Highly cooperative chimeric super-SOX induces naive pluripotency across species.

Our understanding of pluripotency remains limited: iPSC generation has only been established for a few model species, pluripotent stem cell lines exhibit inconsistent developmental potential, and germline transmission has only been demonstrated for mice and rats. By swapping structural elements between Sox2 and Sox17, we built a chimeric super-SOX factor, Sox2-17, that enhanced iPSC generation in five tested species: mouse, human, cynomolgus monkey, cow, and pig. A swap of alanine to valine at the interface between Sox2 and Oct4 delivered a gain of function by stabilizing Sox2/Oct4 dimerization on DNA, enabling generation of high-quality OSKM iPSCs capable of supporting the development of healthy all-iPSC mice.

Evaluation of the determinants for improved pluripotency induction and maintenance by engineered SOX17.

An engineered SOX17 variant with point mutations within its DNA binding domain termed SOX17FNV is a more potent pluripotency inducer than SOX2, yet the underlying mechanism remains unclear. Although wild-type SOX17 was incapable of inducing pluripotency, SOX17FNV outperformed SOX2 in mouse and human pluripotency reprogramming. In embryonic stem cells, SOX17FNV could replace SOX2 to maintain pluripotency despite considerable sequence differences and upregulated genes expressed in cleavage-stage embryos.

OCT4 interprets and enhances nucleosome flexibility.

Pioneer transcription factors are proteins that induce cellular identity transitions by binding to inaccessible regions of DNA in nuclear chromatin. They contribute to chromatin opening and recruit other factors to regulatory DNA elements. The structural features and dynamics modulating their interaction with nucleosomes are still unresolved.

Oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cells.

The transcription factor Oct4 is essential for the maintenance and induction of stem cell pluripotency, but its functional roles are not fully understood. Here, we investigate the functions of Oct4 by depleting and subsequently recovering it in mouse embryonic stem cells (ESCs) and conducting a time-resolved multiomics analysis. Oct4 depletion leads to an immediate loss of its binding to enhancers, accompanied by a decrease in mRNA synthesis from its target genes that are part of the transcriptional network that maintains pluripotency.

A balanced Oct4 interactome is crucial for maintaining pluripotency.

Oct4 collaborates primarily with other transcriptional factors or coregulators to maintain pluripotency. However, how Oct4 exerts its function is still unclear. Here, we show that the Oct4 linker interface mediates competing yet balanced Oct4 protein interactions that are crucial for maintaining pluripotency.

Reprogramming competence of OCT factors is determined by transactivation domains.

OCT4 (also known as POU5F1) plays an essential role in reprogramming. It is the only member of the POU (Pit-Oct-Unc) family of transcription factors that can induce pluripotency despite sharing high structural similarities to all other members. Here, we discover that OCT6 (also known as POU3F1) can elicit reprogramming specifically in human cells.

Nucleosomal DNA Dynamics Mediate Oct4 Pioneer Factor Binding.

Transcription factor (TF) proteins bind to DNA to regulate gene expression. Normally, accessibility to DNA is required for their function. However, in the nucleus, the DNA is often inaccessible, wrapped around histone proteins in nucleosomes forming the chromatin.

Excluding Oct4 from Yamanaka Cocktail Unleashes the Developmental Potential of iPSCs.

Oct4 is widely considered the most important among the four Yamanaka reprogramming factors. Here, we show that the combination of Sox2, Klf4, and cMyc (SKM) suffices for reprogramming mouse somatic cells to induced pluripotent stem cells (iPSCs). Simultaneous induction of Sox2 and cMyc in fibroblasts triggers immediate retroviral silencing, which explains the discrepancy with previous studies that attempted but failed to generate iPSCs without Oct4 using retroviral vectors.

Fusion of Reprogramming Factors Alters the Trajectory of Somatic Lineage Conversion.

Simultaneous expression of Oct4, Klf4, Sox2, and cMyc induces pluripotency in somatic cells (iPSCs). Replacing Oct4 with the neuro-specific factor Brn4 leads to transdifferentiation of fibroblasts into induced neural stem cells (iNSCs). However, Brn4 was recently found to induce transient acquisition of pluripotency before establishing the neural fate.

Changing POU dimerization preferences converts Oct6 into a pluripotency inducer.

