Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells.

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective white blood cell differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation and by hijacking normal chromatin regulation. Kat2a is a histone acetyltransferase central to promoter activity, that we recently associated with stability of pluripotency networks, and identified as a genetic vulnerability in AML. Through combined chromatin profiling and single-cell transcriptomics of a conditional knockout mouse, we demonstrate that Kat2a contributes to leukemia propagation through preservation of leukemia stem-like cells. Kat2a loss impacts transcription factor binding and reduces transcriptional burst frequency in a subset of gene promoters, generating enhanced variability of transcript levels. Destabilization of target programs shifts leukemia cell fate out of self-renewal into differentiation. We propose that control of transcriptional variability is central to leukemia stem-like cell propagation, and establish a paradigm exploitable in different tumors and distinct stages of cancer evolution

Renormalized Coupled Cluster Approaches in the Cluster-in-Molecule Framework: Predicting Vertical Electron Binding Energies of the Anionic Water Clusters (H2O)n–

Anionic water clusters are generally considered to be extremely challenging to model using fragmentation approaches due to the diffuse nature of the excess electron distribution. The local correlation coupled cluster (CC) framework cluster-in-molecule (CIM) approach combined with the completely renormalized CR-CC(2,3) method [abbreviated CIM/CR-CC(2,3)] is shown to be a viable alternative for computing the vertical electron binding energies (VEBE). CIM/CR-CC(2,3) with the threshold parameter ζ set to 0.001, as a trade-off between accuracy and computational cost, demonstrates the reliability of predicting the VEBE, with an average percentage error of ∼15% compared to the full ab initio calculation at the same level of theory. The errors are predominantly from the electron correlation energy. The CIM/CR-CC(2,3) approach provides the ease of a black-box type calculation with few threshold parameters to manipulate. The cluster sizes that can be studied by high-level ab initio methods are significantly increased in comparison with full CC calculations. Therefore, the VEBE computed by the CIM/CR-CC(2,3) method can be used as benchmarks for testing model potential approaches in small-to-intermediate-sized water clusters

Use of gonadotrophin releasing hormone (Gn RH

Because of their size and reproductive anatomy, surgical castration is not a practical option in adult elephants. However, similar to other species in human care, the effects of gonadectomy are desired in specific situations. This may be for contraceptive purposes, or for behavioural or veterinary management of elephants in human care or wild elephants managed in small reserves. Research into non‐surgical contraceptive measures for wild and domestic animals has resulted in an array of hormonal and immunological options to downregulate gonadal function. Driven by the production‐animal industry, commercial gonadotrophin releasing hormone (GnRH) vaccines are readily and cheaply available. This immunocontraceptive is effective in both males and females as it inhibits gonadotrophic hormone release and, thus, downstream stimulation of testicles and ovaries. Here, available studies from the past 10 years on the GnRH vaccine application in male and female elephants are reviewed. Furthermore, we add our own experience gathered from the treatment of male African elephants Loxodonta africana and female Asian elephants Elephas maximus in human care. The GnRH vaccine offers a viable approach for various management purposes. It should be noted that the GnRH vaccine was not primarily designed as a reversible contraceptive. Therefore, its use must be well justified on an individual basis and the effects closely monitored.https://zslpublications.onlinelibrary.wiley.com/journal/174810902020-07-01hj2020Anatomy and PhysiologyProduction Animal Studie