The human papillomavirus-18 genome is efficiently targeted by cellular DNA methylation

AbstractHuman papillomaviruses (HPVs) infect epithelia, including the simple and the squamous epithelia of the cervix, where they can cause cancer and precursor lesions. The molecular events leading from asymptomatic HPV infections to neoplasia are poorly understood. There is evidence that progression is modulated by transcriptional mechanisms that control HPV gene expression. Here, we report the frequent methylation of HPV-18 genomes in cell culture and in situ. DNA methylation is generally known to lead to transcriptional repression due to chromatin changes. We investigated two cell lines derived from cervical cancers, namely, C4-1, which contains one HPV-18 genome, and different clones of HeLa, with 50 HPV-18 genomes. By restriction cleavage, we detected strong methylation of the L1 gene and absence of methylation of parts of the long control region (LCR). A 3-kb segment of the HPV-18 genomes downstream of the oncogenes was deleted in both cell lines. Bisulfite sequencing showed that in C4-1 cells and two HeLa clones, 18 of the 19 CpG residues in the 1.2-kb terminal part of the L1 gene were methylated, whereas a third HeLa clone had only eight methylated CpG groups, indicating changes of the methylation pattern after the establishment of the HeLa cell line. In the same four clones, none of the 12 CpG residues that overlapped with the enhancer and promoter was methylated. In six HPV-18 containing cancers and five smears from asymptomatic patients, most of the CpG residues in the L1 gene were methylated. There was complete or partial methylation, respectively, of the HPV enhancer in three of the cancers, and lack of methylation in the remaining eight samples. The promoter sequences were methylated in three of the six cancers and four of the six smears, and unmethylated elsewhere. Our data show that epithelial cells efficiently target HPV-18 genomes for DNA methylation, which may affect late and early gene transcription

La ocupación solutrense del Abrigo de la Boja (Mula, Murcia, España)

El relleno pleistoceno del Abrigo de la Boja (ADB) empieza con un nivel adscrito al Magdaleniense superior, seguido de un potente paquete con ocupación difusa bajo el cual se desarrolla una secuencia depositada durante el último máximo glacial caracterizada por una serie de estructuras de combustión, de tipo hogar plano/amorfo (open hearth), existiendo también hogares de cubeta. Destaca un hogar enlosado, completo y muy bien conservado, excavado en 2012 y adscrito provisionalmente al Solutreogravetiense. Los niveles solutrenses subyacentes son ricos en elementos de adorno, entre los cuales conchas perforadas de Littorina obtusata y Smaragdia viridis; su industria lítica incluye raspadores, algunas puntas, y escasos buriles. La datación 14C de muestras de carbón de Juniperus sp. sitúa este paquete entre 16990 ± 70 BP (VERA-5364a), a techo, y 20980 ± 120 BP (VERA-5366), a muro. The Pleistocene fill of the La Boja rock shelter (ADB) starts with an Upper Magdalenian level, followed by a thick package with poorly defined occupations under which there is a Last Glacial Maximum sequence with combustion features, mostly of the open hearth type. A particularly well preserved and seemingly complete stone-paved hearth of probable Solutreogravettian age was excavated in 2012. The abundant ornaments in the Solutrean levels include pierced Littorina obtusata and Smaragdia viridis shells and the stone tool assem- blages feature endscrapers, some points and rare burins. The 14C dating of Juniperus sp. charcoal samples places this sequence between 16990 ± 70 BP (VERA-5364a), at the top, and 20980 ± 120 BP (VERA-5366), at the bottom

Efficacy and Safety of High Potent P2Y12 Inhibitors Prasugrel and Ticagrelor in Patients With Coronary Heart Disease Treated With Dual Antiplatelet Therapy: A Sex-Specific Systematic Review and Meta-Analysis

Background Sex differences in efficacy and safety of dual antiplatelet therapy remain uncertain because of the underrepresentation of women in cardiovascular trials. The aim of this study was to perform a sex-specific analysis of the pooled efficacy and safety data of clinical trials comparing a high potent P2Y12 inhibitor+aspirin with clopidogrel+aspirin in patients with acute coronary syndrome. Methods and Results A systematic literature search was performed. Randomized clinical trials that compared patients following percutaneous coronary intervention/acute coronary syndrome who were taking high potent P2Y12 inhibitors+aspirin versus clopidogrel+aspirin were selected. Random effects estimates were calculated and relative risks with 95% CIs on efficacy and safety end points were determined per sex. We included 6 randomized clinical trials comparing prasugrel/ticagrelor versus clopidogrel in 43 990 patients (13 030 women), with a median follow-up time of 1.06 years. Women and men had similar relative risk (RR) reduction for major cardiovascular events (women: RR, 0.89 [95% CI, 0.80-1.00; men: RR, 0.84 [95% CI, 0.79-0.91) (P for interaction=0.39). Regarding safety, women and men had similar risk of major bleeding by high-potency dual antip

