Tissue-specific and ubiquitous factors binding next to the glucocorticoid receptor modulate transcription from the mouse mammary tumor virus promoter

Steroid hormones complexed with their receptors play an essential role in the regulation of mouse mammary tumor virus (MMTV) transcription. However, the need for additional tissue-specific regulatory factors is suggested by the lack of virus expression in liver, in which glucocorticoid receptors are highly abundant, and by the tissue-specific transcription of reporter genes linked to an MMTV long terminal repeat in transgenic mice. In this study, we characterized two distal-region regulatory elements, DRa and DRc, which, together with the distal glucocorticoid receptor binding site (DRb), increased transcription from the MMTV promoter in permissive cells. This was demonstrated by transfection of these sequences (DRa, DRb, and DRc) in different combinations with the natural MMTV promoter in mouse fibroblasts and mammary epithelial cells, followed by quantitative S1 nuclease mapping of the transcripts. We further showed by DNase I footprinting, methylation interference, and gel retardation assays with various nuclear extracts from permissive or nonpermissive tissues and cell lines that the factors binding to the DRa site are distinct and tissue-specific whereas those binding to DRc are ubiquitous

Coffee bean extracts rich and poor in kahweol both give rise to elevation of liver enzymes in healthy volunteers

BACKGROUND: Coffee oil potently raises serum cholesterol levels in humans. The diterpenes cafestol and kahweol are responsible for this elevation. Coffee oil also causes elevation of liver enzyme levels in serum. It has been suggested that cafestol is mainly responsible for the effect on serum cholesterol levels and that kahweol is mainly responsible for the effect on liver enzyme levels. The objective of this study was to investigate whether coffee oil that only contains a minute amount of kahweol indeed does not cause elevation of liver enzyme levels. METHODS: The response of serum alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) to Robusta coffee oil (62 mg/day cafestol, 1.6 mg/day kahweol) was measured in 18 healthy volunteers. RESULTS: After nine days one subject was taken off Robusta oil treatment due to an ALAT level of 3.6 times the upper limit of normal (ULN). Another two subjects stopped treatment due to other reasons. After 16 days another two subjects were taken off Robusta oil treatment. One of those subjects had levels of 5.8 ULN for ALAT and 2.0 ULN for ASAT; the other subject had an ALAT level of 12.4 ULN and an ASAT level of 4.7 ULN. It was then decided to terminate the study. The median response of subjects to Robusta oil after 16 days was 0.27 ULN (n = 15, 25(th),75(th )percentile: 0.09;0.53) for ALAT and 0.06 ULN (25(th),75(th )percentile -0.06;0.22) for ASAT. CONCLUSIONS: We conclude that the effect on liver enzyme levels of coffee oil containing hardly any kahweol is similar to that of coffee oil containing high amounts of kahweol. Therefore it is unlikely that kahweol is the component of coffee oil that is responsible for the effect. Furthermore, we conclude that otherwise unexplained elevation of liver enzyme levels observed in patients might be caused by a switch from consumption of filtered coffee to unfiltered coffee

Influence of phenolic acids on growth and inactivation of Oenococcus oeni and Lactobacillus hilgardii

Aims: To determine the effect of several wine-associated, phenolic acids on the growth and viability of strains of Oenococcus oeni and Lactobacillus hilgardii. Methods and Results: Growth was monitored in ethanol-containing medium supplemented with varying concentrations of hydroxybenzoic acids (p-hydroxybenzoic, protocatechuic, gallic, vanillic and syringic acids) and hydroxycinnamic acids (p-coumaric, caffeic and ferulic acids). Progressive inactivation was monitored in ethanolcontaining phosphate buffer supplemented in a similar manner to the growth experiments. Hydroxycinnamic acids proved to be more inhibitory to the growth of O. oeni than hydroxybenzoic acids. On the other hand, some acids showed a beneficial effect on growth of Lact. hilgardii. p-Coumaric acid showed the strongest inhibitory effect on growth and survival of both bacteria. Conclusions: Most phenolic acids had a negative effect on growth of O. oeni, for Lact. hilgardii this effect was only noted for p-coumaric acid. Generally, O. oeni was more sensitive to phenolic acid inactivation than Lact. hilgardii. Significance and Impact of the Study: Eight wine-derived, phenolic acids were compared for their effects on wine lactic acid bacteria. Results indicate that phenolic acids have the capacity to influence growth and survival parameters. The differences found between phenolic compounds could be related to their different chemical structures

