Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy

Leishmania pyrimidine salvage is replete with opportunities for therapeutic intervention with enzyme inhibitors or antimetabolites. Their uptake into cells depends upon specific transporters; therefore it is essential to establish whether various Leishmania species possess similar pyrimidine transporters capable of drug uptake. Here, we report a comprehensive characterization of pyrimidine transport in L. major and L. mexicana. In both species, two transporters for uridine/adenosine were detected, one of which also transported uracil and the antimetabolites 5-fluoruracil (5-FU) and 5F,2′deoxyuridine (5F,2′dUrd), and was designated uridine-uracil transporter 1 (UUT1); the other transporter mediated uptake of adenosine, uridine, 5F,2′dUrd and thymidine and was designated Nucleoside Transporter 1 (NT1). To verify the reported L. donovani model of two NT1-like genes encoding uridine/adenosine transporters, and an NT2 gene encoding an inosine transporter, we cloned the corresponding L. major and L. mexicana genes, expressing each in T. brucei. Consistent with the L. donovani reports, the NT1-like genes of either species mediated the adenosine-sensitive uptake of [3H]-uridine but not of [3H]-inosine. Conversely, the NT2-like genes mediated uptake of [3H]-inosine but not [3H]-uridine. Among pyrimidine antimetabolites tested, 5-FU and 5F,2′dUrd were the most effective antileishmanials; resistance to both analogs was induced in L. major and L. mexicana. In each case it was found that the resistant cells had lost the transport capacity for the inducing drug. Metabolomics analysis found that the mechanism of action of 5-FU and 5F-2′dUrd was similar in both Leishmania species, with major changes in deoxynucleotide metabolism. We conclude that the pyrimidine salvage system is highly conserved in Leishmania species - essential information for the development of pyrimidine-based chemotherapy

Correlations of structural, magnetic, and dielectric properties of undoped and doped CaCu3Ti4O12

The present work reports synthesis, as well as a detailed and careful characterization of structural, magnetic, and dielectric properties of differently tempered undoped and doped CaCu3Ti4O12 (CCTO) ceramics. For this purpose, neutron and x-ray powder diffraction, SQUID measurements, and dielectric spectroscopy have been performed. Mn-, Fe-, and Ni-doped CCTO ceramics were investigated in great detail to document the influence of low-level doping with 3d metals on the antiferromagnetic structure and dielectric properties. In the light of possible magnetoelectric coupling in these doped ceramics, the dielectric measurements were also carried out in external magnetic fields up to 7 T, showing a minor but significant dependence of the dielectric constant on the applied magnetic field. Undoped CCTO is well-known for its colossal dielectric constant in a broad frequency and temperature range. With the present extended characterization of doped as well as undoped CCTO, we want to address the question why doping with only 1% Mn or 0.5% Fe decreases the room-temperature dielectric constant of CCTO by a factor of ~100 with a concomitant reduction of the conductivity, whereas 0.5% Ni doping changes the dielectric properties only slightly. In addition, diffraction experiments and magnetic investigations were undertaken to check for possible correlations of the magnitude of the colossal dielectric constants with structural details or with magnetic properties like the magnetic ordering, the Curie-Weiss temperatures, or the paramagnetic moment. It is revealed, that while the magnetic ordering temperature and the effective moment of all investigated CCTO ceramics are rather similar, there is a dramatic influence of doping and tempering time on the Curie-Weiss constant.Comment: 10 pages, 11 figure

Increased bone mineral density in Aboriginal and Torres Strait Islander Australians: Impact of body composition differences

Bone mineral density (BMD) has been reported to be both higher and lower in Indigenous women from different populations. Body composition data have been reported for Indigenous Australians, but there are few published BMD data in this population. We assessed BMD in 161 Indigenous Australians, identified as Aboriginal (n = 70), Torres Strait Islander (n = 68) or both (n = 23). BMD measurements were made on Norland-XR46 (n = 107) and Hologic (n = 90) dual-energy X-ray absorptiometry (DXA) machines. Norland BMD and body composition measurements in these individuals, and also in 36 Caucasian Australians, were converted to equivalent Hologic BMD (BMDH) and body composition measurements for comparison

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

The effect on melanoma risk of genes previously associated with telomere length.

Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/jnci/dju26

Correction:Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population

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Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10-16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC (sites VCF available via FTP at ftp.broadinstitute.org/pub/ExAC_release/release0.3/) to pinpoint genetic variation that contributes to variable disease predisposition across populations

The Pediatric Cell Atlas: defining the growth phase of human development at single-cell resolution

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan

Determination of the Form Factors for the Decay B0 --> D*-l+nu_l and of the CKM Matrix Element |Vcb|

We present a combined measurement of the Cabibbo-Kobayashi-Maskawa matrix element $|V_{cb}|$ and of the parameters $\rho^2$, $R_1$, and $R_2$, which fully characterize the form factors of the $B^0 \to D^{*-}\ell^{+}\nu_\ell$ decay in the framework of HQET, based on a sample of about 52,800 $B^0 \to D^{*-}\ell^{+}\nu_\ell$ decays recorded by the BABAR detector. The kinematical information of the fully reconstructed decay is used to extract the following values for the parameters (where the first errors are statistical and the second systematic): $\rho^2 = 1.156 \pm 0.094 \pm 0.028$, $R_1 = 1.329 \pm 0.131 \pm 0.044$, $R_2 = 0.859 \pm 0.077 \pm 0.022$, $\mathcal{F}(1)|V_{cb}| = (35.03 \pm 0.39 \pm 1.15) \times 10^{-3}$. By combining these measurements with the previous BABAR measurements of the form factors which employs a different technique on a partial sample of the data, we improve the statistical accuracy of the measurement, obtaining: $\rho^2 = 1.179 \pm 0.048 \pm 0.028, R_1 = 1.417 \pm 0.061 \pm 0.044, R_2 = 0.836 \pm 0.037 \pm 0.022,$ and $\mathcal{F}(1)|V_{cb}| = (34.68 \pm 0.32 \pm 1.15) \times 10^{-3}.$ Using the lattice calculations for the axial form factor $\mathcal{F}(1)$, we extract $|V_{cb}| =(37.74 \pm 0.35 \pm 1.25 \pm ^{1.23}_{1.44}) \times 10^{-3}$, where the third error is due to the uncertainty in $\mathcal{F}(1)$