HST Observations of Heavy Elements in Metal-Poor Galactic Halo Stars

We present new abundance determinations of neutron-capture elements Ge, Zr, Os, Ir, and Pt in a sample of 11 metal-poor (-3.1 <= [Fe/H] <= -1.6) Galactic halo giant stars, based on Hubble Space Telescope UV and Keck I optical high-resolution spectroscopy. The stellar sample is dominated by r-process-rich stars such as the well-studied CS 22892-052 and bd+173248, but also includes the r-process-poor, bright giant HD 122563. Our results demonstrate that abundances of the 3rd r-process peak elements Os, Ir and Pt in these metal-poor halo stars are very well-correlated among themselves, and with the abundances of the canonical r-process element Eu (determined in other studies), thus arguing for a common origin or site for r-process nucleosynthesis of heavier (Z>56) elements. However, the large (and correlated) scatters of [Eu,Os,Ir,Pt/Fe] suggests that the heaviest neutron-capture r-process elements are not formed in all supernovae. In contrast, the Ge abundances of all program stars track their Fe abundances, very well. An explosive process on iron-peak nuclei (e.g., the alpha-rich freeze-out in supernovae), rather than neutron capture, appears to have been the dominant synthesis mechanism for this element at low metallicities -- Ge abundances seem completely uncorrelated with Eu.Comment: 35 pages, 5 tables, 7 figures; To appear in the Astrophysical Journa

The Chemical Composition and Age of the Metal-Poor Halo Star BD +17^\circ 3248

We have combined new high-resolution spectra obtained with the Hubble Space Telescope (HST) and ground-based facilities to make a comprehensive new abundance analysis of the metal-poor, halo star BD +17^\circ 3248. We have detected the third r-process peak elements osmium, platinum, and (for the first time in a metal-poor star) gold, elements whose abundances can only be reliably determined using HST. Our observations illustrate a pattern seen in other similar halo stars with the abundances of the heavier neutron-capture elements, including the third r-process peak elements, consistent with a scaled solar system r-process distribution. The abundances of the lighter neutron-capture elements, including germanium and silver, fall below that same scaled solar r-process curve, a result similar to that seen in the ultra-metal-poor star CS 22892--052. A single site with two regimes or sets of conditions, or perhaps two different sites for the lighter and heavier neutron-capture elements, might explain the abundance pattern seen in this star. In addition we have derived a reliable abundance for the radioactive element thorium. We tentatively identify U II at 3859 A in the spectrum of BD +17^\circ 3248, which makes this the second detection of uranium in a very metal-poor halo star. Our combined observations cover the widest range in proton number (from germanium to uranium) thus far of neutron-capture elements in metal-poor Galactic halo stars. Employing the thorium and uranium abundances in comparison with each other and with several stable elements, we determine an average cosmochronological age for BD +17^\circ 3248 of 13.8 +/- 4 Gyr, consistent with that found for other similar metal-poor halo stars.Comment: 58 pages, 4 tables, 11 figures; To appear in ApJ Typo correcte

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.United States. National Institutes of Health (HG002668)United States. National Institutes of Health (CA109901

Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.United States. National Institutes of Health (HG002668)United States. National Institutes of Health (CA109901

The Extremely Metal-Poor, Neutron-Capture-Rich Star CS 22892-052: A Comprehensive Abundance Analysis