Late Cretaceous continental and marine vertebrate assemblages of the Laño Quarry (Basque-Cantabrian Region, Iberian Peninsula): an update

The vertebrate-bearing beds of the Laño quarry (Condado de Treviño) are among the most relevant sites from the Late Cretaceous of Europe. Geologically, Laño and the adjacent region are set on the southern limb of the South-Cantabrian Synclinorium (SE Basque-Cantabrian Region, northern Iberian Peninsula). The Laño sites were discovered in 1984; thousands of bones and teeth, including microfossils, have been collected during the prospection in the field and excavation campaigns. The vertebrate remains occur at two different stratigraphic horizons within a continental to shallow marine succession of Late Campanian-Maastrichtian age. The lower horizon contains the Laño 1 and Laño 2 sites, whereas the upper horizon contains the Albaina site. In the Laño sites, three fossiliferous beds (called L1A, L1B and L2) are known within an alluvial system composed mainly of fluvial sands and silts. The sedimentary structures are consistent with channel areas within an extensive braided river system. Based mainly on stratigraphic correlations, the fluvial beds of Laño are regarded as Late Campanian to Early Maastrichtian in age. These deposits have yielded a very diverse vertebrate assemblage, which consists of nearly 40 species, including actinopterygians, lissamphibians, lepidosaurs, turtles, crocodyliforms, dinosaurs, pterosaurs, and mammals. Seven genera and ten species have been erected to date in Laño. With reference to the marine vertebrate association of Albaina, it consists of at least 37 species, including sharks and rays, actinopterygians, mosasaurids, and plesiosaurs. Two genera and species of rhinobatoids (family indet.) and two new species of rhinobatids have been erected in Albaina. The fossil association indicates a Late (but not latest) Maastrichtian age. Recently, isolated turtle and dinosaur fossils have been discovered in the sublittoral beds of Albaina. The Laño quarry is one of the most noteworthy Campanian-Maastrichtian vertebrate localities of Europe by its taxonomic diversity, and provides useful information about the composition and affinities of both continental and marine vertebrate faunas from the latest Cretaceous of southwestern Europe.Los niveles con fósiles de vertebrados de la cantera de Laño (Condado de Treviño) se cuentan entre los más importantes del Cretácico Superior de Europa. Desde un punto de vista geológico, Laño y la región adyacente forman parte del flanco sur del Sinclinorio Subcantábrico (SE de la Región Vasco-Cantábrica). El descubrimiento de los niveles fosilíferos remonta a 1984; las prospecciones de campo y las campañas de excavación han proporcionado miles de huesos y dientes, incluyendo microfósiles. Los restos de vertebrados aparecen en dos horizontes estratigráficos diferentes formando parte de una sucesión continental a marina litoral de edad Campaniense superior a Maastrichtiense. El horizonte inferior contiene los yacimientos de Laño 1 y Laño 2, mientras que el superior contiene solo uno: Albaina. En los yacimientos de Laño, se reconocen tres niveles fosilíferos (llamados L1A, L1B y L2) formados en el seno de un sistema aluvial compuesto por arenas y limos fluviales. Las estructuras sedimentarias indican áreas de canal dentro de un sistema trenzado muy extendido. Según las correlaciones estratigráficas, los depósitos fluviales de Laño son de edad Campaniense superior a Maastrichtiense inferior. Estos depósitos han proporcionado una asociación muy diversa de vertebrados, que consiste en cerca de 40 especies, incluyendo actinopterigios, lisanfibios, lepidosaurios, tortugas, cocodrilos, dinosaurios, pterosaurios y mamíferos. En Laño se han definido hasta el momento siete géneros y diez especies. Por lo que respecta a la asociación de vertebrados marinos de Albaina, se han reconocido al menos 37 especies, que incluyen tiburones y rayas, actinopterigios, mosasaurios y plesiosaurios. Hasta la fecha se han definido en Albaina cuatro nuevos rinobatoideos: dos especies de rinobátidos y dos géneros y especies cuya familia es indeterminada. La asociación fósil es de edad Maastrichtiense superior no terminal. Recientemente se ha descrito el hallazgo de restos fósiles aislados de tortugas y dinosaurios en los niveles marinos de Albaina. La cantera de Laño es una de las localidades de vertebrados más destacadas del Campaniense-Maastrichtiense por su diversidad taxonómica, y proporciona información relevante sobre la composición y afinidades de las faunas de vertebrados continentales y marinos del Cretácico final del suroeste de Europa

