Deciphering enhancer sequence using thermodynamics-based models and convolutional neural networks

Deciphering the sequence-function relationship encoded in enhancers holds the key to interpreting non-coding variants and understanding mechanisms of transcriptomic variation. Several quantitative models exist for predicting enhancer function and underlying mechanisms; however, there has been no systematic comparison of these models characterizing their relative strengths and shortcomings. Here, we interrogated a rich data set of neuroectodermal enhancers in Drosophila, representing cis- and trans- sources of expression variation, with a suite of biophysical and machine learning models. We performed rigorous comparisons of thermodynamics-based models implementing different mechanisms of activation, repression and cooperativity. Moreover, we developed a convolutional neural network (CNN) model, called CoNSEPT, that learns enhancer ‘grammar’ in an unbiased manner. CoNSEPT is the first general-purpose CNN tool for predicting enhancer function in varying conditions, such as different cell types and experimental conditions, and we show that such complex models can suggest interpretable mechanisms. We found model-based evidence for mechanisms previously established for the studied system, including cooperative activation and short-range repression. The data also favored one hypothesized activation mechanism over another and suggested an intriguing role for a direct, distance-independent repression mechanism. Our modeling shows that while fundamentally different models can yield similar fits to data, they vary in their utility for mechanistic inference. CoNSEPT is freely available at: https://github.com/PayamDiba/CoNSEPT.

Three-dimensional reduction method with a modified C2 isthmus screw in irreducible atlantoaxial dislocation: a technical note

Background Three-dimensional reduction plays a vital role in surgical reduction of irreversible atlantoaxial dislocation (IAAD). However, the most commonly used combination of C1 pedicle screw (PS) or lateral mass screw (LMS) and C2 PS or isthmus screw often fails to achieve satisfactory reduction at one time. The difficulty is usually caused by short anteroposterior and vertical distance between heads of C1 and C2 screws, which lack enough space for reduction operation. The objective of this study is to describe a three-dimensional reduction method with a modified C2 isthmus screw and to illustrate its advantage and effectiveness for IAAD. Methods Twelve patients with IAAD underwent reduction and fixation with modified C2 isthmus screw combined with C1 PS or LMS, fusion with autologous bone graft. The insertion point was lateral to the intersection of caudal edge of C2 lamina and lateral mass, with a trajectory towards C2 isthmus, via lateral mass. The three-dimensional reduction was achieved through pulling and distracting. Radiographic evaluation included anteroposterior and direct distance between different insertion points, the occipitoaxial angle (O-C2A), clivus-canal angle (CCA) and cervicomedullary angle (CMA). Clinical outcomes evaluation included the Japanese Orthopaedic Association (JOA) score, Visual analog scale (VAS) and Neck Disability Index (NDI). Results All the patients maintained effective reduction during the follow-up. The anteroposterior and direct distance was significantly higher in modified C2 isthmus screw than C2 PS whether combined with C1 PS or LMS (P < 0.05). The degree of O-C2A, CCA and CMA, JOA score, NDI, and VAS were significantly improved after the surgery (P < 0.05). Conclusions Three-dimensional reduction method with a modified C2 isthmus screw is effective and safe in managing IAAD. It can increase the anteroposterior and vertical distance between the heads of C1 and C2 screws, which is benefit for the three-dimensional reduction operation of IAAD.

Which Risk Factors Matter More for Psychological Distress during the COVID-19 Pandemic? An Application Approach of Gradient Boosting Decision Trees

Background: A growing body of scientific literature indicates that risk factors for COVID-19 contribute to a high level of psychological distress. However, there is no consensus on which factors contribute more to predicting psychological health. Objectives: The present study quantifies the importance of related risk factors on the level of psychological distress and further explores the threshold effect of each rick factor on the level of psychological distress. Both subjective and objective measures of risk factors are considered in the model. Methods: We sampled 937 individual items of data obtained from an online questionnaire between 20 January and 13 February 2020 in China. Objective risk factors were measured in terms of direct distance from respondents’ housing to the nearest COVID-19 hospital, direct distance from respondents’ housing to the nearest park, and the air quality index (AQI). Perceived risk factors were measured in regard to perceived distance to the nearest COVID-19 hospital, perceived air quality, and perceived environmental quality. Psychological distress was measured with the Kessler psychological distress scale K6 score. The following health risk factors and sociodemographic factors were considered: self-rated health level, physical health status, physical activity, current smoker or drinker, age, gender, marital status, educational attainment level, residence location, and household income level. A gradient boosting decision tree (GBDT) was used to analyse the data. Results: Health risk factors were the greatest contributors to predicting the level of psychological distress, with a relative importance of 42.32% among all influential factors. Objective risk factors had a stronger predictive power than perceived risk factors (23.49% vs. 16.26%). Furthermore, it was found that there was a dramatic rise in the moderate level of psychological distress regarding the threshold of AQI between 40 and 50, and 110 and 130, respectively. Gender-sensitive analysis revealed that women and men responded differently to psychological distress based on different risk factors. Conclusion: We found evidence that perceived indoor air quality played a more important role in predicting psychological distress compared to ambient air pollution during the COVID-19 pandemic.

