Optical High Content Nanoscopy of Epigenetic Marks Decodes Phenotypic Divergence in Stem Cells

While distinct stem cell phenotypes follow global changes in chromatin marks, single-cell chromatin technologies are unable to resolve or predict stem cell fates. We propose the first such use of optical high content nanoscopy of histone epigenetic marks (epi-marks) in stem cells to classify emergent cell states. By combining nanoscopy with epi-mark textural image informatics, we developed a novel approach, termed EDICTS (Epi-mark Descriptor Imaging of Cell Transitional States), to discern chromatin organizational changes, demarcate lineage gradations across a range of stem cell types and robustly track lineage restriction kinetics. We demonstrate the utility of EDICTS by predicting the lineage progression of stem cells cultured on biomaterial substrates with graded nanotopographies and mechanical stiffness, thus parsing the role of specific biophysical cues as sensitive epigenetic drivers. We also demonstrate the unique power of EDICTS to resolve cellular states based on epi-marks that cannot be detected via mass spectrometry based methods for quantifying the abundance of histone posttranslational modifications. Overall, EDICTS represents a powerful new methodology to predict single cell lineage decisions by integrating high content super-resolution nanoscopy and imaging informatics of the nuclear organization of epi-marks.National Institutes of Health (U.S.) (Grant GM110174

The IPIN 2019 Indoor Localisation Competition—Description and Results

IPIN 2019 Competition, sixth in a series of IPIN competitions, was held at the CNR Research Area of Pisa (IT), integrated into the program of the IPIN 2019 Conference. It included two on-site real-time Tracks and three off-site Tracks. The four Tracks presented in this paper were set in the same environment, made of two buildings close together for a total usable area of 1000 m 2 outdoors and and 6000 m 2 indoors over three floors, with a total path length exceeding 500 m. IPIN competitions, based on the EvAAL framework, have aimed at comparing the accuracy performance of personal positioning systems in fair and realistic conditions: past editions of the competition were carried in big conference settings, university campuses and a shopping mall. Positioning accuracy is computed while the person carrying the system under test walks at normal walking speed, uses lifts and goes up and down stairs or briefly stops at given points. Results presented here are a showcase of state-of-the-art systems tested side by side in real-world settings as part of the on-site real-time competition Tracks. Results for off-site Tracks allow a detailed and reproducible comparison of the most recent positioning and tracking algorithms in the same environment as the on-site Tracks

Prediction of overall survival for patients with metastatic castration-resistant prostate cancer : development of a prognostic model through a crowdsourced challenge with open clinical trial data

Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial-ENTHUSE M1-in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0.791; Bayes factor >5) and surpassed the reference model (iAUC 0.743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3.32, 95% CI 2.39-4.62, p Interpretation Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer.Peer reviewe

Does disclosure regulation affect mutual fund families’ proxy voting?

77 pagesThis paper examines the effect of disclosure regulation on mutual fund families’ proxy voting. I study beneficial ownership reporting rules requiring more-than-5% equity investors to file either a 13D, which allows them to influence the firm and its management, or a less costly 13G, which prohibits such actions. Using a regression discontinuity design, I find that mutual fund families that file beneficial ownership reports (i.e., just above 5%) are more likely to vote in favor of management on executive compensation than families that do not (i.e., just below 5%). Consistent with the idea that mutual fund families opt for a low-cost 13G at the expense of their ability to influence the firm, I also document that the effect of the reporting rules is greater when the cost of filing a 13D is higher or when voting against management is more likely to be seen as influencing the firm. My findings suggest that the regulatory mandates aimed at improving transparency can incentivize mutual fund families to refrain from confronting management in voting.2023-06-0

Antimicrobial Resistance in Foot rot Bacteria

This study set out to determine tetracycline and erythromycin resistance profiles and detect various tetracycline (tetB, tetC, tetL, tetM, tetQ and tetW) or erythromycin (ermA, ermB and ermF) resistance determinants from clinical isolates of bovine foot rot bacteria isolated from affected animals in Alberta. Using agar dilution assay, we determined that 82% (32/39) of Fusobacterium necrophorum were tetracycline resistant and 62% (24/39) were classified intermediate to erythromycin. Approximately 82% (18/22) and 91% (20/22) of Prevotella melaninogenica was sensitive to tetracycline and erythromycin respectively, For Porphyromonas levii, 88% (21/24) were sensitive to tetracycline and 100% (24/24) were erythromycin sensitive. Polymerase chain reaction amplification revealed that tetC, tetL, tetM and ermF were commonly detected in F.necrophorum, and tetQ in Pr.melaninogenica and P.levii. Special resistance determinant patterns were not observed in antibiotic resistant strains compared to sensitive isolates in all three pathogens because as high as 90% of resistance determinants were detected in both resistant and sensitive strains of bacteria

Three-dimensional reconstitution of miniature bladders that structurally and functionally recapitulate in vivo tissue regeneration and cancer

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Biomechanical and Neuromuscular Investigation on the Mechanism of Neck Pain During Smartphone Use

