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Open Access Publications from the University of California

Scholarly Works (47 results)

  • Article
  • Peer Reviewed
Lawrence Berkeley National Laboratory (2008)

We analyze the mean rest-frame ultraviolet (UV) spectrum of Type Ia Supernovae (SNe) and its dispersion using high signal-to-noise ratio Keck-I/LRIS-B spectroscopy for a sample of 36 events at intermediate redshift (z=0.5) discovered by the Canada-France-Hawaii Telescope Supernova Legacy Survey (SNLS). We introduce a new method for removing host galaxy contamination in our spectra, exploiting the comprehensive photometric coverage of the SNLS SNe and their host galaxies, thereby providing the first quantitative view of the UV spectral properties of a large sample of distant SNe Ia. Although the mean SN Ia spectrum has not evolved significantly over the past 40percent of cosmic history, precise evolutionary constraints are limited by the absence of a comparable sample of high-quality local spectra. The mean UV spectrum of our z~;;=0.5 SNe Ia and its dispersion is tabulated for use in future applications. Within the high-redshift sample, we discover significant UV spectral variations and exclude dust extinction as the primary cause by examining trends with the optical SN color. Although progenitor metallicity may drive some of these trends, the variations we see are much larger than predicted in recent models and do not follow expected patterns. An interesting new result is a variation seen in the wavelength of selected UV features with phase. We also demonstrate systematic differences in the SN Ia spectral features with SN light curve width in both the UV and the optical. We show that these intrinsic variations could represent a statistical limitation in the future use of high-redshift SNe Ia for precision cosmology. We conclude that further detailed studies are needed, both locally and at moderate redshift where the rest-frame UV can be studied precisely, in order that future missions can confidently be planned to fully exploit SNe Ia as cosmological probes.