La cueva de el Sidron (Borines, Piloña, Asturias) : primeros resultados

Se exponen los resultados preliminares de las excavaciones arqueológicas llevadas a cabo en la Cueva de El Sidrón entre 2000 y 2002, de acuerdo con los tres objetivos principales que conciernen al registro fósil humano: las características antropológicas, cómo y cuándo llegaron allí y la relación entre fósiles y cultura. Las primeras conclusiones obtenidas son que los restos humanos pertenecen al Neandertal, que el registro arqueológico corresponde a un tecno-complejo del Paleolítico Medio y que están en posición secundaria.We expose the preliminary results ofthe archaeological excavations developed between 2000-2002 in Sidrón's Cave, according to the three main objectives that concern the human fossil record: the anthropological characteristics, how and when they arrived there and the relation between fossils and culture. We conclude preliminarily that the record belongs to Horno Neanderthalensis, archeological remains to the Middle Paleolithic techno-complex, and they are in a secondary [email protected]

Dating of the hominid (homo neanderthalensis) remains accumulation from el sidrón cave (piloña, asturias, north spain): An example of a multi-methodological approach to the dating of upper pleistocene sites

The age of Neanderthal remains and associated sediments from El Sidrón cave has been obtained through different dating methods (14CAMS, U/TH, OSL, ESR and AAR) and samples (charcoal debris, bone, tooth dentine, stalagmitic flowstone, carbonate-rich sedi

Dating of the hominid (Homo neanderthalensis) remains accumulation from El Sidrón Cave (Piloña, Asturias, North Spain): an example of a multi-methodological approach to the dating of Upper Pleistocene sites.

The age of Neanderthal remains and associated sediments from El Sidrón cave has been obtained through different dating methods (14CAMS, U/TH, OSL, ESR and AAR) and samples (charcoal debris, bone, tooth dentine, stalagmitic flowstone, carbonate-rich sediments, sedi- mentary quartz grains, tooth enamel and land snail shells). Detrital Th contamination ren- dered Th/U dating analyses of flowstone unreliable. Recent 14C contamination produced spurious age-values from charcoal samples as well as from inadequately pretreated tooth samples. Most consistent 14C dates are grouped into two series: one between 35 and 40 ka and the other between 48 and 49 ka. Most ESR and AAR samples yielded concordant ages, ranging between 39 and 45 ka; OSL dating results permitted adequate bracketing of the sedimentary layer that contained the human remains. Our results emphasize the value of multi-dating approaches for the establishment of reliable chronologies of human remains

Evolución paleoambiental de la mitad sur de la Península Ibérica. Aplicación a la evaluación del comportamiento de los repositorios de residuos radiactivos

Esta publicación refleja los resultados obtenidos de la realización de los proyectos "EQUIP: Evidency from Quaternary Infills Palaeohydrogeology" (F 14W/ CT96/0031), financiado por la UE, "Evolución Paleoclimática de [a Mitad Sur de [a Península Ibérica" financiado por ENRESA y "Paleoclima" financiado por el Consejo de Seguridad Nuclear y ENRESA. La cuenca de Guadix-Baza, sector oriental, es una de las escasas zonas europeas donde se ha conservado un registro razonablemente completo del Pleistoceno. La cuenca de Guadix Baza, en régimen continental desde el Plioceno, funcionó bajo un régimen centrípeto, con abanicos aluviales en los bordes y una zona compleja lacustre en mosaico en su centro. Se ha podido establecer la existencia de una amplia variedad de facies aluviales y fluviales y sus interrelaciones. La sedimentación en el margen lacustre estaba constituida por arenas bioclásticas y lutitas con fósiles, mientras que en zonas más centrales predominaron lutitas yesíferas, lutitas con yeso intrasedimentario, arenas yesíferas yesos y, ocasionalmente, carbonatos que durante un período concreto depositaron los materiales que configuran el "Nivel Calcáreo de Orce", calizas y dolomías con cantidades variables de yeso y terrígenos cerca de los bordes. El trabajo de campo permitió el establecimiento de una serie estratigráfica tipo compuesta, que refleja los principales acontecimiento paleoambientales que tuvieron lugar durante el Pleistoceno. Con el fin de evitar la yesificación de la calcita y aragonito, propia del ambiente lacustre, la serie tipo de ha establecido en el registro del margen lacustre. Con ayuda del análisis paleomagnético y el análisis de la racemización de aminoácidos en conchas de moluscos y ostrácodos se ha establecido la cronología numérica de la sección estratigráfica tipo que cubre desde el límite Plioceno-Pleistoceno hasta unos 250 ka BP, cuando la erosión de la cabecera del río Fardes alcanza la cuenca abriéndola hacia el valle del Guadalquivir y cesando [a sedimentación lacustre. También se ha datado un depósito de terraza fluvial. Se han obtenido datos paleoambientales "instantáneos" mediante el estudio palinológico, el análisis paleobotánico de material silicificado (madera opalizada) o carbonizado (análisis paleoantracológico), el análisis geoquímico orgánico de algunos niveles especialmente favorables. La geoquímica orgánica de biomarcadores de algunos niveles concretos proporcionó datos sobre su origen (plantas terrestres o acuáticas) y confirmó que un conspicuo nivel carbonoso tuvo su origen en un incendio forestal. El análisis paleobiológico basado en la distribución de especies de ostrácodos, gasterópodos y pelecípodos ha permitido una primera aproximación paleoambiental, pese al evidente sesgo introducido por la presencia de fuentes salinas y materiales yesíferos en el área fuente de los abanicos aluviales del límite oriental de la cuenca. Esta interpretación se ha depurado mediante el estudio geoquímico inorgánico, isótopos estables y elementos traza de las conchas calcíticas de ostrácodos. Ello ha permitido el establecimiento de una alternancia de períodos "fríos y húmedos" y "cálidos y áridos" que permiten reconocer de las clases climáticas "mediterráneo seco" y "mediterráneo húmedo" sensu Horowitz (1989), que tienen sus correlatos en el registro paleoclimático de los grandes lagos del rift del Mar Muerto, el Mar Caspio y lagos pluviales de Norte América. La correlación de los datos isotópicos con las paleosalinidades deducidas del estudio de las inclusiones fluidas en yeso intrasedimentario ha permitido corroborar estas interpretaciones. Esto plantea un nuevo enfoque en el análisis del comportamiento de los repositorios de residuos radiactivos de alta

