Loneliness among Homeless Individuals during the First Wave of the COVID-19 Pandemic.

The feeling of loneliness is a major public health concern associated with multiple somatic and psychiatric illnesses. Studies have shown increasing incidence of loneliness in the general population during the first wave of the COVID-19 pandemic. Homeless individuals are a particularly vulnerable group; however, little is known about loneliness among homeless individuals. We therefore aimed to examine the prevalence of loneliness among homeless individuals during the pandemic. Furthermore, we estimated the association between loneliness and sociodemographic and lifestyle factors, as well as the self-perceived risk of contracting COVID-19. Data from the Hamburg survey of homeless individuals were used, including 151 homeless individuals that were recruited in spring of 2020. Loneliness was measured by the 3- item version of the UCLA-3 Loneliness Scale. To summarize, 48.5% of the participants experienced loneliness. Multiple linear regressions showed increased loneliness to be associated with male gender (β = 1.07, p = 0.01), being single (β = 1.33, p = 0.00), originating from Germany (β = 1.48, p = 0.00), high frequency of sharing a sleeping space with more than three people (β = 0.42, p = 0.02) and a higher self-perceived risk of contracting COVID-19 (β = 0.41, p = 0.02). On the contrary, there was no association of loneliness with age, educational level, chronic alcohol consumption or frequently sharing a sleeping space. In conclusion, the magnitude of loneliness among homeless individuals during the pandemic was highlighted. Description of factors determining loneliness may help to identify homeless individuals at risk

Zeb2 is essential for Schwann cell differentiation, myelination and nerve repair

Schwann cell development and peripheral nerve myelination require the serial expression of transcriptional activators, such as Sox10, Oct6 (also called Scip or Pou3f1) and Krox20 (also called Egr2). Here we show that transcriptional repression, mediated by the zinc-finger protein Zeb2 (also known as Sip1), is essential for differentiation and myelination. Mice lacking Zeb2 in Schwann cells develop a severe peripheral neuropathy, caused by failure of axonal sorting and virtual absence of myelin membranes. Zeb2-deficient Schwann cells continuously express repressors of lineage progression. Moreover, genes for negative regulators of maturation such as Sox2 and Ednrb emerge as Zeb2 target genes, supporting its function as an inhibitor of inhibitors in myelination control. When Zeb2 is deleted in adult mice, Schwann cells readily dedifferentiate following peripheral nerve injury and become repair cells. However, nerve regeneration and remyelination are both perturbed, demonstrating that Zeb2, although undetectable in adult Schwann cells, has a latent function throughout life

The role of chromatin remodeling complexes in Schwann cell development

Abstract Schwann cells develop from neural crest cells in an ordered series of events and give rise to myelinating and nonmyelinating subtypes. In their mature state, myelinating Schwann cells produce myelin sheaths that provide trophic support to axons and allow saltatory conduction in the vertebrate peripheral nervous system. Each step of Schwann cell development requires defined changes in chromatin structure that are catalyzed by chromatin remodeling complexes. Over the last years, all major types of chromatin remodeling complexes have been detected in Schwann cells and several have been functionally analyzed. SWI/SNF‐type, CHD‐type, and INO80/SWR‐type chromatin remodelers in particular have been shown to interact with multiple cell‐type specific transcription factors and histone modifiers and to be important regulators of Schwann cell development. As a result of different recruitment strategies, each chromatin remodeler targets defined genomic areas and impacts unique mechanisms at specific stages of Schwann cell development. Chromatin remodeling complexes undoubtedly constitute essential components of the Schwann cell regulatory network

PBAF Subunit Pbrm1 Selectively Influences the Transition from Progenitors to Pre-Myelinating Cells during Oligodendrocyte Development

Oligodendrocyte development is accompanied by defined changes in the state of chromatin that are brought about by chromatin remodeling complexes. Many such remodeling complexes exist, but only a few have been studied for their impact on oligodendrocytes as the myelin-forming cells of the central nervous system. To define the role of the PBAF remodeling complex, we focused on Pbrm1 as an essential subunit of the PBAF complex and specifically deleted it in the oligodendrocyte lineage at different times of development in the mouse. Deletion in late oligodendrocyte progenitor cells did not lead to substantial changes in the ensuing differentiation and myelination processes. However, when Pbrm1 loss had already occurred in oligodendrocyte progenitor cells shortly after their specification, fewer cells entered the pre-myelinating state. The reduction in pre-myelinating cells later translated into a comparable reduction in myelinating oligodendrocytes. We conclude that Pbrm1 and, by inference, the activity of the PBAF complex is specifically required at the transition from oligodendrocyte progenitor to pre-myelinating oligodendrocyte and ensures the generation of normal numbers of myelinating oligodendrocytes

Role of the Pbrm1 subunit and the PBAF complex in Schwann cell development

Myelin sheath formation in the peripheral nervous system and the ensuing saltatory conduction rely on differentiated Schwann cells. We have previously shown that transition of Schwann cells from an immature into a differentiated state requires Brg1 that serves as the central energy generating subunit in two related SWI/SNF-type chromatin remodelers, the BAF and the PBAF complex. Here we used conditional deletion of Pbrm1 to selectively interfere with the PBAF complex in Schwann cells. Despite efficient loss of Pbrm1 early during lineage progression, we failed to detect any substantial alterations in the number, proliferation or survival of immature Schwann cells as well as in their rate and timing of terminal differentiation. As a consequence, postnatal myelin formation in peripheral nerves appeared normal. There were no inflammatory alterations in the nerve or other signs of a peripheral neuropathy. We conclude from our study that Pbrm1 and very likely the PBAF complex are dispensable for proper Schwann cell development and that Schwann cell defects previously observed upon Brg1 deletion are mostly attributable to altered or absent function of the BAF complex

Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system

Differentiating oligodendrocytes generate myelin to ensure rapid saltatory conduction in the vertebrate central nervous system. Although oligodendroglial differentiation and myelination are accompanied by dramatic chromatin reorganizations, previously studied chromatin remodelers had only limited direct effects on the process. To study the functional significance of chromatin changes for myelination and identify relevant remodelers, we deleted Ep400, the central ATP-hydrolyzing subunit of the TIP60/EP400 complex, at defined times of mouse oligodendrocyte development. Whereas Ep400-deficient oligodendrocyte precursors develop normally, terminal differentiation and myelination are dramatically impaired. Mechanistically, Ep400 interacts with transcription factor Sox10, binds to regulatory regions of the Myrf gene and is required to induce this central transcriptional regulator of the myelination program. In addition to reduced and aberrant myelin formation, oligodendrocytes exhibit increased DNA damage and apoptosis so that numbers never reach wildtype levels during the short lifespan of Ep400-deficient mice. Ep400 deletion in already mature oligodendrocytes remains phenotypically inapparent arguing that Ep400 is dispensable for myelin maintenance. Given its essential function in myelin formation, modulation of Ep400 activity may be beneficial in conditions such as multiple sclerosis where this process is compromised

The Transcription Factors Sox10 and Myrf Define an Essential Regulatory Network Module in Differentiating Oligodendrocytes

<div><p>Myelin is essential for rapid saltatory conduction and is produced by Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. In both cell types the transcription factor Sox10 is an essential component of the myelin-specific regulatory network. Here we identify Myrf as an oligodendrocyte-specific target of Sox10 and map a Sox10 responsive enhancer to an evolutionarily conserved element in intron 1 of the <i>Myrf</i> gene. Once induced, Myrf cooperates with Sox10 to implement the myelination program as evident from the physical interaction between both proteins and the synergistic activation of several myelin-specific genes. This is strongly reminiscent of the situation in Schwann cells where Sox10 first induces and then cooperates with Krox20 during myelination. Our analyses indicate that the regulatory network for myelination in oligodendrocytes is organized along similar general principles as the one in Schwann cells, but is differentially implemented.</p></div

Ep400 deficiency in Schwann cells causes persistent expression of early developmental regulators and peripheral neuropathy

Schwann cells ensure efficient nerve impulse conduction in the peripheral nervous system. Their development is accompanied by defined chromatin changes, including variant histone deposition and redistribution. To study the importance of variant histones for Schwann cell development, we altered their genomic distribution by conditionally deleting Ep400, the central subunit of the Tip60/Ep400 complex. Ep400 absence causes peripheral neuropathy in mice, characterized by terminal differentiation defects in myelinating and non-myelinating Schwann cells and immune cell activation. Variant histone H2A.Z is differently distributed throughout the genome and remains at promoters of Tfap2a, Pax3 and other transcriptional regulator genes with transient function at earlier developmental stages. Tfap2a deletion in Ep400-deficient Schwann cells causes a partial rescue arguing that continued expression of early regulators mediates the phenotypic defects. Our results show that proper genomic distribution of variant histones is essential for Schwann cell differentiation, and assign importance to Ep400-containing chromatin remodelers in the process

SoxD transcription factor deficiency in Schwann cells delays myelination in the developing peripheral nervous system

The three SoxD proteins, Sox5, Sox6 and Sox13, represent closely related transcription factors with important roles during development. In the developing nervous system, SoxD proteins have so far been primarily studied in oligodendroglial cells and in interneurons of brain and spinal cord. In oligodendroglial cells, Sox5 and Sox6 jointly maintain the precursor state, interfere with terminal differentiation, and thereby ensure the proper timing of myelination in the central nervous system. Here we studied the role of SoxD proteins in Schwann cells, the functional counterpart of oligodendrocytes in the peripheral nervous system. We show that Schwann cells express Sox5 and Sox13 but not Sox6. Expression was transient and ceased with the onset of terminal differentiation. In mice with early Schwann cell-specific deletion of both Sox5 and Sox13, embryonic Schwann cell development was not substantially affected and progressed normally into the promyelinating stage. However, there was a mild and transient delay in the myelination of the peripheral nervous system of these mice. We therefore conclude that SoxD proteins-in stark contrast to their action in oligodendrocytes-promote differentiation and myelination in Schwann cells

Consequences of CNS-specific Sox10 deletion on the expression of myelination-associated genes in OL.

<p>Differentiating OL were visualized by in situ hybridization on transverse spinal cord sections from the forelimb region of wildtype (wt) (<b>A–D,I–L,Q–T</b>) or <i>Sox10^ΔCNS</i> (ko) (<b>E–H,M–P,U–X</b>) mice at P3 (<b>A,E,I,M,Q,U</b>), P7 (<b>B,F,J,N,R,V</b>), P14 (<b>C,G,K,O,S,W</b>) and P21 (<b>D,H,L,P,T,X</b>) using antisense probes against <i>Mbp</i> (<b>A–H</b>), <i>Plp</i> (<b>I–P</b>), and <i>Myrf</i> (<b>Q–X</b>). Ventral horn region is shown. Scale bar, 200 µm.</p