The Cosmological Constant

This is a review of the physics and cosmology of the cosmological constant. Focusing on recent developments, I present a pedagogical overview of cosmology in the presence of a cosmological constant, observational constraints on its magnitude, and the physics of a small (and potentially nonzero) vacuum energy.Comment: 50 pages. Submitted to Living Reviews in Relativity (http://www.livingreviews.org/), December 199

Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer

Transcriptional reactivation of telomerase catalytic subunit (TERT) is a frequent hallmark of cancer, occurring in 90% of human malignancies. However, specific mechanisms driving TERT reactivation remain obscure for many tumor types and in particular gastric cancer (GC), a leading cause of global cancer mortality. Here, through comprehensive genomic and epigenomic analysis of primary GCs and GC cell lines, we identified the transcription factor early B cell factor 1 (EBF1) as a TERT transcriptional repressor and inactivation of EBF1 function as a major cause of TERT upregulation. Abolishment of EBF1 function occurs through 3 distinct (epi)genomic mechanisms. First, EBF1 is epigenetically silenced via DNA methyltransferase, polycomb-repressive complex 2 (PRC2), and histone deacetylase activity in GCs. Second, recurrent, somatic, and heterozygous EBF1 DNA–binding domain mutations result in the production of dominant-negative EBF1 isoforms. Third, more rarely, genomic deletions and rearrangements proximal to the TERT promoter remobilize or abolish EBF1-binding sites, derepressing TERT and leading to high TERT expression. EBF1 is also functionally required for various malignant phenotypes in vitro and in vivo, highlighting its importance for GC development. These results indicate that multimodal genomic and epigenomic alterations underpin TERT reactivation in GC, converging on transcriptional repressors such as EBF1

Contact metamorphism associated to the Penamacor - Monsanto granitic intrusion (Central Portugal): geochemical, isotopic and mineralogical features

Contact metamorphism related to Variscan and late-Variscan granitic plutons in the Iberian Peninsula is superimposed on medium-grade regional metamorphism, making it often difficult to evaluate per se the thermal effects due to those intrusions and explaining the paucity of scientific literature on the subject. An exhaustive set of geochemical, isotopic and mineralogical data on the contact-zone metasediments hosting the Penamacor-Monsanto granite (Central Iberian Zone, Portugal) provides a significant contribution to the characterization of low- to intermediate-grade contact metamorphism in geological contexts formerly affected by regional metamorphism. The metasediments hosting the Penamacor-Monsanto pluton belong to the extensive detrital sequence of the ante-Ordovician Schist-Greywacke Complex. Bulk geochemistry, oxygen isotope data and crystal-chemistry of key minerals from those contact-zone and neighbouring metasediments have made it possible to infer metamorphic conditions on the contact zone of this granitic intrusion, and to distinguish them from late boron-metasomatism at the exocontact. Mineral paragenesis (muscovite + biotite + chlorite quartz plagioclase cordierite, in spotted-schists; biotite + chlorite quartz plagioclase ( cordierite), in hornfelses) and the composition of these coexisting mineral phases indicate that most of the contact rocks reached the biotite zone (or even the cordierite zone, in some cases), equivalent to upper greenschist – lower amphibolite metamorphic grade. The relatively narrow range of O-isotope temperatures estimated for the crystallization of the marginal granites (550-625ºC) explains the absence of significant effects of thermal flow anisotropy on the contact-zone rocks. Besides, textural, paragenetic, mineralogical, isotopic and geochemical nuances observed in hornfelses and spotted-schists seem mainly related to the local host-rock heterogeneities, rather than to thermal effects. The relatively low temperatures estimated for granitoid emplacement and their restricted isotopic and mineralogical impacts on the metasedimentary host-rocks account for the narrow metamorphic aureole associated with the Penamacor-Monsanto pluton, and suggest this massif may correspond to the outcropping tip of a larger granitic intrusion at depth.Las intrusions graníticas Varíscicas y tardivaríscicas de la Península Ibérica dieron lugar a un metamorfsmo de contacto que afecta a un encajante previamente sometido a un metamorfsmo regional de grado medio, lo que difculta separar los efectos térmicos de aquellos regionales, y explica la escasez de estudios sobre el mismo. El estudio detallado de la zona de contacto entre el Granito de Penamacor-Monsanto (Zona Centro-Ibérica; Portugal) y su encajante metasedimentario mediante técnicas geoquímicas, mineralógicas e isotópicas supone una notable contribución al conocimiento y caracterización del metamorfsmo de contacto de grados bajos a intermedios en contextos geológicos previamente afectados por metamorfsmo regional. El encajante metasedimentario del Plutón de Penamacor-Monsanto es parte de la amplia secuencia detrítica ante-Ordovícia conocida como Complejo Esquisto-Grawackico. Datos geoquímicos de roca total y cristaloquímicos de los minerales más característicos, y relaciones isotópicas de oxígeno en la zona de contacto y metasedimentos aledaños permiten inferir las condiciones metamórfcas en la zona de contacto de dicha intrusión, y diferenciarla de aquella afectada por metasomatismo tardío por B. La paragénesis mineral (muscovita + biotita + clorita ± cuarzo ± plagioclasa ± cordierita en los esquistos moteados; biotita + clorita ± cuarzo ± plagiclasa (± cordierita) en corneanas) y la composición de las fases minerales coexistentes indican que la mayoría de rocas del contacto alcanzaron la zona de la biotita (e incluso, en algunos casos, aquella de la cordierita), equivalente a la parte alta del grado metamórfco de los esquistos verdes, o a la parte baja de las anfbolitas. El rango relativamente pequeño de temperaturas de cristalización de los granitos marginales (550-625°C), calculado mediante isótopos de oxígeno, explica la carencia de anisotropías térmicas signifcativas en las rocas del contacto. Las sutiles diferencias texturales, paragenéticas, mineralógicas, isotópicas y geoquímicas en esquistos moteados y corneanas parecen relacionadas con heterogeneidades locales de los encajantes, y no con efectos térmicos diferenciados. Las temperaturas relativamente bajas estimadas durante la intrusión del granito de Penamacor-Monsanto, y el limitado efecto mineralógico e isotópico sobre el encajante metasedimentario, dan lugar a una aureola de contacto estrecha, y sugieren que este macizo puede corresponder al techo de una intrusión mayor en profundidad.Funding was provided by FCT—Fundação para a Ciên cia e Tecnologia, through project METMOB (PTDC/CTE-GIX/116204/2009

