The Expanded mtDNA Phylogeny of the Franco-Cantabrian Region Upholds the Pre-Neolithic Genetic Substrate of Basques

The European genetic landscape has been shaped by several human migrations occurred since Paleolithic times. The accumulation of archaeological records and the concordance of different lines of genetic evidence during the last two decades have triggered an interesting debate concerning the role of ancient settlers from the Franco-Cantabrian region in the postglacial resettlement of Europe. Among the Franco-Cantabrian populations, Basques are regarded as one of the oldest and more intriguing human groups of Europe. Recent data on complete mitochondrial DNA genomes focused on macrohaplogroup R0 revealed that Basques harbor some autochthonous lineages, suggesting a genetic continuity since pre-Neolithic times. However, excluding haplogroup H, the most representative lineage of macrohaplogroup R0, the majority of maternal lineages of this area remains virtually unexplored, so that further refinement of the mtDNA phylogeny based on analyses at the highest level of resolution is crucial for a better understanding of the European prehistory. We thus explored the maternal ancestry of 548 autochthonous individuals from various Franco-Cantabrian populations and sequenced 76 mitogenomes of the most representative lineages. Interestingly, we identified three mtDNA haplogroups, U5b1f, J1c5c1 and V22, that proved to be representative of Franco-Cantabria, notably of the Basque population. The seclusion and diversity of these female genetic lineages support a local origin in the Franco-Cantabrian area during the Mesolithic of southwestern Europe, ∼10,000 years before present (YBP), with signals of expansions at ∼3,500 YBP. These findings provide robust evidence of a partial genetic continuity between contemporary autochthonous populations from the Franco-Cantabrian region, specifically the Basques, and Paleolithic/Mesolithic hunter-gatherer groups. Furthermore, our results raise the current proportion (≈15%) of the Franco-Cantabrian maternal gene pool with a putative pre-Neolithic origin to ≈35%, further supporting the notion of a predominant Paleolithic genetic substrate in extant European populations.     

Prevalence and upper limit of cardiac hypertrophy in professional cyclists

The term athlete's heart refers to an increased left ventricular mass. Few studies have assessed the prevalence and normal upper limit of cardiac hypertrophy in highly trained cyclists and this was the aim of this study. A group of 40 professional road cyclists [mean age 26 (SD 3) years] who had participated in European competitions for 3–10 years, were evaluated at the beginning of the 1992–93 season. Evaluation included a clinical history and physical examination, one and two-dimensional echocardiography, 12-lead resting electrocardiogram and a graded exercise test. Determination of the left ventricular mass index (LVMI) was performed using Devereux's formula with correction for the body surface area. Systolic and diastolic blood pressure were measured at rest and at peak exercise. Of the group 23 cyclists (58%) presented a LVMI greater than 130 g · m^–2, 21 cyclists presented a diastolic ventricular thickness equal to or greater than 13 mm, with a superior limit of 19 mm; 3 cyclists presented asymmetrical septum hypertrophy; and the relationship between posterior wall and left ventricular diastolic radius was equal to or greater than 0.45 in 14 cases (35%). Electrocardiographic abnormalities of ST-T segment were seen in only 1 subject. No correlation was found between the degree of ventricular hypertrophy and arterial blood pressure. We concluded that these professional cyclists showed a high prevalence of cardiac hypertrophy (58%). The distribution of this hypertrophy was concentric in 20/33 and asymmetric in 3/23 of the subjects with left ventricular hypertrophy. The electrocardiograms were normal in 98% of the subjects.     

Skates and rays (Elasmobranchii,Batomorphii) from the Eocene La Meseta and Submeseta formations,Seymour Island,Antarctica

Abstract

Eocene deposits of the famous La Meseta Formation of Seymour Island, Antarctic Peninsula, yielded the most diverse Paleogene fossil elasmobranch association of the Southern Hemisphere. In this assemblage, sharks clearly dominate the fauna, whereas batoids are very rare components. Herein, we describe two new taxa of cold water tolerant skates, Marambioraja leiostemma gen. et sp. nov., and Mesetaraja maleficapelli gen. et sp. nov., two new species of the genus Raja, Raja amphitrita sp. nov. and Raja manitaria sp. nov., as well as remains of warm water adapted myliobatiforms. It is, however, not possible to unambiguously assign these remains either to Myliobatidae or Rhinopteridae, or to any specific genus. Previously reported remains of Raja/Bathyraja sp. are assigned to the new described species Raja manitaria sp. nov. The biogeographic distribution of extant and extinct rays and skates clearly shows that both groups are more widely distributed today than in the past, and additionally seem to have been more diverse in the Northern than the Southern Hemisphere. The occurrence, albeit rare of isolated teeth of skates (Rajidae) and rays (Myliobatidae) in the La Meseta Formation representes a minimum age constraint for their first appearance in the Southern Ocean.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:E507D86C-FFEC-4047-A337-AE77606BB1A6     

Soluble Adhesion Molecules in Patients Coinfected with HIV and HCV: A Predictor of Outcome

Background

Higher serum levels of adhesion molecules (sICAM-1 and sVCAM-1) are associated with advanced liver fibrosis in patients coinfected with human immunodeficiency virus and hepatitis C virus. We assessed the relationship between serum levels of adhesion molecules and liver-related events (LRE) or death, in coinfected patients.

