Additional Common Polymorphisms in the PON Gene Cluster Predict PON1 Activity but Not Vascular Disease

Background. Paraoxonase 1 (PON1) enzymatic activity has been consistently predictive of cardiovascular disease, while the genotypes at the four functional polymorphisms at PON1 have not. The goal of this study was to identify additional variation at the PON gene cluster that improved prediction of PON1 activity and determine if these variants predict carotid artery disease (CAAD). Methods. We considered 1,328 males in a CAAD cohort. 51 tagging single-nucleotide polymorphisms (tag SNPs) across the PON cluster were evaluated to determine their effects on PON1 activity and CAAD status. Results. Six SNPs (four in PON1 and one each in PON2/3) predicted PON1 arylesterase (AREase) activity, in addition to the four previously known functional SNPs. In total, the 10 SNPs explained 30.1% of AREase activity, 5% of which was attributable to the six identified predictive SNPs. We replicate rs854567 prediction of 2.3% of AREase variance, the effects of rs3917510, and a PON3 haplotype that includes rs2375005. While AREase activity strongly predicted CAAD, none of the 10 SNPs predicting AREase predicted CAAD. Conclusions. This study identifies new genetic variants that predict additional PON1 AREase activity. Identification of SNPs associated with PON1 activity is required when evaluating the many phenotypes associated with genetic variation near PON1

Rare loss of function variants in candidate genes and risk of colorectal cancer

Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P

Detection of human papillomavirus DNA and p53 codon 72 polymorphism in prostate carcinomas of patients from Argentina

BACKGROUND: Infections with high-risk human papillomaviruses (HPVs), causatively linked to cervical cancer, might also play a role in the development of prostate cancer. Furthermore, the polymorphism at codon 72 (encoding either arginine or proline) of the p53 tumor-suppressor gene is discussed as a possible determinant for cancer risk. The HPV E6 oncoprotein induces degradation of the p53 protein. The aim of this study was to analyse prostate carcinomas and hyperplasias of patients from Argentina for the presence of HPV DNA and the p53 codon 72 polymorphism genotype. METHODS: HPV DNA detection and typing were done by consensus L1 and type-specific PCR assays, respectively, and Southern blot hybridizations. Genotyping of p53 codon 72 polymorphism was performed both by allele specific primer PCRs and PCR-RFLP (Bsh1236I). Fischer's test with Woolf's approximation was used for statistical analysis. RESULTS: HPV DNA was detected in 17 out of 41 (41.5 %) carcinoma samples, whereas all 30 hyperplasia samples were HPV-negative. Differences in p53 codon 72 allelic frequencies were not observed, neither between carcinomas and hyperplasias nor between HPV-positive and HPV-negative carcinomas. CONCLUSION: These results indicate that the p53 genotype is probably not a risk factor for prostate cancer, and that HPV infections could be associated with at least a subset of prostate carcinomas

A Probiotic Adjuvant Lactobacillus rhamnosus Enhances Specific Immune Responses after Ocular Mucosal Immunization with Chlamydial Polymorphic Membrane Protein C

Recent advances in the development of chlamydia vaccines, using live-attenuated or ultraviolet light-inactivated chlamydia, are paving the way for new possibilities to oppose the societal challenges posed by chlamydia-related diseases, such as blinding trachoma. An effective subunit vaccine would mitigate the risks associated with the use of a whole-cell vaccine. Our rationale for the design of an efficient subunit vaccine against Chlamydia trachomatis (Ct) is based on the membrane proteins involved in the initial Ct-host cell contact and on the route of immunization that mimics the natural infection process (i.e., via the ocular mucosa). The first aim of our study was to characterize the specific conjunctival and vaginal immune responses following eye drop immunization in BALB/c mice, using the N-terminal portion of the Ct serovar E polymorphic membrane protein C (N-PmpC) as the subunit vaccine antigen. Second, we aimed to examine the adjuvant properties of the probiotic Lactobacillus rhamnosus (LB) when formulated with N-PmpC. N-PmpC applied alone stimulated the production of N-PmpC-and Ct serovar B-specific antibodies in serum, tears and vaginal washes, whereas the combination with LB significantly enhanced these responses. The N-PmpC/LB combination initiated a T cell response characterized by an elevated percentage of CD25+ T cells and CD8+ effector T cells, enhanced CD4+ T-helper 1 skewing, and increased regulatory T cell responses. Together, these results show that eye drop vaccination with combined use of N-PmpC and a live probiotic LB stimulates specific cellular and humoral immune responses, not only locally in the conjunctiva but also in the vaginal mucosa, which could be a promising approach in Ct vaccine development

Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes

The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants’ pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine

Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome.