Occurrence of whale barnacles in Nerja Cave (Málaga, southern Spain): Indirect evidence of whale consumption by humans in the Upper Magdalenian

A total of 167 plates of two whale barnacle species (Tubicinella majorLamarck, 1802 and Cetopirus complanatusMörch, 1853) have been found in the Upper Magdalenian layers of Nerja Cave, Mina Chamber (Maro, Málaga, southern Spain). This is the first occurrence of these species in a prehistoric site. Both species are specific to the southern right whale Eubalena australis, today endemic in the Southern Hemisphere. Because of Antarctic sea-ice expansion during the Last Glacial Period, these whales could have migrated to the Northern Hemisphere, and reached southern Spain. Whale barnacles indicate that maritime-oriented forager human groups found stranded whales on the coast and, because of the size and weight of the large bones, transported only certain pieces (skin, blubber and meat) to the caves where they were consumed

Formation processes at a high resolution Middle Paleolithic site: Cueva Antón (Murcia, Spain)

Cueva Antón is a Middle Paleolithic rockshelter located in the valley of the River Mula (Murcia, Spain). The archeological investigation of the site, which began with salvage work in 1991, resumed in 2006 and is still ongoing, uncovered a succession spanning most of MIS 3 and MIS 4 (ca. 75e36 ka) and featuring a well preserved human occupation record. This paper presents the first information about site stratigraphy and site formation processes. Geoarcheological data collected in the field and through micromorphological observation show that the archeological succession at Cueva Antón is mainly composed of alluvial sediments, with thin intercalations of gravitational and slope material. The sedimentary characteristics of the alluvial succession are well preserved as the result of a rapid accumulation rate and the protective effect of the rockshelter. Several sedimentary facies produced by the shifting of distinct fluvial sub-environments (channel, bar and floodplain) are recognized. With the exception of a few units (II-u, a thin buried alluvial soil, and the archeologically richest units at the base of the succession), postdepositional modification is rare. The site was occupied within a framework of infrequent, short-term visits, resulting in a relatively low overall density of finds and the formation of well-defined archeological lenses that correspond to synchronous paleosurfaces preserving the spatial distribution of finds and features. This pattern explains the limited anthropogenic evidence observed in thin sections, even those from units where archeological excavation uncovered significant remains of human occupation

Sexually transmitted infections among HIV serodiscordant partners: A secondary analysis of HIV Prevention Trial Network 052

Sexually transmitted infections (STIs) remain a public health concern because of their interaction(s) with HIV. In the HPTN 052 study, STIs were evaluated in both HIV-positive index cases and their HIV-negative partners at enrollment and at yearly follow-up visits. Our definition for STI was based on any infection with Chlamydia trachomatis, Neisseria gonorrhoeae, syphilis, or Trichomonas vaginalis. We used log-binomial regression models to identify factors associated with prevalent STIs. Generalized estimating equation models with the Poisson distribution were used to compare STI incidence between HIV-positive index cases and HIV-negative partners. 8.1% of the participants had STIs at enrollment. The prevalence of STIs (8.9 vs. 7.2) was higher in HIV-positive index cases than HIV-negative partners. Being female (prevalence ratio (PR) = 1.61; 95% CI: 1.20–2.16) or unmarried (PR = 1.92; 95% CI: 1.17–3.14) was associated with prevalent STIs. Compared to HIV-negative male partners, HIV-positive female index cases had a higher risk of STI acquisition (incidence rate ratio (IRR) = 2.25; 95% CI: 1.70–2.97). While we are implementing HIV prevention interventions for HIV-negative people, we should also intensify targeted STI prevention interventions, especially among HIV-positive women