Estrogen signaling in the cardiovascular system

Estrogen exerts complex biological effects through the two isoforms of estrogen receptors (ERs): ERα and ERβ. Whether through alteration of gene expression or rapid, plasma membrane-localized signaling to non-transcriptional actions, estrogen-activated ERs have significant implications in cardiovascular physiology. 17-β-estradiol (E2) generally has a protective property on the vasculature. Estrogen treatment is anti-atherogenic, protecting injured endothelial surfaces and lowering LDL oxidation in animal models. Increased NO production stimulated by E2 results in vasodilation of the coronary vascular bed, and involves rapid activation of phosphotidylinositol-3 kinase (PI3K)/Akt signaling to eNOS in carotid and femoral arteries. Both isoforms of ERs impact various vascular functions, modulating ion channel integrity, mitigating the response to arterial injury, inducing vasodilation, and preventing development of hypertension in animal models. In addition to reducing afterload by vasodilation, ERs have a direct antihypertrophic effect on the myocardium. E2-activated ERs (E2/ER) antagonize the hypertrophic pathway induced by vasoactive peptides such as angiotensin II by activating PI3K, subsequent MICIP gene expression, leading to the inhibition of calcineurin activity and the induction of hypertrophic genes. In models of ischemia-reperfusion, E2/ER is antiapoptotic for cardiomyocytes, exerting the protective actions via PI3K and p38 MAP kinases and suppressing the generation of reactive oxygen species. In sum, E2-activated ERs consistently and positively modulate multiple aspects of the cardiovascular system

SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Atherosclerosis, which underlies life-threatening cardiovascular disorders such as myocardial infarction and stroke1, is initiated by passage of low-density lipoprotein (LDL) cholesterol into the artery wall and its engulfment by macrophages, which leads to foam cell formation and lesion development2,3. It is unclear how circulating LDL enters the artery wall to instigate atherosclerosis. Here we show in mice that scavenger receptor class B type 1 (SR-B1) in endothelial cells mediates the delivery of LDL into arteries and its accumulation by artery wall macrophages, thereby promoting atherosclerosis. LDL particles are colocalized with SR-B1 in endothelial cell intracellular vesicles in vivo, and transcytosis of LDL across endothelial monolayers requires its direct binding to SR-B1 and an eight-amino-acid cytoplasmic domain of the receptor that recruits the guanine nucleotide exchange factor dedicator of cytokinesis 4 (DOCK4)4. DOCK4 promotes internalization of SR-B1 and transport of LDL by coupling the binding of LDL to SR-B1 with activation of RAC1. The expression of SR-B1 and DOCK4 is increased in atherosclerosis-prone regions of the mouse aorta before lesion formation, and in human atherosclerotic arteries when compared with normal arteries. These findings challenge the long-held concept that atherogenesis involves passive movement of LDL across a compromised endothelial barrier. Interventions that inhibit the endothelial delivery of LDL into artery walls may represent a new therapeutic category in the battle against cardiovascular disease

TSIS-1 SIM V09 Solar Spectral Irradiance

NASA&rsquo;s Total and Spectral Solar Irradiance Sensor-1 (TSIS-1) operates on the International Space Station. TSIS-1 provides absolute measurements of the total solar irradiance (TSI) and spectral solar irradiance (SSI), important for accurate scientific models of climate change and solar variability. TSIS-1 is comprised of two instruments, the Total Irradiance Monitor (TIM), and the Spectral Irradiance Monitor (SIM). This repository archives Version 9 (V09) of the TSIS-1 SIM Level 3 (L3) data release, and contains SSI in two cadences, 12-hour and 24-hour. The TSIS-1 SIM L3 V09 data release contains data from 2018-03-14 to 2022-11-11. TSIS-1 SIM data obtained between 2022-03-19 and 2022-05-19 were affected by an anomaly of the sun-pointing sensor (HFSS-B), which offset pointing by ~1 arcminute. V08 introduced a spectral correction for this period, and V09 introduced the ADDITIONAL_UNCERTAINTY column in the data release which reflects the additional irradiance uncertainty associated with the spectral correction. See the attached TSIS_SIM_V09_Release_Notes.pdf or the TSIS SIM Data Products Release Notes page (https://lasp.colorado.edu/tsis/data/ssi-data/sim-ssi-release-notes/) for further details. Data is archived in ASCII, netCDF, and IDL SAVfile format. Creator Penton, Steven Chambliss, Michael Richard, Erik B&eacute;land, St&eacute;phane Brooks, Keira Charbonneau, Luke Coddington, Odele </ul