Laboratory-Evolved Mutants of an Exogenous Global Regulator, IrrE from Deinococcus radiodurans, Enhance Stress Tolerances of Escherichia coli

The tolerance of cells toward different stresses is very important for industrial strains of microbes, but difficult to improve by the manipulation of single genes. Traditional methods for enhancing cellular tolerances are inefficient and time-consuming. Recently, approaches employing global transcriptional or translational engineering methods have been increasingly explored. We found that an exogenous global regulator, irrE from an extremely radiation-resistant bacterium, Deinococcus radiodurans, has the potential to act as a global regulator in Escherichia coli, and that laboratory-evolution might be applied to alter this regulator to elicit different phenotypes for E. coli.To extend the methodology for strain improvement and to obtain higher tolerances toward different stresses, we here describe an approach of engineering irrE gene in E. coli. An irrE library was constructed by randomly mutating the gene, and this library was then selected for tolerance to ethanol, butanol and acetate stresses. Several mutants showing significant tolerances were obtained and characterized. The tolerances of E. coli cells containing these mutants were enhanced 2 to 50-fold, based on cell growth tests using different concentrations of alcohols or acetate, and enhanced 10 to 100-fold based on ethanol or butanol shock experiments. Intracellular reactive oxygen species (ROS) assays showed that intracellular ROS levels were sharply reduced for cells containing the irrE mutants. Sequence analysis of the mutants revealed that the mutations distribute cross all three domains of the protein.To our knowledge, this is the first time that an exogenous global regulator has been artificially evolved to suit its new host. The successes suggest the possibility of improving tolerances of industrial strains by introducing and engineering exogenous global regulators, such as those from extremophiles. This new approach can be applied alone or in combination with other global methods, such as global transcriptional machinery engineering (gTME) for strain improvements

Is There a Seamount Effect on Microbial Community Structure and Biomass? The Case Study of Seine and Sedlo Seamounts (Northeast Atlantic)

Seamounts are considered to be “hotspots” of marine life but, their role in oceans primary productivity is still under discussion. We have studied the microbial community structure and biomass of the epipelagic zone (0–150 m) at two northeast Atlantic seamounts (Seine and Sedlo) and compared those with the surrounding ocean. Results from two cruises to Sedlo and three to Seine are presented. Main results show large temporal and spatial microbial community variability on both seamounts. Both Seine and Sedlo heterotrophic community (abundance and biomass) dominate during winter and summer months, representing 75% (Sedlo, July) to 86% (Seine, November) of the total plankton biomass. In Seine, during springtime the contribution to total plankton biomass is similar (47% autotrophic and 53% heterotrophic). Both seamounts present an autotrophic community structure dominated by small cells (nano and picophytoplankton). It is also during spring that a relatively important contribution (26%) of large cells to total autotrophic biomass is found. In some cases, a “seamount effect” is observed on Seine and Sedlo microbial community structure and biomass. In Seine this is only observed during spring through enhancement of large autotrophic cells at the summit and seamount stations. In Sedlo, and despite the observed low biomasses, some clear peaks of picoplankton at the summit or at stations within the seamount area are also observed during summer. Our results suggest that the dominance of heterotrophs is presumably related to the trapping effect of organic matter by seamounts. Nevertheless, the complex circulation around both seamounts with the presence of different sources of mesoscale variability (e.g. presence of meddies, intrusion of African upwelling water) may have contributed to the different patterns of distribution, abundances and also changes observed in the microbial community