Development of the InTelligence And Machine LEarning (TAME) Toolkit for Introductory Data Science, Chemical-Biological Analyses, Predictive Modeling, and Database Mining for Environmental Health Research

Research in environmental health is becoming increasingly reliant upon data science and computational methods that can more efficiently extract information from complex datasets. Data science and computational methods can be leveraged to better identify relationships between exposures to stressors in the environment and human disease outcomes, representing critical information needed to protect and improve global public health. Still, there remains a critical gap surrounding the training of researchers on these in silico methods. We aimed to address this gap by developing the inTelligence And Machine lEarning (TAME) Toolkit, promoting trainee-driven data generation, management, and analysis methods to “TAME” data in environmental health studies. Training modules were developed to provide applications-driven examples of data organization and analysis methods that can be used to address environmental health questions. Target audiences for these modules include students, post-baccalaureate and post-doctorate trainees, and professionals that are interested in expanding their skillset to include recent advances in data analysis methods relevant to environmental health, toxicology, exposure science, epidemiology, and bioinformatics/cheminformatics. Modules were developed by study coauthors using annotated script and were organized into three chapters within a GitHub Bookdown site. The first chapter of modules focuses on introductory data science, which includes the following topics: setting up R/RStudio and coding in the R environment; data organization basics; finding and visualizing data trends; high-dimensional data visualizations; and Findability, Accessibility, Interoperability, and Reusability (FAIR) data management practices. The second chapter of modules incorporates chemical-biological analyses and predictive modeling, spanning the following methods: dose-response modeling; machine learning and predictive modeling; mixtures analyses; -omics analyses; toxicokinetic modeling; and read-across toxicity predictions. The last chapter of modules was organized to provide examples on environmental health database mining and integration, including chemical exposure, health outcome, and environmental justice indicators. Training modules and associated data are publicly available online (https://uncsrp.github.io/Data-Analysis-Training-Modules/). Together, this resource provides unique opportunities to obtain introductory-level training on current data analysis methods applicable to 21st century science and environmental health

Sensitivity of the IceCube Detector to Astrophysical Sources of High Energy Muon Neutrinos