    Cover page: Verifying the Cosmological Utility of Type Ia Supernovae: Implications of a Dispersion in the Ultraviolet Spectra
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    • Peer Reviewed
    UC Irvine Previously Published Works (2014)
    The existence and function of extranuclear steroid receptors (SR) to rapidly modulate signal transduction is now acknowledged as present in cells and organs throughout the body. Work over the past 15 years has defined key mechanisms that are required for sex steroid receptors to traffic to the plasma membrane, but mechanisms of localization in other cell organelles such as mitochondria is still unclear. Signaling by membrane-localized SR has now been reported to impact many aspects of adult organ functions, while the roles in organ development are under investigation. In hormone-responsive cancers, both extranuclear and nuclear sex steroid receptors appear to collaborate in the regulation of some key genes that promote malignancy. Here, I review what is understood about the impact of extranuclear steroid receptor signaling to mitigate or promote disease processes.
      Cover page: Translating Extranuclear Steroid Receptor Signaling to Clinical Medicine
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      • Peer Reviewed
      UC Irvine Previously Published Works (2006)
      Estrogen exerts complex biological effects through the two isoforms of estrogen receptors (ERs): ERalpha and ERbeta. 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-beta-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.
        Cover page: Estrogen signaling in the cardiovascular systemCreative Commons 'BY' version 4.0 license
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        • Peer Reviewed
        UC Irvine Previously Published Works (2019)
        Androgens and estrogens are known to be critical regulators of mammalian physiology and development. While these two classes of steroids share similar structures (in general, estrogens are derived from androgens via the enzyme aromatase), they subserve markedly different functions via their specific receptors. In the past, estrogens such as estradiol were thought to be most important in the regulation of female biology, while androgens such as testosterone and dihydrotestosterone were believed to primarily modulate development and physiology in males. However, the emergence of patients with deficiencies in androgen or estrogen hormone synthesis or actions, as well as the development of animal models that specifically target androgen- or estrogen-mediated signaling pathways, have revealed that estrogens and androgens regulate critical biological and pathological processes in both males and females. In fact, the concept of "male" and "female" hormones is an oversimplification of a complex developmental and biological network of steroid actions that directly impacts many organs. In this Review, we will discuss important roles of estrogens in males and androgens in females.
          Cover page: Impact of estrogens in males and androgens in females
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          • Peer Reviewed
          UC Irvine Previously Published Works (2016)
          Steroid hormone receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most steroid receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of steroid hormone signalling and its roles in health and disease.
            Cover page: Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors
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            • Peer Reviewed
            UC Irvine Previously Published Works (2020)
            Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17β-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2018)
              Maintaining a healthy, anti-hypertrophic state in the heart prevents progression to cardiac failure. In humans, angiotensin II (AngII) indirectly and directly stimulates hypertrophy and progression, while estrogens acting through estrogen receptor beta (ERβ) inhibit these AngII actions. The KLF15 transcription factor has been purported to provide anti-hypertrophic action. In cultured neonatal rat cardiomyocytes, we found AngII inhibited KLF1 expression and nuclear localization, substantially prevented by estradiol (E2) or β-LGND2 (β-LGND2), an ERβ agonist. AngII stimulation of transforming growth factor beta expression in the myocytes activated p38α kinase via TAK1 kinase, inhibiting KLF15 expression. All was comparably reduced by E2 or β-LGND2. Knockdown of KLF15 in the myocytes induced myocyte hypertrophy and limited the anti-hypertrophic actions of E2 and β-LGND2. Key aspects were confirmed in an in-vivo model of cardiac hypertrophy. Our findings define additional anti-hypertrophic effects of ERβ supporting testing specific receptor agonists in humans to prevent progression of cardiac disease.
                Cover page: Estrogen receptor beta maintains expression of KLF15 to prevent cardiac myocyte hypertrophy in female rodents
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                • Peer Reviewed
                UC Irvine Previously Published Works (2012)
                Classical estrogen, progesterone, and androgen receptors (ERs, PRs, and ARs) localize outside the nucleus at the plasma membrane of target cells. From the membrane, the receptors signal to activate kinase cascades that are essential for the modulation of transcription and nongenomic functions in many target cells. ER, PR, and AR trafficking to the membrane requires receptor palmitoylation by palmitoylacyltransferase (PAT) protein(s). However, the identity of the steroid receptor PAT(s) is unknown. We identified the DHHC-7 and -21 proteins as conserved PATs for the sex steroid receptors. From DHHC-7 and -21 knockdown studies, the PATs are required for endogenous ER, PR, and AR palmitoylation, membrane trafficking, and rapid signal transduction in cancer cells. Thus the DHHC-7 and -21 proteins are novel targets to selectively inhibit membrane sex steroid receptor localization and function.
                  Cover page: DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptorsCreative Commons 'BY' version 4.0 license
                  • Article
                  • Peer Reviewed
                  ICTS Publications (2013)
                    Cover page: Acid-degradable core-shell nanoparticles for reversed tamoxifen-resistance in breast cancer by silencing manganese superoxide dismutase (MnSOD)Creative Commons 'BY' version 4.0 license
                    • Article
                    • Peer Reviewed
                    UC Irvine Previously Published Works (2014)
                    Steroid receptors are found in discrete cellular locations, but it is unknown whether extranuclear pools are necessary for normal organ development. To assess this, we developed a point mutant estrogen receptor α (ERα) knockin mouse (C451A) that precludes palmitoylation and membrane trafficking of the steroid receptor in all organs. Homozygous knockin female mice (nuclear-only ERα [NOER]) show loss of rapid signaling that occurs from membrane ERα in wild-type mice. Multiple developmental abnormalities were found, including infertility, relatively hypoplastic uteri, abnormal ovaries, stunted mammary gland ductal development, and abnormal pituitary hormone regulation in NOER mice. These abnormalities were rescued in heterozygous NOER mice that were comparable to wild-type mice. mRNAs implicated in organ development were often poorly stimulated by estrogen only in homozygous NOER mice. We conclude that many organs require membrane ERα and resulting signal transduction to collaborate with nuclear ERα for normal development and function.
                      Cover page: Membrane-Localized Estrogen Receptor α Is Required for Normal Organ Development and Function
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