Department of Biomedical Engineering (Human Factors Engineering)As screen time and dependence on the smartphone have increased, the prevalence of neck discomfort and pain has also increased. Since many people adopt a smartphone posture, concerns about neck pain or injury risks related to excessive smartphone use have been increasing. Prolonged and excessive exposure to smartphone use posture can affect the active and passive tissues of the neck, and the changes in neck tissues can be connected to the development of neck pain. The biomechanical and neuromuscular response changes in active and passive tissues were observed in extreme cases, such as exposure to the maximum flexion of the spine, and fatiguing protocols with high muscle contractions. Therefore, the relationship between exposure to that extreme posture and its effect on the changes in tissues is well established. However, there is a lack of biomechanical and neuromuscular investigation related to the smartphone use posture that requires sub-maximal flexion and low-level muscle contraction. It was unclear whether the passive tissues were deformed, or whether muscle fatigue developed during prolonged smartphone use. Objectively evaluating the effect of smartphone use on the active and passive tissues of the neck and understanding their relationship with pain development is essential to understand musculoskeletal pain related to smartphone use, and to prevent related neck injuries. With the aim of concluding which tissues would be changed by prolonged smartphone use and related neck pain, three experiments were conducted in Study 1. The first experiment investigated the viscoelastic changes in passive tissues, but passive tissue laxity was not observed. The second experiment was conducted to investigate the occurrence of neck muscle fatigue. However, it also failed to observe local muscle fatigue. The third experiment aimed to explore the changes in passive tissues by evaluating head stability, but it also did not observe any changes in head stability. In the three experiments, neck pain developed during smartphone use. It implies that prolonged smartphone use might affect the active and passive tissues in the pain development pathway, but no objective evidence about changed tissue properties was found. It is determined that the effect of prolonged smartphone posture on the active and passive tissues should be investigated independently and sensitively with various measurements. Three independent smartphone-use conditions that depart from each tissue's effects were newly designed to investigate the effect of each tissue on subjective pain development, excluding the other tissues' effects in Study 2. The "normal" condition was the common smartphone-use posture of flexing the head approximately 40 ??. The "posture-only" condition induced only flexed posture without muscle activation. Finally, the "muscle-only" condition activated muscles similar to the "normal" condition, without flexed posture. The biomechanical and neuromuscular changes in each tissue were also investigated in the controlled and independent conditions during 60 minutes of exposure. Pain levels, head kinematics, and electromyography (EMG) were collected over time during smartphone use. In the flexion relaxation phenomenon (FRP), tissue laxity and load-sharing timing were observed. The reflexive responses of muscles and passive tissues were evaluated in the presence of unexpected head perturbations. The local muscle fatigue was confirmed through EMG responses in isometric contraction. The seven responses were investigated three times intermittently: pre-, mid-, and post-exposure. The results of Study 2 revealed that increasing musculoskeletal symptoms with smartphones were highly related to sustained muscle activation, but local muscle fatigue was not related to pain development. The possible mechanisms between sustained muscle activation and pain development are capillary compression and reduced oxygenation, spine joint compression, and irritating byproducts. In addition, passively stretched passive tissue was not significantly related to pain, but its micro-damage was confirmed through biomechanical and neuromuscular investigation. Repetitive micro-damage to passive tissues without full recovery could lead to chronic neck pain or future injuries, so it should be carefully considered. These newly designed experimental conditions allowed for observing changes in each tissue that were not revealed in previous studies. The findings of this study may help understand the mechanism of neck pain resulting from prolonged smartphone use and its effect on each tissue.clos

The relationship between personal cognition, social context, and knowledge sharing in global communities of practice

The purpose of this study was to identify the structural pathways of personal cognition and social context as they influence knowledge sharing behaviors in communities of practice. Based on the existing literature, ten hypotheses and a conceptual model built on the basis of the social cognitive theory were developed regarding the interrelationships of the five constructs: self-efficacy for knowledge sharing, outcome expectations, sense of community, leadership of a community, and knowledge sharing. The data were collected through an online questionnaire from the employees who have participated in communities of practice in a Fortune 100 corporation. A total of 438 usable questionnaires were collected. Overall, three analyses were conducted in order to prove the given hypotheses: (a) hypothesized measurement model fit, (b) relational and influential associations among the constructs, and (c) structural equation model analysis (SEM). In addition, open-ended responses were analyzed. The results presented that (a) hypothesized measurement models were valid and reliable, (b) personal cognitive factors, self-efficacy and outcome expectations for knowledge sharing, were found to be significant predictors of community members’ sense of community and knowledge sharing behaviors, (c) sense of community had the most significant impact on the knowledge sharing, (d) as the perceived social context, sense of community mediated the effects of personal cognition on knowledge sharing behaviors, and (e) personal cognition and social context jointly contributed to knowledge sharing. In brief, all of the hypotheses were positively supported. A conclusive summary is provided along with contributive discussion. Implications and contributions to HRD researchers and practitioners are discussed, and recommendations are provided

Cox Proportional Hazards Regression for Interval-Censored Data with an Application to College Entrance and Parental Job Loss

This study involved conducting a survival analysis by fitting a Cox proportional hazards model to Korea Labor Panel data to analyze the impact of parental job loss on children’s delayed admission to colleges and universities in South Korea, using 376 subjects whose parental education levels were college-level or higher. Since Korea Labor Panel data are interval- and right-censored, we compared three imputation methods: simple omission, imputation as the average of the left and right values of the interval, and multiple imputation. Their integrated areas under the ROC curve (AUC) and mean square errors (MSE) were compared to assess their predictive and estimation performances. It was found that, within the simulation, the multiple imputation method exhibited a lower MSE than the other two methods. However, no difference was observed in the iAUC values. In the group where each householder had at least a college degree, parental job loss was significantly related to the delayed college or university admission of the first-born child regardless of the use of the interval censoring imputation method. In particular, when the first-born children experienced their parents’ unemployment at the age of 18, the probability of college admission was reduced nearly by 53% compared to cases where they did not. This analysis implies that the government should develop a policy in the education system offering psychosocial support for adolescents who cannot expect parental help