The X-Ray Crystal Structure of Escherichia coli Succinic Semialdehyde Dehydrogenase; Structural Insights into NADP+/Enzyme Interactions

In mammals succinic semialdehyde dehydrogenase (SSADH) plays an essential role in the metabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to succinic acid (SA). Deficiency of SSADH in humans results in elevated levels of GABA and gamma-Hydroxybutyric acid (GHB), which leads to psychomotor retardation, muscular hypotonia, non-progressive ataxia and seizures. In Escherichia coli, two genetically distinct forms of SSADHs had been described that are essential for preventing accumulation of toxic levels of succinic semialdehyde (SSA) in cells.Here we structurally characterise SSADH encoded by the E coli gabD gene by X-ray crystallographic studies and compare these data with the structure of human SSADH. In the E. coli SSADH structure, electron density for the complete NADP+ cofactor in the binding sites is clearly evident; these data in particular revealing how the nicotinamide ring of the cofactor is positioned in each active site.Our structural data suggest that a deletion of three amino acids in E. coli SSADH permits this enzyme to use NADP+, whereas in contrast the human enzyme utilises NAD+. Furthermore, the structure of E. coli SSADH gives additional insight into human mutations that result in disease

Effects of anharmonic strain on phase stability of epitaxial films and superlattices: applications to noble metals

Epitaxial strain energies of epitaxial films and bulk superlattices are studied via first-principles total energy calculations using the local-density approximation. Anharmonic effects due to large lattice mismatch, beyond the reach of the harmonic elasticity theory, are found to be very important in Cu/Au (lattice mismatch 12%), Cu/Ag (12%) and Ni/Au (15%). We find that is the elastically soft direction for biaxial expansion of Cu and Ni, but it is for large biaxial compression of Cu, Ag, and Au. The stability of superlattices is discussed in terms of the coherency strain and interfacial energies. We find that in phase-separating systems such as Cu-Ag the superlattice formation energies decrease with superlattice period, and the interfacial energy is positive. Superlattices are formed easiest on (001) and hardest on (111) substrates. For ordering systems, such as Cu-Au and Ag-Au, the formation energy of superlattices increases with period, and interfacial energies are negative. These superlattices are formed easiest on (001) or (110) and hardest on (111) substrates. For Ni-Au we find a hybrid behavior: superlattices along and like in phase-separating systems, while for they behave like in ordering systems. Finally, recent experimental results on epitaxial stabilization of disordered Ni-Au and Cu-Ag alloys, immiscible in the bulk form, are explained in terms of destabilization of the phase separated state due to lattice mismatch between the substrate and constituents.Comment: RevTeX galley format, 16 pages, includes 9 EPS figures, to appear in Physical Review

During COVID Sickle Cell Continues: Coping Among Young Adults

To culminate a virtual photovoice research project, artists created a photo exhibition. During this photo exhibition, you will hear from those living with sickle cell disease as they share their realities and experiences of navigating the COVID-19 pandemic. The title carries great significance: \u27During COVID, Sickle Cell Continues.\u27 It echoes the fact that despite civil unrest, a global pandemic, and political shifts, sickle cell disease persists. Our artists share photographs that capture their experiences, and a Q&A session with some of the artists takes place at the end