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The POU (Pit-Oct-Unc) protein family is an evolutionary ancient group of transcription factors (TFs) that bind specific DNA sequences to direct gene expression programs. The fundamental importance of POU TFs to orchestrate embryonic development and to direct cellular fate decisions is well established, but the molecular basis for this activity is insufficiently understood. POU TFs possess a bipartite ‘two-in-one’ DNA binding domain consisting of two independently folding structural units connected by a poorly conserved and flexible linker. Therefore, they represent a paradigmatic example to study the molecular basis for the functional versatility of TFs. Their modular architecture endows POU TFs with the capacity to accommodate alternative composite DNA sequences by adopting different quaternary structures. Moreover, associations with partner proteins crucially influence the selection of their DNA binding sites. The plentitude of DNA binding modes confers the ability to POU TFs to regulate distinct genes in the context of different cellular environments. Likewise, different binding modes of POU proteins to DNA could trigger alternative regulatory responses in the context of different genomic locations of the same cell. Prominent POU TFs such as Oct4, Brn2, Oct6 and Brn4 are not only essential regulators of development but have also been successfully employed to reprogram somatic cells to pluripotency and neural lineages. Here we review biochemical, structural, genomic and cellular reprogramming studies to examine how the ability of POU TFs to select regulatory DNA, alone or with partner factors, is tied to their capacity to epigenetically remodel chromatin and drive specific regulatory programs that give cells their identities.

Oct4, along with Sox2 and Klf4 (SK), can induce pluripotency but structurally similar factors like Oct6 cannot. To decode why Oct4 has this unique ability, we compare Oct4-binding, accessibility patterns and transcriptional waves with Oct6 and an Oct4 mutant defective in the dimerization with Sox2 (Oct4 defSox2 ). We find that initial silencing of the somatic program proceeds indistinguishably with or without Oct4. Oct6 mitigates the mesenchymal-to-epithelial transition and derails reprogramming. These effects are a consequence of differences in genome-wide binding, as the early binding profile of Oct4 defSox2 resembles Oct4, whilst Oct6 does not bind pluripotency enhancers. Nevertheless, in the Oct6-SK condition many otherwise Oct4-bound locations become accessible but chromatin opening is compromised when Oct4 defSox2 occupies these sites. We find that Sox2 predominantly facilitates chromatin opening, whilst Oct4 serves an accessory role. Formation of Oct4/Sox2 heterodimers is essential for pluripotency establishment; however, reliance on Oct4/Sox2 heterodimers declines during pluripotency maintenance. Oct4, along with Sox2 and Klf4 can induce pluripotency, but structurally similar factors like Oct6 cannot. Here, using pluripotency competent and incompetent factors, the authors show that Sox2 plays a dominant role in facilitating chromatin opening at Oct4 bound DNA early during reprogramming to pluripotency.

The prognosis of AML patients with adverse genetics, such as a complex, monosomal karyotype and TP53 lesions, is still dismal even with standard chemotherapy. DNA-hypomethylating agent monotherapy induces an encouraging response rate in these patients. When combined with decitabine (DAC), all-trans retinoic acid (ATRA) resulted in an improved response rate and longer overall survival in a randomized phase II trial (DECIDER; NCT00867672). The molecular mechanisms governing this in vivo synergism are unclear. We now demonstrate cooperative antileukemic effects of DAC and ATRA on AML cell lines U937 and MOLM-13. By RNA-sequencing, derepression of >1200 commonly regulated transcripts following the dual treatment was observed. Overall chromatin accessibility (interrogated by ATAC-seq) and, in particular, at motifs of retinoic acid response elements were affected by both single-agent DAC and ATRA, and enhanced by the dual treatment. Cooperativity regarding transcriptional induction and chromatin remodeling was demonstrated by interrogating the HIC1, CYP26A1, GBP4, and LYZ genes, in vivo gene derepression by expression studies on peripheral blood blasts from AML patients receiving DAC + ATRA. The two drugs also cooperated in derepression of transposable elements, more effectively in U937 (mutated TP53) than MOLM-13 (intact TP53), resulting in a “viral mimicry” response. In conclusion, we demonstrate that in vitro and in vivo, the antileukemic and gene-derepressive epigenetic activity of DAC is enhanced by ATRA.

Due to their exceptional solubility and stability, nanobodies have emerged as powerful building blocks for research tools and therapeutics. However, their generation in llamas is cumbersome and costly. Here, by inserting an engineered llama immunoglobulin heavy chain (IgH) locus into IgH-deficient mice, we generate a transgenic mouse line, which we refer to as ‘LamaMouse’. We demonstrate that LamaMice solely express llama IgH molecules without association to Igκ or λ light chains. Immunization of LamaMice with AAV8, the receptor-binding domain of the SARS-CoV-2 spike protein, IgE, IgG2c, and CLEC9A enabled us to readily select respective target-specific nanobodies using classical hybridoma and phage display technologies, single B cell screening, and direct cloning of the nanobody-repertoire into a mammalian expression vector. Our work shows that the LamaMouse represents a flexible and broadly applicable platform for a facilitated selection of target-specific nanobodies. Nanobodies are normally made from immunized camelids, Ig transgenic mice or synthetic libraries. In this study, the authors introduce the llama Ig heavy chain locus into mice lacking this locus, thereby generating a line in which nanobodies can be made by direct immunization in the absence of an endogenous antibody repertoire.