Telehealth to increase access to transplant survivorship care for allogeneic stem cell transplant recipients regardless of distance to transplant center or neighborhood income.

e13615 Background: Transplant Survivorship Clinic at our institution serves to improve outcomes and overall health of allogeneic transplant survivors. The COVID19 pandemic allowed for growth of telemedicine in our program. We examine the patterns of use of telehealth and hypothesize that the use of telemedicine allowed continued access to care compared to the era prior to availability. We compared our transplant survivorship clinic data from July- December 2020, when telehealth was well established and compared to July-December 2019. Methods: All patients seen by the survivorship team for end of treatment visits, graft versus host disease assessments and survivorship visits annually between July-December 2019 and July-December 2020 were included. Their zip codes were used to get direct distance to survivorship clinic, average drive time, driving distance and average household income as in zip-codes.com database. Results: Total number of office visits in July-Dec 2019 was 163 visits (0% via telehealth) and in July-Dec 2020 was 228 (66.2% via telehealth). All encounters (telehealth and office visits) were lower in July and August 2020 compared to July and August 2019 but higher in months of September -December 2020 compared to 2019. Comparing all encounters during 7/2019-12/2019 to 7/2020-12/2020, there was no statistically significant difference in median age (58yr vs 60 yr), gender (males: 58% vs 59%), race (non-white: 11% vs 8.7%), median years from transplant (4yr vs 3 yrs), median income of patient neighborhood ($63,735 vs $60,465) and average drive time to center from zip code (40 min vs 51min). Comparison of patients who chose telehealth vs. office visit is summarized in table. While there was no statistically significant difference in age when comparing all encounters in 2019 and 2020, those who chose telehealth were younger (55yrs vs 60yrs, p=0.003). Conclusions: There were higher patient encounters in the 2020 period compared to 2019. Most of these 2020 encounters were via were telehealth, demonstrating the role of telehealth in increasing access. Younger patients appeared to choose telehealth, but telehealth served patients up to the age of 77 yrs. Utilization of telehealth appeared to be irrespective of demographics such as gender, neighborhood income and driving distance to the center. Comparison of telehealth vs office visit for July-December 2019 and 2020.[Table: see text]

Deciphering enhancer sequence using thermodynamics-based models and convolutional neural networks

Deciphering the sequence-function relationship encoded in enhancers holds the key to interpreting non-coding variants and understanding mechanisms of transcriptomic variation. Several quantitative models exist for predicting enhancer function and underlying mechanisms; however, there has been no systematic comparison of these models characterizing their relative strengths and shortcomings. Here, we interrogated a rich data set of neuroectodermal enhancers in Drosophila, representing cis- and trans- sources of expression variation, with a suite of biophysical and machine learning models. We performed rigorous comparisons of thermodynamics-based models implementing different mechanisms of activation, repression, and cooperativity. Moreover, we developed a convolutional neural network (CNN) model, called CoNSEPT, that learns enhancer “grammar” in an unbiased manner. CoNSEPT is the first general-purpose CNN tool for predicting enhancer function in varying conditions, and we show that such complex models can suggest interpretable mechanisms. We found model-based evidence for mechanisms previously established for the studied system, including cooperative activation and short-range repression. The data also favored one hypothesized activation mechanism over another and suggested an intriguing role for a direct, distance-independent repression mechanism. Our modeling shows that while fundamentally different models can yield similar fits to data, they vary in their utility for mechanistic inference. CoNSEPT is freely available at: https://github.com/PayamDiba/CoNSEPT.

IMPROVING THE METHODOLOGY FOR METROLOGICAL CERTIFICATION OF TOTAL STATIONS AND LIGHT RANGE FINDERS

To ensure the uniformity of measurements, it is necessary to perform periodic verifications of ge-odetic instruments in accordance with the requirements of the relevant regulatory documents. In relation to total stations and light meters, ensuring the uniformity of measurements should be carried out by conducting annual periodic checks with the use of stationary reference bases of the 2nd or 3rd category, which were previously created in almost all regions of the country. However, to date, only two such bases have been preserved on the territory of the Russian Federation. The reason for this situa-tion was the lack of proper metrological support for the line lengths of the reference bases themselves, caused by the need for organizational measures, the lack of trained specialists, as well as significant financial expenses for field work. In this regard, there was a scientific and technical task of developing a local calibration scheme (LCS) to provide periodic verifications of total stations and light-emitting diodes over the entire range of measured distances, which does not require the creation of stationary reference bases. For this purpose, the LCS scheme is proposed, based on the use of the method of direct distance measurements. Its essence lies in the simultaneous measurement of the selected distances by reference and verified total stations. To do this, a reference total station and a verifiable one are installed on two tripods located next to each other, which measure the same distance. After that, the total stations are swapped and the measurements are repeated. At the end of the measurement, the measured distances are compared with the reference and verified total stations. Then, based on the difference between these distances, a conclusion is made about the accuracy of the de-vice being tested, as stated in the technical data sheet. The results of the implementation of the proposed LCS showed that its scheme provides the accuracy of measurements at the level of the 2nd category reference basis, and the methodology and accuracy of the length unit transmission meets the of regulatory requirements.