High-resolution spectra obtained with three ground-based facilities and the Hubble Space Telescope (HST) have been combined to produce a new abundance analysis of CS 22892-052, an extremely metal-poor giant with large relative enhancements of neutron-capture elements. A revised model stellar atmosphere has been derived with the aid of a large number of Fe-peak transitions, including both neutral and ionized species of six elements.Several elements, including Mo, Lu, Au, Pt and Pb, have been detected for the first time in CS 22892-052, and significant upper limits have been placed on the abundances of Ga, Ge, Cd, Sn, and U in this star. In total, abundance measurements or upper limits have been determined for 57 elements, far more than previously possible. New Be and Li detections in CS 22892-052 indicate that the abundances of both these elements are significantly depleted compared to unevolved main-sequence turnoff stars of similar metallicity. Abundance comparisons show an excellent agreement between the heaviest n-capture elements (Z >= 56) and scaled solar system r-process abundances, confirming earlier results for CS 22892-052 and other metal-poor stars. New theoretical r-process calculations also show good agreement with CS 22892-052 abundances as well as the solar r-process abundance components.The abundances of lighter elements (40<= Z <= 50), however, deviate from the same scaled abundance curves that match the heavier elements, suggesting different synthesis conditions or sites for the low-mass and high-mass ends of the abundance distribution. The detection of Th and the upper limit on the U abundance together imply a lower limit of 10.4 Gyr on the age of CS 22892-052, quite consistent with the Th/Eu age estimate of 12.8 +/- ~= 3 Gyr. An average of several chronometric ratios yields an age 14.2 +/- ~= 3 Gyr.Comment: 65 pages, 8 figures, 10 tables; To appear in the Astrophysical Journa

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Tumor oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state1, but direct pharmacological inhibition of transcription factors has thus far proven difficult2. However, the transcriptional machinery contains various enzymatic co-factors that can be targeted for development of new therapeutic candidates3, including cyclin-dependent kinases (CDKs)4. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-ALL, exhibit exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and this transcription factor’s key role in the core transcriptional regulatory circuitry of these tumor cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state

Project #37: Management Guidelines for Patients with COVID-19: Rapid Cycle Improvement

Project’s purpose is to rapidly devise, continually improve, educate, and implement a live and changing COVID-19 management guideline based upon emerging best available evidence. This project also aims to optimize the care of patients with COVID-19 and improve patient outcomes.https://scholarlycommons.henryford.com/qualityexpo2022/1004/thumbnail.jp

Wdpcp, a PCP Protein Required for Ciliogenesis, Regulates Directional Cell Migration and Cell Polarity by Direct Modulation of the Actin Cytoskeleton

Planar cell polarity (PCP) regulates cell alignment required for collective cell movement during embryonic development. This requires PCP/PCP effector proteins, some of which also play essential roles in ciliogenesis, highlighting the long-standing question of the role of the cilium in PCP. Wdpcp, a PCP effector, was recently shown to regulate both ciliogenesis and collective cell movement, but the underlying mechanism is unknown. Here we show Wdpcp can regulate PCP by direct modulation of the actin cytoskeleton. These studies were made possible by recovery of a Wdpcp mutant mouse model. Wdpcp-deficient mice exhibit phenotypes reminiscent of Bardet-Biedl/Meckel-Gruber ciliopathy syndromes, including cardiac outflow tract and cochlea defects associated with PCP perturbation. We observed Wdpcp is localized to the transition zone, and in Wdpcp-deficient cells, Sept2, Nphp1, and Mks1 were lost from the transition zone, indicating Wdpcp is required for recruitment of proteins essential for ciliogenesis. Wdpcp is also found in the cytoplasm, where it is localized in the actin cytoskeleton and in focal adhesions. Wdpcp interacts with Sept2 and is colocalized with Sept2 in actin filaments, but in Wdpcp-deficient cells, Sept2 was lost from the actin cytoskeleton, suggesting Wdpcp is required for Sept2 recruitment to actin filaments. Significantly, organization of the actin filaments and focal contacts were markedly changed in Wdpcp-deficient cells. This was associated with decreased membrane ruffling, failure to establish cell polarity, and loss of directional cell migration. These results suggest the PCP defects in Wdpcp mutants are not caused by loss of cilia, but by direct disruption of the actin cytoskeleton. Consistent with this, Wdpcp mutant cochlea has normal kinocilia and yet exhibits PCP defects. Together, these findings provide the first evidence, to our knowledge, that a PCP component required for ciliogenesis can directly modulate the actin cytoskeleton to regulate cell polarity and directional cell migration

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.National Institutes of Health (U.S.) (Grant HG002668)National Institutes of Health (U.S.) (Grant CA109901