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Abstract Bayesian networks represent a useful tool to explore interactions within biological systems. The aims of this study were to identify a reduced number of genes associated with a stress condition in chickens (Gallus gallus) and to unravel their interactions by implementing a Bayesian network approach. Initially, one publicly available dataset (3 control vs. 3 heat-stressed chickens) was used to identify the stress signal, represented by 25 differentially expressed genes (DEGs). The dataset was augmented by looking for the 25 DEGs in other four publicly available databases. Bayesian network algorithms were used to discover the informative relationships between the DEGs. Only ten out of the 25 DEGs displayed interactions. Four of them were Heat Shock Proteins that could be playing a key role, especially under stress conditions, where maintaining the correct functioning of the cell machinery might be crucial. One of the DEGs is an open reading frame whose function is yet unknown, highlighting the power of Bayesian networks in knowledge discovery. Identifying an initial stress signal, augmenting it by combining other databases, and finally learning the structure of Bayesian networks allowed us to find genes closely related to stress, with the possibility of further exploring the system in future studies.

Abstract Heavy-isotope substitution into enzymes slows down bond vibrations and may alter transition-state barrier crossing probability if this is coupled to fast protein motions. ATP phosphoribosyltransferase from Acinetobacter baumannii is a multi-protein complex where the regulatory protein HisZ allosterically enhances catalysis by the catalytic protein HisGS. This is accompanied by a shift in rate-limiting step from chemistry to product release. Here we report that isotope-labelling of HisGS has no effect on the nonactivated reaction, which involves negative activation heat capacity, while HisZ-activated HisGS catalytic rate decreases in a strictly mass-dependent fashion across five different HisGS masses, at low temperatures. Surprisingly, the effect is not linked to the chemical step, but to fast motions governing product release in the activated enzyme. Disruption of a specific enzyme-product interaction abolishes the isotope effects. Results highlight how altered protein mass perturbs allosterically modulated thermal motions relevant to the catalytic cycle beyond the chemical step.

Abstract Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue (n = 408) and single nucleus RNAseq (n = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM, and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas ( https://rtools.mayo.edu/PSP_RNAseq_Atlas/ ). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases.

Abstract Background Relationships among genetic or epigenetic features can be explored by learning probabilistic networks and unravelling the dependencies among a set of given genetic/epigenetic features. Bayesian networks (BNs) consist of nodes that represent the variables and arcs that represent the probabilistic relationships between the variables. However, practical guidance on how to make choices among the wide array of possibilities in Bayesian network analysis is limited. Our study aimed to apply a BN approach, while clearly laying out our analysis choices as an example for future researchers, in order to provide further insights into the relationships among epigenetic features and a stressful condition in chickens (Gallus gallus). Results Chickens raised under control conditions (n = 22) and chickens exposed to a social isolation protocol (n = 24) were used to identify differentially methylated regions (DMRs). A total of 60 DMRs were selected by a threshold, after bioinformatic pre-processing and analysis. The treatment was included as a binary variable (control = 0; stress = 1). Thereafter, a BN approach was applied: initially, a pre-filtering test was used for identifying pairs of features that must not be included in the process of learning the structure of the network; then, the average probability values for each arc of being part of the network were calculated; and finally, the arcs that were part of the consensus network were selected. The structure of the BN consisted of 47 out of 61 features (60 DMRs and the stressful condition), displaying 43 functional relationships. The stress condition was connected to two DMRs, one of them playing a role in tight and adhesive intracellular junctions in organs such as ovary, intestine, and brain. Conclusions We clearly explain our steps in making each analysis choice, from discrete BN models to final generation of a consensus network from multiple model averaging searches. The epigenetic BN unravelled functional relationships among the DMRs, as well as epigenetic features in close association with the stressful condition the chickens were exposed to. The DMRs interacting with the stress condition could be further explored in future studies as possible biomarkers of stress in poultry species.

Abstract Differences in the expression patterns of genes have been used to measure the effects of non-stress or stress conditions in poultry species. However, the list of genes identified can be extensive and they might be related to several biological systems. Therefore, the aim of this study was to identify a small set of genes closely associated with stress in a poultry animal model, the chicken (Gallus gallus), by reusing and combining data previously published together with bioinformatic analysis and Bayesian networks in a multi-step approach. Two datasets were collected from publicly available repositories and pre-processed. Bioinformatics analyses were performed to identify genes common to both datasets that showed differential expression patterns between non-stress and stress conditions. Bayesian networks were learnt using a Simulated Annealing algorithm implemented in the software Banjo. The structure of the Bayesian network consisted of 16 out of 19 genes together with the stress condition. Network structure showed CARD19 directly connected to the stress condition plus highlighted CYGB, BRAT1, and EPN3 as relevant, suggesting these genes could play a role in stress. The biological functionality of these genes is related to damage, apoptosis, and oxygen provision, and they could potentially be further explored as biomarkers of stress.

