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Pathogenic variants underlying Mendelian diseases often disrupt the normal physiology of a few tissues and organs. However, variant effect prediction tools that aim to identify pathogenic variants are typically oblivious to tissue contexts. Here we report a machine-learning framework, denoted "Tissue Risk Assessment of Causality by Expression for variants" (TRACEvar, https://netbio.bgu.ac.il/TRACEvar/ ), that offers two advancements. First, TRACEvar predicts pathogenic variants that disrupt the normal physiology of specific tissues. This was achieved by creating 14 tissue-specific models that were trained on over 14,000 variants and combined 84 attributes of genetic variants with 495 attributes derived from tissue omics. TRACEvar outperformed 10 well-established and tissue-oblivious variant effect prediction tools. Second, the resulting models are interpretable, thereby illuminating variants' mode of action. Application of TRACEvar to variants of 52 rare-disease patients highlighted pathogenicity mechanisms and relevant disease processes. Lastly, the interpretation of all tissue models revealed that top-ranking determinants of pathogenicity included attributes of disease-affected tissues, particularly cellular process activities. Collectively, these results show that tissue contexts and interpretable machine-learning models can greatly enhance the etiology of rare diseases., (© 2024. The Author(s).)

In this study, the three-person officiating (3PO) principle was employed as an innovative method to examine decision-making (DM) processes among basketball referees. We aimed at exploring whether the ranking, experience, and teamwork among 25 basketball referees could predict accuracy of DM in ambiguous situations taken from basketball games. An analysis of 283 officiating cases taken from 100 filmed games was conducted. The events were then classified by nine experts according to whether the officiating decision was accurate, and which referee (Lead, Centre or Trail) was standing in the main coverage area, as per the 3PO principle, when the decision was made. Our findings indicate that the teamwork (coordination) component was associated with the quality of DM. Of the 283 events, 60 decisions (21%) were not made from the recommended position according to the 3PO principle; 49 of those decisions were incorrect. The findings are discussed from both developmental and instructional perspectives., Competing Interests: The authors declare no conflict of interest., (Copyright: © Academy of Physical Education in Katowice.)

Sodium hypochlorite (NaOCl) is the most common irrigant used in modern endodontics due to the antimicrobial properties against bacteria, the powerful oxidative activity, and the ability to dissolve organic soft tissues. When NaOCl extrudes the apex of the root, commonly referred as "sodium hypochlorite accident," it can lead to devastating outcomes leading to long-term functional and esthetic deficits. Currently, no clear guidelines exist as to how these patients should be managed. The purpose of this paper is to present a case report and a review of literature and to propose an adequate surgical treatment protocol for this unfortunate event.

Krox20/EGR2 is a zinc finger transcription factor, implicated in the development of the hindbrain, nerve myelination, and tumor suppression. In skeletal biology, we have demonstrated that Krox20 also regulates adult bone metabolism. We and others have characterized several functions of Krox20 in the osteoclast lineage, namely, preosteoclast proliferation and differentiation, and mature osteoclast apoptosis. We have previously reported that systemically Krox20-haploinsufficient mice have a low bone mass with increased bone resorption. However, new data have now revealed that this phenotype is restricted to females. In addition, we discovered that conditional knockout of Krox20 (cKO) restricted to osteoclast progenitors is sufficient to induce the same female-specific bone loss observed in systemic mutants. To test whether this sexual dimorphism results from an interaction between Krox20 and sex hormones, we examined the sex- and hormone-dependent role of Krox20 deficiency on proliferation and apoptosis in osteoclastic cells. Our results indicate that male and female sex hormones (dihydrotestosterone [DHT] and estradiol [E2], respectively) as well as Krox20 inhibit preosteoclast proliferation and augment osteoclast apoptosis. The observation that Krox20 expression is inhibited by DHT and E2 negates the hypothesis that the effect of sex hormones is mediated by an increase in Krox20 expression. Interestingly, the effect of Krox20 deficiency was observed only with cells derived from female animals, regardless of any sex hormones added in vitro. In addition, we have identified sexual dimorphism in the expression of several Krox20-related genes, including NAB2. This sex-specific epigenetic profile was established at puberty, maintained in the absence of sex hormones, and explains the female-specific skeletal importance of Krox20. The findings described in this study emphasize the medical importance of sex differences, which may be determined at the epigenetic level. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

An attacking basketball player initiating significant physical contact with a defender who has already established a legal and stationary position, should be called with an offensive foul. Offensive foul situations are particularly ambiguous and complex, making the referee's task a difficult one. In such conditions of complexity and constraints of time, the referee is likely to be prone to systematic biases, as has been documented by previous research in other sport settings. We analyzed the referees' decisions in 250 instances of collisions between an attacking player and a defender. In these collisions the defender fell, and potentially an offensive foul could be called. We found no evidence of favoritism granted to the home team, to star players, or to high-reputation teams, or of small players being tackled by significantly larger opponents. The findings suggest that these biases are not very robust, and are sensitive to the context, and that proper training of referees and enhanced awareness can help to alleviate referees' biases.

Estrogens attenuate bone turnover by inhibiting both osteoclasts and osteoblasts, in part through antagonizing Runx2. Apparently conflicting, stimulatory effects in osteoblast lineage cells, however, sway the balance between bone resorption and bone formation in favor of the latter. Consistent with this dualism, 17ß-estradiol (E2) both stimulates and inhibits Runx2 in a locus-specific manner, and here we provide evidence for such locus-specific regulation of Runx2 by E2 in vivo. We also demonstrate dual, negative and positive, regulation of Runx2-driven alkaline phosphatase (ALP) activity by increasing E2 concentrations in ST2 osteoblast progenitor cells. We further compared the effects of E2 to those of the Selective Estrogen Receptor Modulators (SERMs) raloxifene (ral) and lasofoxifene (las) and the phytoestrogen puerarin. We found that E2 at the physiological concentrations of 0.1-1 nM, as well as ral and las, but not puerarin, antagonize Runx2-driven ALP activity. At ≥10 nM, E2 and puerarin, but not ral or las, stimulate ALP relative to the activity measured at 0.1-1 nM. Contrasting the difference between E2 and SERMs in ST2 cells, they all shared a similar dose-response profile when inhibiting pre-osteoclast proliferation. That ral and las poorly mimic the locus- and concentration-dependent effects of E2 in mesenchymal progenitor cells may help explain their limited clinical efficacy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)