Methods

We studied clinical characteristics and outcomes of 182 coinfected patients with a baseline liver biopsy (58 with advanced fibrosis) and simultaneous plasma samples who were followed for median of 9 years. We used receiver-operating characteristic (ROC) curves to calculate optimized cutoff values (OCV) of sICAM-1 and sVCAM-1, defined as the values with the highest combination of sensitivity and specificity for LRE. We used multivariate regression analysis to test the association between OCVs of sICAM-1 and sVCAM-1 and outcomes. The variables for adjustment were age, HIV transmission category, liver fibrosis, baseline CD4+ T-cell counts, antiretroviral therapy, and sustained virologic response (SVR).

Results

During the study period 51 patients had SVR, 19 had LRE, and 16 died. The OCVs for LRE were 5.68 Log pg/mL for sICAM-1 and 6.25 Log pg/mL for sVCAM-1, respectively. The adjusted subhazard ratio (aSHR) (95% confidence interval [CI]) of death or LRE, whichever occurred first, for sICAM-1 and sVCAM-1 > OCV were 3.98 ([1.14; 13.89], P = 0.030) and 2.81 ([1.10; 7.19], respectively (P = 0.030).

Conclusions

Serum levels of sICAM-1 and sVCAM-1 can serve as markers of outcome in HIV/HCV-coinfected patients. Therapies targeting necroinflammatory damage and fibrogenesis may have a role in the management chronic hepatitis C.     

Fossilized spermatozoa preserved in a 50-Myr-old annelid cocoon from Antarctica

The origin and evolution of clitellate annelids—earthworms, leeches and their relatives—is poorly understood, partly because body fossils of these delicate organisms are exceedingly rare. The distinctive egg cases (cocoons) of Clitellata, however, are relatively common in the fossil record, although their potential for phylogenetic studies has remained largely unexplored. Here, we report the remarkable discovery of fossilized spermatozoa preserved within the secreted wall layers of a 50-Myr-old clitellate cocoon from Antarctica, representing the oldest fossil animal sperm yet known. Sperm characters are highly informative for the classification of extant Annelida. The Antarctic fossil spermatozoa have several features that point to affinities with the peculiar, leech-like ‘crayfish worms'' (Branchiobdellida). We anticipate that systematic surveys of cocoon fossils coupled with advances in non-destructive analytical methods may open a new window into the evolution of minute, soft-bodied life forms that are otherwise only rarely observed in the fossil record.     

Emergence of Amoxicillin-Resistant Variants of Spain9V-ST156 Pneumococci Expressing Serotype 11A Correlates with Their Ability to Evade the Host Immune Response

Capsular switching allows pre-existing clones of Streptococcus pneumoniae expressing vaccine serotypes to escape the vaccine-induced immunity by acquisition of capsular genes from pneumococci of a non-vaccine serotype. Here, we have analysed the clonal composition of 492 clinical isolates of serotype 11A causing invasive disease in Spain (2000–2012), and their ability to evade the host immune response. Antibiograms, serotyping and molecular typing were performed. The restriction profiles of pbp2x, pbp1a and pbp2b genes were also analysed. Interaction with the complement components C1q, C3b, C4BP, and factor H was explored whereas opsonophagocytosis assays were performed using a human cell line differentiated to neutrophils. Biofilm formation and the polymorphisms of the major autolysin LytA were evaluated. The main genotypes of the 11A pneumococci were: ST62 (447 isolates, 90.6%), followed by ST6521 (35 isolates, 7.3%) and ST838 (10 isolates, 2.1%). Beta lactam resistant serotype 11A variants of genotypes ST838 and ST6521 closely related to the Spain^9V-ST156 clone were first detected in 2005. A different pattern of evasion of complement immunity and phagocytosis was observed between genotypes. The emergence of one vaccine escape variant of Spain^9V-ST156 (ST6521^11A), showing a high potential to avoid the host immune response, was observed. In addition, isolates of ST6521^11A showed higher ability to produce biofilms than ST838^11A or ST62^11A, which may have contributed to the emergence of this PEN-resistant ST6521^11A genotype in the last few years. The emergence of penicillin-resistant 11A invasive variants of the highly successful ST156 clonal complex merits close monitoring.     

