Requisite chromatin remodeling for myeloid and erythroid lineage differentiation from erythromyeloid progenitors

The mammalian SWitch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling BAF (BRG1/BRM-associated factor) complex plays an essential role in developmental and pathological processes. We show that the deletion of Baf155, which encodes a subunit of the BAF complex, in the Tie2(+) lineage (Baf155 (CKO) leads to defects in yolk sac myeloid and definitive erythroid (EryD) lineage differentiation from erythromyeloid progenitors (EMPs). The chromatin of myeloid gene loci in Baf155 CKO EMPs is mostly inaccessible and enriched mainly by the ETS binding motif. BAF155 interacts with PU.1 and is recruited to PU.1 target gene loci together with p300 and KDM6a. Treatment of Baf155 CKO embryos with GSK126, an H3K27me2/3 methyltransferase EZH2 inhibitor, rescues myeloid lineage gene expression. This study uncovers indispensable BAF-mediated chromatin remodeling of myeloid gene loci at the EMP stage. Future studies exploiting epigenetics in the generation and application of EMP derivatives for tissue repair, regeneration, and disease are warranted

Early immune factors associated with the development of post-acute sequelae of SARS-CoV-2 infection in hospitalized and non-hospitalized individuals

BackgroundInfection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown.MethodsWe enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood samples collected shortly after study enrollment to investigate early immune signatures associated with the development of PASC.ResultsDuring the first week of COVID-19, we observed a large number of differences in the immune profile of individuals who were hospitalized for COVID-19 compared to those individuals with COVID-19 who were not hospitalized. Differences between individuals who did or did not later develop PASC were, in comparison, more limited, but included significant differences in autoantibodies and in epigenetic and transcriptional signatures in double-negative 1 B cells, in particular.ConclusionsWe found that early immune indicators of incident PASC were nuanced, with significant molecular signals manifesting predominantly in double-negative B cells, compared with the robust differences associated with hospitalization during acute COVID-19. The emerging acute differences in B cell phenotypes, especially in double-negative 1 B cells, in PASC patients highlight a potentially important role of these cells in the development of PASC

Thermoelastic coupling in flexural-mode micromechanical and nanomechanical resonators

Mechanical resonators, with dimensions ranging from hundreds of nanometers to hundreds of micrometers, constitute critical components of many microelectromechanical systems (MEMS) and nanoelectromechanical systems (NEMS) used for applications in sensing, communications, energy harvesting and materials testing. The performance of these micro-and nanosystems relies critically on low levels of damping and carefully designed natural frequencies. This thesis analyzes the influence of thermoelastic coupling between deformation and heat on energy dissipation and frequency shift ill flexural-mode resonators used in MEMS and NEMS. Thermoelastic coupling occurs in every flexural resonator that is made of Cl material with a non-zero coefficient of thermal expansion. Thermoelastic damping (TED) therefore represents an absolute lower limit on damping in fiexural resonators, and has been shown to be the dominant mechanism of energy loss in vacuum-operated resonators. In this thesis, new anaytical models are developed for the calculation of TED in structures, materials and operating conditions relevant to MEMS and NEMS. These iuclude the first two-dimensional (2-D) theory of TED in beam resonators capturing the influence of structural boundary conditions and mode shapes on TED, providing the opportunity to explore the error associated with widely used quasi-one-dimensional (quasi-l-D) models. Frequency shift in flexural resonators as a consequence of thermoelastic coupling is computed using the new 2-D heat conduction model, leading to the resolution of prior discrepancies in the literature. Novel analytical models are developed for the calculation of TED in multilayered composite resonators and resonators with geometrical discontinuities. The theoretical results are used to gain insight into measurements of damping in vacuum-operated monolithic, layered composite, slotted, and hollow flexural-mode micromechanical resonators. Detailed design guidelines are developed for SiC-basLes résonateurs mécaniques dont les dimensions varient entre des centaines de nanomètres aux centaines de micromètres constituent des composantes critiques de la plupart des systèmes micro-électro-mécaniques et des systèmes électro - mécaniques nanométriques utilisés pour les applications de détection, de communications, et d’essais de matériaux. La performance de ces systèmes micro- et nanométriques est liée étroitement aux niveaux bas de l’amortissement et aux fréquences naturelles soigneusement conues. Dans le cadre de cette thèse, nous analysons l’influence des effets du couplage thermo-élastique entre la déformation et la chaleur sur la dissipation de l’énergie et la modification de la fréquence des résonateurs à flexion utilisés dans les systèmes micro-électro-mécaniques et les systèmes électro - mécaniques nanométriques. Le couplage thermo-élastique se produit en tout résonateur à flexion qui est composé d’un matériau à un coefficient (l’expansion thermique nonzéro. Par conséquent, l’amortissement thermo-élastique représente une limite basse absolue pour l’amortissement des résonateurs à flexion. Il s’est prouvé d’tre le mécanisme dominant de la perte d’énergie des résonateurs opérés à vide. Afin de calculer l’amortissement thermo-élastique dans des structures. des matériaux et des conditions opérationnelles des systèmes micro-électro-mécaniques et des systèmes électro - mécaniques nanométriques. de nouveaux modèles analytiques sont présentés dans cette thèse. Parmi ces modèles, la première théorie bidimensionnelle (2-D) de l’amortissement thermo-élastique des résonateurs à traverse permet de déterminer l’influence des conditions aux limites structurales et les formes de mode sur l’amortissement thermo-élastique et d’indiquer les erreurs associées aux modèles quasi monodimensionnels (quasi-l-D) largement utilisés. La modification de la fréquence

