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The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes' 1-3 , with a proposed role in contributing to human bipedalism 4-6 . Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene 7-9 -pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans 10 . Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today., (© 2024. The Author(s).)

Overwriting counterselectable markers is an efficient strategy for removing wild-type DNA or replacing it with payload DNA of interest. Currently, one bottleneck of efficient genome engineering in mammals is the shortage of counterselectable (negative selection) markers that work robustly without affecting organismal developmental potential. Here, we report a conditional Piga knockout strategy that enables efficient proaerolysin-based counterselection in mouse embryonic stem cells. The conditional Piga knockout cells show similar proaerolysin resistance as full (non-conditional) Piga deletion cells, which enables the use of a PIGA transgene as a counterselectable marker for genome engineering purposes. Native Piga function is readily restored in conditional Piga knockout cells to facilitate subsequent mouse development. We also demonstrate the generality of our strategy by engineering a conditional knockout of endogenous Hprt . Taken together, our work provides a new tool for advanced mouse genome writing and mouse model establishment., Competing Interests: Jef Boeke is a Founder and Director of CDI Labs, Inc., a Founder of and consultant to Neochromosome, Inc, a Founder, SAB member of and consultant to Re-Open Diagnostics, LLC and serves or served on the Scientific Advisory Board of the following: Sangamo, Inc., Modern Meadow, Inc., Rome Therapeutics, Inc., Sample6, Inc., Tessera Therapeutics, Inc., and the Wyss Institute., (© 2022 The Authors.)

Prostate cancer (PCa) is a very complex disease that is a major cause of death in men worldwide. Currently, PCa dependence on the androgen receptor (AR) has resulted in use of AR antagonists and antiandrogen therapies that reduce endogenous steroid hormone production. However, within two to three years of receiving first-line androgen deprivation therapy, the majority of patients diagnosed with PCa progress to castration-resistant prostate cancer (CRPC). There is an urgent need for therapies that are more durable than antagonism of the AR axis. Studies of runt-related transcription factors (RUNX) and their heterodimerization partner, core-binding factor subunit b (CBFβ), are revealing that the RUNX family are drivers of CRPC. In this review, we describe what is presently understood about RUNX members in PCa, including what regulates and is regulated by RUNX proteins, and the role of RUNX proteins in the tumor microenvironment and AR signaling. We discuss the implications for therapeutically targeting RUNX, the potential for RUNX as PCa biomarkers, and the current pressing questions in the field., (© 2021 Federation of European Biochemical Societies.)

Aim : Our study aims to characterize the differential efficacy of martensitic and austenitic files in root canal retreatment regarding defiling ability, debris management and morphometric features. Materials and methods : A total of 10 human premolar teeth with two separate fully formed roots were selected, prepared with BioRace system (BR) up to a size BR2 (0.04/25). Root canals were filled and then divided according to the file type into two groups (n = 10). Two geometrically identical files have been used with the only difference between them is heat treatment; One Curve (OC) martensitic and One Shape (OS) austenitic. Preoperative and postoperative Micro-CT scans were done for all the samples, and the percent volume of residual filling materials was calculated. Canals reshaping and remaining debris in the canals were assessed by calculating the volume of the canals before and after retreatment using Micro-CT software. Results : The percentages of removed filling materials were similar between both groups (97.2% OC vs 97.8% OS). OS was significantly faster than OC ( P < 0.05). Retreatment procedure did not significantly change volume, structure model index, surface area, and canal curvature. OS group transported the canals more than OC at the apical third ( P < 0.05). There were no significant differences between both groups concerning un-instrumented surface area and accumulated hard tissue debris (AHTD) ( P > 0.05). Conclusion : Under the circumstances of this study, neither file systems could completely remove the filling materials. However, OC resulted in less transportation than OS in the apical one third ( P < 0.05). Also, OC resulted less AHTD than OS but with no statistical difference., (© 2021 The Author(s). Published by BRI.)