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

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

Complement membrane attack complex is an immunometabolic regulator of NLRP3 activation and IL-18 secretion in human macrophages

The complement system is an ancient and critical part of innate immunity. Recent studies have highlighted novel roles of complement beyond lysis of invading pathogens with implications in regulating the innate immune response, as well as contributing to metabolic reprogramming of T-cells, synoviocytes as well as cells in the CNS. These findings hint that complement can be an immunometabolic regulator, but whether this is also the case for the terminal step of the complement pathway, the membrane attack complex (MAC) is not clear. In this study we focused on determining whether MAC is an immunometabolic regulator of the innate immune response in human monocyte-derived macrophages. Here, we uncover previously uncharacterized metabolic changes and mitochondrial dysfunction occurring downstream of MAC deposition. These alterations in glycolytic flux and mitochondrial morphology and function mediate NLRP3 inflammasome activation, pro-inflammatory cytokine release and gasdermin D formation. Together, these data elucidate a novel signalling cascade, with metabolic alterations at its center, in MAC-stimulated human macrophages that drives an inflammatory consequence in an immunologically relevant cell type

An Effective Method to Purify Plasmodium falciparum DNA Directly from Clinical Blood Samples for Whole Genome High-Throughput Sequencing

Highly parallel sequencing technologies permit cost-effective whole genome sequencing of hundreds of Plasmodium parasites. The ability to sequence clinical Plasmodium samples, extracted directly from patient blood without a culture step, presents a unique opportunity to sample the diversity of “natural” parasite populations in high resolution clinical and epidemiological studies. A major challenge to sequencing clinical Plasmodium samples is the abundance of human DNA, which may substantially reduce the yield of Plasmodium sequence. We tested a range of human white blood cell (WBC) depletion methods on P. falciparum-infected patient samples in search of a method displaying an optimal balance of WBC-removal efficacy, cost, simplicity, and applicability to low resource settings. In the first of a two-part study, combinations of three different WBC depletion methods were tested on 43 patient blood samples in Mali. A two-step combination of Lymphoprep plus Plasmodipur best fitted our requirements, although moderate variability was observed in human DNA quantity. This approach was further assessed in a larger sample of 76 patients from Burkina Faso. WBC-removal efficacy remained high (<30% human DNA in >70% samples) and lower variation was observed in human DNA quantities. In order to assess the Plasmodium sequence yield at different human DNA proportions, 59 samples with up to 60% human DNA contamination were sequenced on the Illumina Genome Analyzer platform. An average ∼40-fold coverage of the genome was observed per lane for samples with ≤30% human DNA. Even in low resource settings, using a simple two-step combination of Lymphoprep plus Plasmodipur, over 70% of clinical sample preparations should exhibit sufficiently low human DNA quantities to enable ∼40-fold sequence coverage of the P. falciparum genome using a single lane on the Illumina Genome Analyzer platform. This approach should greatly facilitate large-scale clinical and epidemiologic studies of P. falciparum

The Impact of Phenotypic and Genotypic G6PD Deficiency on Risk of Plasmodium vivax Infection: A Case-Control Study amongst Afghan Refugees in Pakistan

Analyses of a case-control study among Afghan refugees in Pakistan find that a G6PD (glucose-6-phosphate dehydrogenase) “Mediterranean” type deficiency confers substantial protection against Plasmodium vivax malaria

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Population Genetic Analysis of Plasmodium falciparum Parasites Using a Customized Illumina GoldenGate Genotyping Assay

The diversity in the Plasmodium falciparum genome can be used to explore parasite population dynamics, with practical applications to malaria control. The ability to identify the geographic origin and trace the migratory patterns of parasites with clinically important phenotypes such as drug resistance is particularly relevant. With increasing single-nucleotide polymorphism (SNP) discovery from ongoing Plasmodium genome sequencing projects, a demand for high SNP and sample throughput genotyping platforms for large-scale population genetic studies is required. Low parasitaemias and multiple clone infections present a number of challenges to genotyping P. falciparum. We addressed some of these issues using a custom 384-SNP Illumina GoldenGate assay on P. falciparum DNA from laboratory clones (long-term cultured adapted parasite clones), short-term cultured parasite isolates and clinical (non-cultured isolates) samples from East and West Africa, Southeast Asia and Oceania. Eighty percent of the SNPs (n = 306) produced reliable genotype calls on samples containing as little as 2 ng of total genomic DNA and on whole genome amplified DNA. Analysis of artificial mixtures of laboratory clones demonstrated high genotype calling specificity and moderate sensitivity to call minor frequency alleles. Clear resolution of geographically distinct populations was demonstrated using Principal Components Analysis (PCA), and global patterns of population genetic diversity were consistent with previous reports. These results validate the utility of the platform in performing population genetic studies of P. falciparum

Spread of artemisinin resistance in Plasmodium falciparum malaria.

BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.)