Thermoelastic coupling in flexural-mode micromechanical and nanomechanical resonators

Mechanical resonators, with dimensions ranging from hundreds of nanometers to hundreds of micrometers, constitute critical components of many microelectromechanical systems (MEMS) and nanoelectromechanical systems (NEMS) used for applications in sensing, communications, energy harvesting and materials testing. The performance of these micro-and nanosystems relies critically on low levels of damping and carefully designed natural frequencies. This thesis analyzes the influence of thermoelastic coupling between deformation and heat on energy dissipation and frequency shift in flexural-mode resonators used in MEMS and NEMS. Thermoelastic coupling occurs in every flexural resonator that is made of Cl material with a non-zero coefficient of thermal expansion. Thermoelastic damping (TED) therefore represents an absolute lower limit on damping in flexural resonators, and has been shown to be the dominant mechanism of energy loss in vacuum-operated resonators. In this thesis, new analytical models are developed for the calculation of TED in structures, materials and operating conditions relevant to MEMS and NEMS. These include the first two-dimensional (2-D) theory of TED in beam resonators capturing the influence of structural boundary conditions and mode shapes on TED, providing the opportunity to explore the error associated with widely used quasi-one-dimensional (quasi-l-D) models. Frequency shift in flexural resonators as a consequence of thermoelastic coupling is computed using the new 2-D heat conduction model, leading to the resolution of prior discrepancies in the literature. Novel analytical models are developed for the calculation of TED in multilayered composite resonators and resonators with geometrical discontinuities. The theoretical results are used to gain insight into measurements of damping in vacuum-operated monolithic, layered composite, slotted, and hollow flexural-mode micromechanical resonators. Detailed design guidelines are developed for SiC-baLes résonateurs mécaniques dont les dimensions varient entre des centaines de nanomètres aux centaines de micromètres constituent des composantes critiques de la plupart des systèmes micro-électro-mécaniques et des systèmes électro -mécaniques nanométriques utilisés pour les applications de détection, de communications, et d'essais de matériaux. La performance de ces systèmes micro-et nanométriques est liée étroitement aux niveaux bas de l'amortissement et aux fréquences naturelles soigneusement conues. Dans le cadre de cette thèse, nous analysons l'influence des effets du couplage thermo-clastique entre la déformation et la chaleur sur la dissipation de l'énergie et la modification de la fréquence des résonateurs a flexion utilises dans les systèmes micro-électro-mécaniques et les systèmes électro -mécaniques nanométriques. Le couplage thermo-clastique se produit en tout résonateur a flexion qui est composé d'un matériau a un coefficient d'expansion thermique non zéro. Par conséquent, l'amortissement thermo-élastique représente une limite basse absolue pour l'amortissement des résonateurs à flexion. Il s'est prouve d'tre le mécanisme dominant de la perte d'énergie des résonateurs opérés avide. Afin de calculer l'amortissement thermo-élastique dans des structures, des matériaux et des conditions opérationnelles des systèmes micro-électro-mécaniques et des systèmes électro -mécaniques nanométriques, de nouveaux modèles analytiques sont présentés dans cette thèse. Parmi ces modèles, la première théorie bidimensionnelle (2-D) de l'amortissement thermo-élastique des résonateurs a traverse permet de déterminer l'influence des conditions aux limites structurales et les formes de mode sur l'amortissement thermo-élastique et d'indiquer les erreurs associées aux modèles quasi monodimensionnels (quasi-I-D) largement utilises. La modification de la fréquence des résonateurs a flexion due au couplage t