The application of diffusion theory and Monte Carlo lidar radiative transfer simulations presented in Part I of this series of study suggests that snow depth can be derived from the first-, second- and third-order moments of the lidar backscattering pathlength distribution. These methods are now applied to the satellite ICESat-2 lidar measurements over the Arctic sea ice and land surfaces of Northern Hemisphere. Over the Arctic sea ice, the ICESat-2 retrieved snow depths agree well with co-located IceBridge snow radar measured values with a root-mean-square (RMS) difference of 7.8 cm or 29.2% of the mean snow depth. The terrestrial snow depths derived from ICESat-2 show drastic spatial variation of the snowpack along ICESat-2 ground tracks over the Northern Hemisphere, which are consistent with the University of Arizona (UA) and Canadian Meteorological Centre (CMC) gridded daily snow products. The RMS difference in snow depths between ICESat-2 and UA gridded daily snow products is 14 cm, or 28% of the mean UA snow depth. To better understand these results, we also discuss the possible sources of errors in ICESat-2 derived snow depths, including surface roughness within the laser footprint, atmospheric forward scattering, solar background noise, and detector dark current. Simulation results indicate that the snow depth errors would be less than 5 cm if the standard deviation of pulse spreading due to surface roughness is within 50 cm. Our results demonstrate that the ICESat-2 lidar measurements can be used to reliably derive snow depth, which is a critical geophysical parameter for cryosphere studies including sea ice thickness estimation and also provides important constraints in the modeling of terrestrial hydrological processes.

Snow is a crucial element in the Earth’s system, but snow depth and mass are very challenging to be measured globally. Here, we provide the theoretical foundation for deriving snow depth directly from space-borne lidar (ICESat-2) snow multiple scattering measurements for the first time. First, based on the Monte Carlo lidar radiative transfer simulations of ICESat-2 measurements of 532-nm laser light propagation in snow, we find that the lidar backscattering path length follows Gamma distribution. Next, we derive three simple analytical equations to compute snow depth from the average, second-, and third-order moments of the distribution. As a preliminary application, these relations are then used to retrieve snow depth over the Antarctic ice sheet and the Arctic sea ice using the ICESat-2 lidar multiple scattering measurements. The robustness of this snow depth technique is demonstrated by the agreement of snow depth computed from the three derived relations using both modeled data and ICESat-2 observations.

Recent advances in genomic sequencing technologies have expanded practitioners’ utilization of genetic information in a timely and efficient manner for an accurate diagnosis. With an ever-increasing resource of genomic data from progress in the interpretation of genome sequences, clinicians face decisions about how and when genomic information should be presented to families, and at what potential expense. Presently, there is limited knowledge or experience in establishing the value of implementing genome sequencing into newborn screening. Herein we provide insight into the complexities and the burden and benefits of knowledge resulting from genome sequencing of newborns.

Introduction Increasingly, health care is delivered through a patient-centered model, and patients engage in shared decision-making with their medical providers. As a result, medical educators are placing more emphasis on patient-centered communication skills. However, few published curricula currently offer a comprehensive discussion of skills for providing patient-centered education (PCE), a key component of shared decision-making. We developed an interactive, two-session workshop aiming to improve students’ abilities to provide PCE. Methods Our workshop included didactic instruction, group discussion, and interactive simulations. The workshop was delivered to 50 clinical clerkship medical students. The first session concentrated on educating patients about their diagnoses, while the second session focused on providing patients with information about medications and other treatments. We used detailed and realistic role-play exercises as a core tool for student practice and demonstration of confidence. To evaluate the workshop, we used pre- and postsurveys. Results The sessions were well received by students, who strongly agreed both before and after the workshop that PCE was an important skill. Students also strongly agreed that the role-play exercises were an effective tool for learning PCE. They demonstrated significant improvements in their confidence to name important elements of PCE and to deliver PCE in the future. Discussion This workshop fills a curricular gap in offering a comprehensive and interactive curriculum for improving students’ abilities to provide critical PCE. The format and content should be easily adaptable to various disciplines, learners, and teaching modalities.

Abstract In this study, we design and carry out a survey, asking human experts to predict the aqueous solubility of druglike organic compounds. We investigate whether these experts, drawn largely from the pharmaceutical industry and academia, can match or exceed the predictive power of algorithms. Alongside this, we implement 10 typical machine learning algorithms on the same dataset. The best algorithm, a variety of neural network known as a multi-layer perceptron, gave an RMSE of 0.985 log S units and an R2 of 0.706. We would not have predicted the relative success of this particular algorithm in advance. We found that the best individual human predictor generated an almost identical prediction quality with an RMSE of 0.942 log S units and an R2 of 0.723. The collection of algorithms contained a higher proportion of reasonably good predictors, nine out of ten compared with around half of the humans. We found that, for either humans or algorithms, combining individual predictions into a consensus predictor by taking their median generated excellent predictivity. While our consensus human predictor achieved very slightly better headline figures on various statistical measures, the difference between it and the consensus machine learning predictor was both small and statistically insignificant. We conclude that human experts can predict the aqueous solubility of druglike molecules essentially equally well as machine learning algorithms. We find that, for either humans or algorithms, combining individual predictions into a consensus predictor by taking their median is a powerful way of benefitting from the wisdom of crowds.