The transcription factor Oct4 is a core component of molecular cocktails inducing pluripotent stem cells (iPSCs), while other members of the POU family cannot replace Oct4 with comparable efficiency. Rather, group III POU factors such as Oct6 induce neural lineages. Here, we sought to identify molecular features determining the differential DNA-binding and reprogramming activity of Oct4 and Oct6.

Dissecting the role of distinct OCT4-SOX2 heterodimer configurations in pluripotency.

The transcription factors OCT4 and SOX2 are required for generating induced pluripotent stem cells (iPSCs) and for maintaining embryonic stem cells (ESCs). OCT4 and SOX2 associate and bind to DNA in different configurations depending on the arrangement of their individual DNA binding elements. Here we have investigated the role of the different OCT4-SOX2-DNA assemblies in regulating and inducing pluripotency.

Blood metabolite profiles in cycling and non-cycling Friesian-Sanga cross-bred cows grazing natural pasture during the post-partum period.

An experiment was conducted to investigate the effect of plasma concentrations of the metabolic hormones [Growth hormone (GH), insulin and insulin-like growth factor -I (IGF-I)] and nutritional metabolites (Glucose, cholesterol, total protein, albumin, globulin, urea and creatinine) on the resumption of post-partum ovarian activity in sixteen Friesian-Sanga cows grazing extensively on native grassland. Blood samples were taken from cows from week 1 to 16 post-partum. Cows were classified as having resumed ovarian activity when a plasma progesterone concentration of ≥ 1.

The ENTPD5/mt-PCPH oncoprotein is a catalytically inactive member of the ectonucleoside triphosphate diphosphohydrolase family.

Expression of the ENTPD5/mt-PCPH onco-protein and overexpression of the normal ENTPD5/PCPH protein contribute to the malignant transformation of diverse mammalian cell types, and PCPH is mutated and/or deregulated in various human tumor types. Expression of PCPH or mt-PCPH caused similar phenotypes, yet the effects promoted by mt-PCPH expression were consistently and substantially greater. ATP depletion and increased stress‑resistance are phenotypes commonly associated with PCPH and mt-PCPH expression.

Incidence and outcome of prone positioning following police use of force in a prospective, consecutive cohort of subjects.

The safety of placing suspects in the prone position following police use of force has been debated extensively, particularly in the context of sudden in-custody death. The proportion of individuals who remain in the prone position following police use of force is not known, nor has the epidemiology of sudden in-custody death in any position after police restraint been documented. Using a consecutive cohort of individuals in whom police used force, we prospectively documented the number of individuals who were placed in a prone versus not-prone position, and the prevalence of sudden in-custody death in either position.

PCPH/ENTPD5 expression enhances the invasiveness of human prostate cancer cells by a protein kinase C delta-dependent mechanism.

Previous reports showed that PCPH is mutated or deregulated in some human tumors, suggesting its participation in malignant progression. Immunohistochemical analyses showed that PCPH is not expressed in normal prostate, but its expression increases along cancer progression stages, being detectable in benign prostatic hyperplasia, highly expressed in prostatic intraepithelial neoplasia, and remaining at high levels in prostate carcinoma. Experiments designed to investigate the contribution of PCPH to the malignant phenotype of prostate cancer cells showed that PCPH overexpression in PC-3 cells, which express nearly undetectable PCPH levels, increased collagen I expression and enhanced invasiveness, whereas shRNA-mediated PCPH knockdown in LNCaP cells, which express high PCPH levels, down-regulated collagen I expression and decreased invasiveness.

Local flexibility in molecular function paradigm.

It is generally accepted that the functional activity of biological macromolecules requires tightly packed three-dimensional structures. Recent theoretical and experimental evidence indicates, however, the importance of molecular flexibility for the proper functioning of some proteins. We examined high resolution structures of proteins in various functional categories with respect to the secondary structure assessment.

Safety profile of 3 months' therapy with alfuzosin in 13,389 patients suffering from benign prostatic hypertrophy.

The safety profile of alfuzosin, a selective alpha 1-adrenergic antagonist, was assessed in a total of 13,389 patients (mean age 66.9 +/- 8.5 years) with symptomatic benign prostatic hypertrophy in two open, noncontrolled, multicentre, post-marketing surveillance studies, both conducted in France.