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine

TKS X: Confirmation of TOI-1444b and a Comparative Analysis of the Ultra-short-period Planets with Hot Neptunes

We report the discovery of TOI-1444b, a 1.4-$R_\oplus$ super-Earth on a 0.47-day orbit around a Sun-like star discovered by {\it TESS}. Precise radial velocities from Keck/HIRES confirmed the planet and constrained the mass to be $3.87 \pm 0.71 M_\oplus$. The RV dataset also indicates a possible non-transiting, 16-day planet ($11.8\pm2.9M_\oplus$). We report a tentative detection of phase curve variation and secondary eclipse of TOI-1444b in the {\it TESS} bandpass. TOI-1444b joins the growing sample of 17 ultra-short-period planets with well-measured masses and sizes, most of which are compatible with an Earth-like composition. We take this opportunity to examine the expanding sample of ultra-short-period planets ($<2R_\oplus$) and contrast them with the newly discovered sub-day ultra-hot Neptunes ($>3R_\oplus$, $>2000F_\oplus$ TOI-849 b, LTT9779 b and K2-100). We find that 1) USPs have predominately Earth-like compositions with inferred iron core mass fractions of 0.32$\pm$0.04; and have masses below the threshold of runaway accretion ($\sim 10M_\oplus$), while ultra-hot Neptunes are above the threshold and have H/He or other volatile envelope. 2) USPs are almost always found in multi-planet system consistent with a secular interaction formation scenario; ultra-hot Neptunes ($P_{\rm orb} \lesssim$1 day) tend to be ``lonely' similar to longer-period hot Neptunes($P_{\rm orb}$1-10 days) and hot Jupiters. 3) USPs occur around solar-metallicity stars while hot Neptunes prefer higher metallicity hosts. 4) In all these respects, the ultra-hot Neptunes show more resemblance to hot Jupiters than the smaller USP planets, although ultra-hot Neptunes are rarer than both USP and hot Jupiters by 1-2 orders of magnitude.Comment: Accepted too AJ. 12 Figures, 4 table

Affectus Hispaniae en la historiografía del Alto Imperio

This paper analyses texts written by Greek and Latin High Empire historians dealing with Hispania. Some of the authors have a very positive view (Florus, Iustinus, Appian) while others are clearly negative (Veleius Paterculus, Valerius Maximus) though most of them show little interest, indifference or variety of opinions. When there is interest in the region or praise, it is because the author comes from Hispania or he is trying to please an emperor born in Hispania, but it could also be due to a universal conception of history revealing a critical attitude towards Roman imperialism, as in Appian. The praise found in Iustinus’s epitome should be attributed to the author of the epitome rather than to Pompeius Trogus. This can be taken as evidence for situating Iustinus’s life and work in the 2nd century A.D. Loathing of Hispania seems to have its origins in conservative, ‘optimate’ nationalist circles, who perceive the province as the ‘popular’ region that acclaimed and welcomed ‘seditious’ individuals such as Tiberius Gracchus and Sertorius.Se estudian en este trabajo los textos de historiadores del Alto Imperio, latinos y griegos, que tratan sobre Hispania. En algunos autores encontramos una visión muy positiva (Floro, Justino, Apiano) y en otros claramente negativa (Veleyo Patérculo, Valerio Máximo), aunque en la mayoría de los casos hay escasa atención, indiferencia o diversidad de opiniones. El interés por la región y los elogios pueden estar motivados por el origen hispánico del autor o su voluntad de agradar a algún emperador oriundo de Hispania, pero también por una concepción universal de la historia que denota en ocasiones una posición crítica con el imperialismo romano, como es el caso de Apiano. La alabanza que hallamos en el epítome de Justino creemos que debe atribuirse más al epitomador que a Pompeyo Trogo, lo que apoyaría una datación temprana de la vida y la obra de Justino (s. II d.C.). La aversión hacia Hispania parece haber surgido en medios conservadores, “optimates” nacionalistas, que ven la provincia como el territorio “popular”, que encumbró y acogió a “sediciosos” como Tiberio Graco y Sertorio

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

The TESS-Keck Survey II: An Ultra-Short Period Rocky Planet and its Siblings Transiting the Galactic Thick-Disk Star TOI-561

We report the discovery of TOI-561, a multi-planet system in the galactic thick disk that contains a rocky, ultra-short period planet (USP). This bright ($V=10.2$) star hosts three small transiting planets identified in photometry from the NASA TESS mission: TOI-561 b (TOI-561.02, P=0.44 days, $R_b = 1.45\pm0.11\,R_\oplus$), c (TOI-561.01, P=10.8 days, $R_c=2.90\pm0.13\,R_\oplus$), and d (TOI-561.03, P=16.3 days, $R_d=2.32\pm0.16\,R_\oplus$). The star is chemically ([Fe/H]$=-0.41\pm0.05$, [$\alpha$/H]$=+0.23\pm0.05$) and kinematically consistent with the galactic thick disk population, making TOI-561 one of the oldest ($10\pm3\,$Gyr) and most metal-poor planetary systems discovered yet. We dynamically confirm planets b and c with radial velocities from the W. M. Keck Observatory High Resolution Echelle Spectrometer. Planet b has a mass and density of $3.2\pm0.8\,M_\oplus$ and $5.5^{+2.0}_{-1.6}\,$g$\,$cm$^{-3}$, consistent with a rocky composition. Its lower-than-average density is consistent with an iron-poor composition, although an Earth-like iron-to-silicates ratio is not ruled out. Planet c is $7.0\pm2.3\,M_\oplus$ and $1.6\pm0.6\,$g$\,$cm$^{-3}$, consistent with an interior rocky core overlaid with a low-mass volatile envelope. Several attributes of the photometry for planet d (which we did not detect dynamically) complicate the analysis, but we vet the planet with high-contrast imaging, ground-based photometric follow-up and radial velocities. TOI-561 b is the first rocky world around a galactic thick-disk star confirmed with radial velocities and one of the best rocky planets for thermal emission studies.Comment: Accepted at The Astronomical Journal; 25 pages, 10 figure