Computational Prediction and Experimental Assessment of Secreted/Surface Proteins from Mycobacterium tuberculosis H37Rv

The mycobacterial cell envelope has been implicated in the pathogenicity of tuberculosis and therefore has been a prime target for the identification and characterization of surface proteins with potential application in drug and vaccine development. In this study, the genome of Mycobacterium tuberculosis H37Rv was screened using Machine Learning tools that included feature-based predictors, general localizers and transmembrane topology predictors to identify proteins that are potentially secreted to the surface of M. tuberculosis, or to the extracellular milieu through different secretory pathways. The subcellular localization of a set of 8 hypothetically secreted/surface candidate proteins was experimentally assessed by cellular fractionation and immunoelectron microscopy (IEM) to determine the reliability of the computational methodology proposed here, using 4 secreted/surface proteins with experimental confirmation as positive controls and 2 cytoplasmic proteins as negative controls. Subcellular fractionation and IEM studies provided evidence that the candidate proteins Rv0403c, Rv3630, Rv1022, Rv0835, Rv0361 and Rv0178 are secreted either to the mycobacterial surface or to the extracellular milieu. Surface localization was also confirmed for the positive controls, whereas negative controls were located on the cytoplasm. Based on statistical learning methods, we obtained computational subcellular localization predictions that were experimentally assessed and allowed us to construct a computational protocol with experimental support that allowed us to identify a new set of secreted/surface proteins as potential vaccine candidates.     

β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer

The Wnt–β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer. AKT phosporylates FOXO3a, relocating it from the cell nucleus to the cytoplasm, an effect that is reversed by PI3K and AKT inhibitors. Simultaneous hyperactivation of the Wnt–β-catenin pathway and inhibition of PI3K-AKT signaling promote nuclear accumulation of β-catenin and FOXO3a, respectively, promoting cell scattering and metastasis by regulating a defined set of target genes. Indeed, the anti-tumoral AKT inhibitor API-2 promotes nuclear FOXO3a accumulation and metastasis of cells with high nuclear β-catenin content. Nuclear β-catenin confers resistance to the FOXO3a-mediated apoptosis induced by PI3K and AKT inhibitors in patient-derived primary cultures and in corresponding xenograft tumors in mice. This resistance is reversed by XAV-939, an inhibitor of Wnt–β-catenin signaling. In the presence of high nuclear β-catenin content, activation of FOXO3a by PI3K or AKT inhibitors makes it behave as a metastasis inductor rather than a proapoptotic tumor suppressor. We show that it is possible to evaluate the β-catenin status of patients' carcinomas and the response of patient-derived cells to target-directed drugs that accumulate FOXO3a in the nucleus before deciding on a course of treatment. We propose that this evaluation could be essential to the provision of a safer and more effective personalized treatment.     

Distribution and radiosensitizing effect of cholesterol-coupled Dbait molecule in rat model of glioblastoma

Background

Glioma is the most aggressive tumor of the brain and the most efficient treatments are based on radiotherapy. However, tumors are often resistant to radiotherapy due to an enhanced DNA repair activity. Short and stabilized DNA molecules (Dbait) have recently been proposed as an efficient strategy to inhibit DNA repair in tumor.

Methodology/Principal Findings

The distribution of three formulations of Dbait, (i) Dbait alone, (ii) Dbait associated with polyethylenimine, and (iii) Dbait linked with cholesterol (coDbait), was evaluated one day after intratumoral delivery in an RG2 rat glioma model. Dbait molecule distribution was assessed in the whole organ with 2D-FRI and in brain sections. CoDbait was chosen for further studies given its good retention in the brain, cellular localization, and efficacy in inducing the activation of DNA repair effectors. The radiosensitizing effect of coDbait was studied in four groups of rats bearing RG2-glioma: no treatment, radiotherapy only, coDbait alone, and CoDbait with radiotherapy. Treatment started 7 days after tumor inoculation and consisted of two series of treatment in two weeks: coDbait injection followed by a selective 6-Gy irradiation of the head. We evaluated the radiosensitizing effect using animal survival, tumor volume, cell proliferation, and vasculature characteristics with multiparametric MRI. CoDbait with radiotherapy improved the survival of rats bearing RG2-glioma by reducing tumor growth and cell proliferation without altering tumor vasculature.

Conclusion/Significance

coDbait is therefore a promising molecular therapy to sensitize glioma to radiotherapy.