dra, RR Lyr, and UV Oct; and two type 2 Cepheids: VY Pyx and κ Pav. We obtained these results with astrometric data from Fine Guidance Sensors, white-light interferometers on Hubble Space Telescope. We find absolute parallaxes in milliseconds of arc: RZ Cep, 2.12 ± 0.16 mas; XZ Cyg, 1.67 ± 0.17 mas; SU Dra, 1.42 ± 0.16 mas; RR Lyr, 3.77 ± 0.13 mas; UV Oct, 1.71 ± 0.10 mas; VY Pyx, 6.44 ± 0.23 mas; and κ Pav, 5.57 ± 0.28 mas; an average σπ/π = 5.4%. With these parallaxes, we compute absolute magnitudes in V and K bandpasses corrected for interstellar extinction and Lutz-Kelker-Hanson bias. Using these RR Lyrae variable star absolute magnitudes, we then derive zero points for MV -[Fe/H] and MK -[Fe/H]-log P relations. The technique of reduced parallaxes corroborates these results. We employ our new results to determine distances and ages of several Galactic globular clusters and the distance of the Large Magellanic Cloud. The latter is close to that previously derived from Classical Cepheids uncorrected for any metallicity effect, indicating that any such effect is small. We also discuss the somewhat puzzling results obtained for our two type 2 Cepheids

Design and Synthesis of Broad Spectrum Trypanosomatid Selective Inhibitors

Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern that have a devastating effect on the developing world due to their burden on human and animal health. In this work, we detail the preparation of a focused library of substituted-tetrahydropyran derivatives and their evaluation as selective chemical tools for trypanosomatid inhibition and the follow-on development of photoaffinity probes capable of labeling target protein(s) <i>in vitro</i>. Several of these functionalized compounds maintain low micromolar activity against <i>Trypanosoma brucei</i>, <i>Trypanosoma cruzi</i>, <i>Leishmania major</i>, and <i>Leishmania donovani</i>. In addition, we demonstrate the utility of the photoaffinity probes for target identification through preliminary cellular localization studies