We present the results of a Monte-Carlo study of the sensitivity of the planned IceCube detector to predicted fluxes of muon neutrinos at TeV to PeV energies. A complete simulation of the detector and data analysis is used to study the detector's capability to search for muon neutrinos from sources such as active galaxies and gamma-ray bursts. We study the effective area and the angular resolution of the detector as a function of muon energy and angle of incidence. We present detailed calculations of the sensitivity of the detector to both diffuse and pointlike neutrino emissions, including an assessment of the sensitivity to neutrinos detected in coincidence with gamma-ray burst observations. After three years of datataking, IceCube will have been able to detect a point source flux of E^2*dN/dE = 7*10^-9 cm^-2s^-1GeV at a 5-sigma significance, or, in the absence of a signal, place a 90% c.l. limit at a level E^2*dN/dE = 2*10^-9 cm^-2s^-1GeV. A diffuse E-2 flux would be detectable at a minimum strength of E^2*dN/dE = 1*10^-8 cm^-2s^-1sr^-1GeV. A gamma-ray burst model following the formulation of Waxman and Bahcall would result in a 5-sigma effect after the observation of 200 bursts in coincidence with satellite observations of the gamma-rays.Comment: 33 pages, 13 figures, 6 table

A Phylogenetic Perspective on the Evolution of Mediterranean Teleost Fishes

The Mediterranean Sea is a highly diverse, highly studied, and highly impacted biogeographic region, yet no phylogenetic reconstruction of fish diversity in this area has been published to date. Here, we infer the timing and geographic origins of Mediterranean teleost species diversity using nucleotide sequences collected from GenBank. We assembled a DNA supermatrix composed of four mitochondrial genes (12S ribosomal DNA, 16S ribosomal DNA, cytochrome c oxidase subunit I and cytochrome b) and two nuclear genes (rhodopsin and recombination activating gene I), including 62% of Mediterranean teleost species plus 9 outgroups. Maximum likelihood and Bayesian phylogenetic and dating analyses were calibrated using 20 fossil constraints. An additional 124 species were grafted onto the chronogram according to their taxonomic affinity, checking for the effects of taxonomic coverage in subsequent diversification analyses. We then interpreted the time-line of teleost diversification in light of Mediterranean historical biogeography, distinguishing non-endemic natives, endemics and exotic species. Results show that the major Mediterranean orders are of Cretaceous origin, specifically ∼100–80 Mya, and most Perciformes families originated 80–50 Mya. Two important clade origin events were detected. The first at 100–80 Mya, affected native and exotic species, and reflects a global diversification period at a time when the Mediterranean Sea did not yet exist. The second occurred during the last 50 Mya, and is noticeable among endemic and native species, but not among exotic species. This period corresponds to isolation of the Mediterranean from Indo-Pacific waters before the Messinian salinity crisis. The Mediterranean fish fauna illustrates well the assembly of regional faunas through origination and immigration, where dispersal and isolation have shaped the emergence of a biodiversity hotspot

A New Eusuchian Crocodyliform with Novel Cranial Integument and Its Significance for the Origin and Evolution of Crocodylia

Crocodyliforms were one of the most successful groups of Mesozoic tetrapods, radiating into terrestrial, semiaquatic and marine environments, while occupying numerous trophic niches, including carnivorous, insectivorous, herbivorous, and piscivorous species. Among these taxa were the enigmatic, poorly represented flat-headed crocodyliforms from the late Cretaceous of northern Africa. Here we report a new, giant crocodyliform from the early Late Cretaceous (Cenomanian) Kem Kem Formation of Morocco. Represented by a partial braincase, the taxon has an extremely long, flat skull with large jaw and craniocervical muscles. The skull roof is ridged and ornamented with a broad, rough boss surrounded by significant vascular impressions, likely forming an integumentary structure unique among crocodyliforms. Size estimates using endocranial volume indicate the specimen was very large. The taxon possesses robust laterosphenoids with laterally oriented capitate processes and isolated epipterygoids, features allying it with derived eusuchians. Phylogenetic analysis finds the taxon to be a derived eusuchian and sister taxon to Aegyptosuchus, a poorly understood, early Late Cretaceous taxon from the Bahariya formation. This clade forms the sister clade of crown-group Crocodylia, making these taxa the earliest eusuchian crocodyliforms known from Africa. These results shift phylogenetic and biogeographical hypotheses on the origin of modern crocodylians towards the circum-Tethyean region and provide important new data on eusuchian morphology and evolution