Background Mutations in the EZH2 gene are recurrently found in patients with myeloid neoplasms and are associated with a poor prognosis. We aimed to characterize genetic and epigenetic alterations of EZH2 in 58 patients (51 with acute myeloid leukemia and 7 with myelodysplastic or myeloproliferative neoplasms) by integrating data on EZH2 mutational status, co-occurring mutations, and EZH2 copy number status with EZH2 protein expression, histone H3K27 trimethylation, and EZH2 promoter methylation. Results EZH2 was mutated in 6/51 acute myeloid leukemia patients (12%) and 7/7 patients with other myeloid neoplasms. EZH2 mutations were not overrepresented in patients with chromosome 7q deletions or losses. In acute myeloid leukemia patients, EZH2 mutations frequently co-occurred with CEBPA (67%), ASXL1 (50%), TET2 and RAD21 mutations (33% each). In EZH2 -mutated patients with myelodysplastic or myeloproliferative neoplasms, the most common co-mutations were in ASXL1 (100%), NRAS , RUNX1 , and STAG2 (29% each). EZH2 mutations were associated with a significant decrease in EZH2 expression ( p  = 0.0002), which was similar in patients with chromosome 7 aberrations and patients with intact chromosome 7. An association between EZH2 protein expression and H3K27 trimethylation was observed in EZH2 -unmutated patients ( R 2  = 0.2, p  = 0.01). The monoallelic state of EZH2 was not associated with EZH2 promoter hypermethylation. In multivariable analyses, EZH2 mutations were associated with a trend towards an increased risk of death (hazard ratio 2.51 [95% confidence interval 0.87–7.25], p  = 0.09); similarly, low EZH2 expression was associated with elevated risk (hazard ratio 2.54 [95% confidence interval 1.07–6.04], p  = 0.04). Conclusions Perturbations of EZH2 activity in AML/MDS occur on different, genetic and non-genetic levels. Both low EZH2 protein expression and, by trend, EZH2 gene mutations predicted inferior overall survival of AML patients receiving standard chemotherapy.

An amendment to this paper has been published and can be accessed via the original article.

JS: I can't find a \"smoking gun\" in this case, but CD manufacturers generally quote a CD-RW longevity figure about half that for CD-R, and they cost more, so I can't see a good argument for using them. Also, historically, CD-RW discs have not been compatible with as many drives.

•gGM-CSF coupling serves as a non-invasive measure of the ventricular CSF system.•We analyzed fMRI-based coupling after sleep deprivation and regular sleep.•gGM-CSF coupling increased after sleep deprivation in young, healthy adults.•This increase may reflect a compensatory adaptive response to sleep loss.•Younger adults may exhibit greater responsiveness in CSF dynamics than older adults. Evidence indicates that brain waste clearance happens more efficiently during sleep. Recent studies suggest that the correlation, i.e., coupling, between the cortical grey matter (gGM) blood oxygenation level-dependent signal and cerebrospinal fluid (CSF) signal in the foramen magnum, measured via resting-state functional MRI (fMRI), serves as a non-invasive measure of the ventricular CSF system. Sleep deprivation has been demonstrated to affect brain function and health. Our aim is to assess gGM-CSF coupling after partial sleep deprivation, hypothesizing a change in the coupling measure relative to normal sleep. To test this hypothesis, we analyzed resting-state fMRI data from 63 healthy participants in the “The Stockholm Sleepy Brain Study”, grouped according to age: younger (20 - 29 years) and older (65 - 75 years) adults. We examined gGM-CSF coupling twice in each subject, in the evening following a night of normal sleep and after a night of partial sleep deprivation (≤ 3 h of sleep). Our results revealed significantly increased gGM-CSF coupling after sleep deprivation compared to normal sleep (mean r = -0.30 ± 0.19 vs. -0.25 ± 0.14; t(62) = 2.05, p = 0.045). A linear mixed model demonstrated a significant interaction of age with the sleep condition (β = 0.0031, t = 2.73, p = 0.0083), showing significant changes only in the younger subgroup (t(35) = 2.99, p = 0.0050). These findings indicate that gGM-CSF coupling increases after partial sleep deprivation in younger adults, which may reflect compensatory mechanisms in response to reduced sleep duration. Furthermore, the results suggest that this compensatory response could be diminished in older adults.

In this cluster-randomized trial, the use of expanded barrier precautions did not decrease the incidence of vancomycin-resistant enterococcus and methicillin-resistant Staphylococcus aureus (MRSA) in intensive care units; however, adherence to the precautions was suboptimal. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE) are major causes of health care–associated infection. 1 Infections caused by these bacteria are usually preceded by colonization of mucous membranes, skin, wounds, or the gastrointestinal tract. Colonization occurs by means of indirect patient-to-patient transmission of MRSA and VRE through the hands of health care providers and through contaminated fomites and environmental surfaces 2 , 3 or, less commonly, by direct transmission from colonized health care providers. 4 Standard interventions to prevent the transmission of MRSA and VRE in health care facilities include hand hygiene, the use of barrier precautions (gloves and gowns) in the care . . .

Premature-born infants have impaired amygdala structure, presumably due to increased stress levels of premature birth mediated by the amygdala. However, accounting for lifelong plasticity of amygdala, it is unclear whether such structural changes persist into adulthood. To address this problem, we stated the following questions: first, are whole amygdala volumes reduced in premature-born adults? And second, as adult anxiety traits are often increased after prematurity and linked with amygdala structure, are alterations in amygdala associated with adults’ anxiety traits after premature birth? We addressed these questions by automated amygdala segmentation of MRI volumes in 101 very premature-born adults (< 32 weeks of gestation and/or birth weight below 1500 g) and 108 full-term controls at 26 years of age of a prospectively and longitudinally collected cohort. We found significantly lower whole amygdala volumes in premature-born adults. While premature-born adults had significantly higher T score for avoidant personality reflecting increased social anxiety trait, this trait was not correlated with amygdala volume alterations. Results demonstrate reduced amygdala volumes in premature born adults. Data suggest lasting effects of prematurity on amygdala structure.