Mouse Ribosomal RNA Genes Contain Multiple Differentially Regulated Variants

Previous cytogenetic studies suggest that various rDNA chromosomal loci are not equally active in different cell types. Consistent with this variability, rDNA polymorphism is well documented in human and mouse. However, attempts to identify molecularly rDNA variant types, which are regulated individually (i.e., independent of other rDNA variants) and tissue-specifically, have not been successful. We report here the molecular cloning and characterization of seven mouse rDNA variants (v-rDNA). The identification of these v-rDNAs was based on restriction fragment length polymorphisms (RFLPs), which are conserved among individuals and mouse strains. The total copy number of the identified variants is less than 100 and the copy number of each individual variant ranges from 4 to 15. Sequence analysis of the cloned v-rDNA identified variant-specific single nucleotide polymorphisms (SNPs) in the transcribed region. These SNPs were used to develop a set of variant-specific PCR assays, which permitted analysis of the v-rDNAs' expression profiles in various tissues. These profiles show that three v-rDNAs are expressed in all tissues (constitutively active), two are expressed in some tissues (selectively active), and two are not expressed (silent). These expression profiles were observed in six individuals from three mouse strains, suggesting the pattern is not randomly determined. Thus, the mouse rDNA array likely consists of genetically distinct variants, and some are regulated tissue-specifically. Our results provide the first molecular evidence for cell-type-specific regulation of a subset of rDNA

Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling

The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H)/E(spl)-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl)-HLH genes are required in different neuroblast lineages. The Notch/Su(H)/E(spl)-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21CIP1/p27KIP1/p57Kip2). ChIP and DamID analysis of Su(H) and E(spl)-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems

Candida albicans AGE3, the Ortholog of the S. cerevisiae ARF-GAP-Encoding Gene GCS1, Is Required for Hyphal Growth and Drug Resistance

BACKGROUND: Hyphal growth and multidrug resistance of C. albicans are important features for virulence and antifungal therapy of this pathogenic fungus. METHODOLOGY/PRINCIPAL FINDINGS: Here we show by phenotypic complementation analysis that the C. albicans gene AGE3 is the functional ortholog of the yeast ARF-GAP-encoding gene GCS1. The finding that the gene is required for efficient endocytosis points to an important functional role of Age3p in endosomal compartments. Most C. albicans age3Delta mutant cells which grew as cell clusters under yeast growth conditions showed defects in filamentation under different hyphal growth conditions and were almost completely disabled for invasive filamentous growth. Under hyphal growth conditions only a fraction of age3Delta cells shows a wild-type-like polarization pattern of the actin cytoskeleton and lipid rafts. Moreover, age3Delta cells were highly susceptible to several unrelated toxic compounds including antifungal azole drugs. Irrespective of the AGE3 genotype, C-terminal fusions of GFP to the drug efflux pumps Cdr1p and Mdr1p were predominantly localized in the plasma membrane. Moreover, the plasma membranes of wild-type and age3Delta mutant cells contained similar amounts of Cdr1p, Cdr2p and Mdr1p. CONCLUSIONS/SIGNIFICANCE: The results indicate that the defect in sustaining filament elongation is probably caused by the failure of age3Delta cells to polarize the actin cytoskeleton and possibly of inefficient endocytosis. The high susceptibility of age3Delta cells to azoles is not caused by inefficient transport of efflux pumps to the cell membrane. A possible role of a vacuolar defect of age3Delta cells in drug susceptibility is proposed and discussed. In conclusion, our study shows that the ARF-GAP Age3p is required for hyphal growth which is an important virulence factor of C. albicans and essential for detoxification of azole drugs which are routinely used for antifungal therapy. Thus, it represents a promising antifungal drug target

Do herbivorous minnows have “plug-flow reactor” guts? Evidence from digestive enzyme activities, gastrointestinal fermentation, and luminal nutrient concentrations

Few investigations have empirically analyzed fish gut function in the context of chemical reactor models. In this study, digestive enzyme activities, levels of gastrointestinal fermentation products [short chain fatty acids (SCFA)], luminal nutrient concentrations, and the mass of gut contents were measured along the digestive tract in herbivorous and carnivorous minnows to ascertain whether their guts function as “plug-flow reactors” (PFRs). Four of the species, Campostoma anomalum, C. ornatum, C. oligolepis, and C. pauciradii, are members of a monophyletic herbivorous clade, whereas the fifth species, Nocomis micropogon, is a carnivore from an adjacent carnivorous clade. In the context of a PFR model, the activities of amylase, trypsin and lipase, and the concentrations of glucose, protein, and lipid were predicted to decrease moving from the proximal to the distal intestine. I found support for this as these enzyme activities and nutrient concentrations generally decreased moving distally along the intestine of the four Campostoma species. Furthermore, gut content mass and the low SCFA concentrations did not change (increase or decrease) along the gut of any species. Combined with a previous investigation suggesting that species of Campostoma have rapid gut throughput rates, the data presented here generally support Campostoma as having guts that function as PFRs. The carnivorous N. micropogon showed some differences in the measured parameters, which were interpreted in the contexts of intake and retention time to suggest that PFR function breaks down in this carnivorous species