Features of Cryptic Promoters and Their Varied Reliance on Bromodomain-Containing Factors

The Set2-Rpd3S pathway is important for the control of transcription memory. Mutation of components of this pathway results in cryptic transcription initiation within the coding region of approximately 30% of yeast genes. Specifically, deletion of the Set2 histone methyltransferase or Rco1, a component of the Rpd3S histone deacetylase complex leads to hyperacetylation of certain open reading frames (ORFs). We used this mutant as a system to study the role of histone modifications and co-activator recruitment in preinitiation complex (PIC) formation. Specifically, we looked at the dependence of promoters on the bromodomain-containing RSC complex and the Bdf1 protein. We found that the dependence of cryptic promoters for these proteins varied. Overall, our data indicate that cryptic promoters are independently regulated, and their activation is dependent on factors that govern gene activation at canonical promoters

Duloxetine in the treatment of Major Depressive Disorder: A comparison of efficacy in patients with and without melancholic features

BACKGROUND: The most prominent feature of melancholic depression is a near-total loss of the capacity to derive pleasure from activities or other positive stimuli. Additional symptoms can include psychomotor disturbances, anorexia, excessive guilt, and early awakening from sleep. Melancholic patients may exhibit treatment responses and outcomes that differ from those of non-melancholic patients. Pooled data from double-blind, placebo-controlled studies were utilized to compare the efficacy of duloxetine in depressed patients with and without melancholic features. METHODS: Efficacy data were pooled from 8 double-blind, placebo-controlled clinical trials of duloxetine. The presence of melancholic features (DSM-IV criteria) was determined using results from the Mini International Neuropsychiatric Interview (MINI). Patients (aged ≥ 18 years) meeting DSM-IV criteria for major depressive disorder (MDD) received duloxetine (40–120 mg/d; melancholic, N = 759; non-melancholic, N = 379) or placebo (melancholic, N = 519; non-melancholic, N = 256) for up to 9 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD(17)) total score, HAMD(17 )subscales (Maier, anxiety, retardation, sleep), the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain. RESULTS: In data from all 8 studies, duloxetine's advantage over placebo did not differ significantly between melancholic and non-melancholic patients (treatment-by-melancholic status interactions were not statistically significant). Duloxetine demonstrated significantly greater improvement in depressive symptom severity, compared with placebo, within both melancholic and non-melancholic cohorts (p ≤ .001 for HAMD(17 )total score, CGI-S and PGI-I). When analyzed by gender, the magnitude of improvement in efficacy outcomes did not differ significantly between duloxetine-treated male and female melancholic patients. In the two studies that assessed duloxetine 60 mg once-daily dosing, duloxetine-treated melancholic patients had significantly greater improvement compared with placebo on HAMD(17 )total score, CGI-S, PGI-I, 3 of 4 subscales of the HAMD(17), and VAS overall pain severity (p < .01). Estimated probabilities of response and remission were significantly greater for melancholic patients receiving duloxetine 60 mg QD compared with placebo (response 74.7% vs. 42.2%, respectively, p < .001; remission 44.4% vs. 24.7%, respectively, p = .002 CONCLUSIONS: In this analysis of pooled data, the efficacy of duloxetine in patients with melancholic features did not differ significantly from that observed in non-melancholic patients

The efficacy of duloxetine: A comprehensive summary of results from MMRM and LOCF_ANCOVA in eight clinical trials

BACKGROUND: A mixed-effects model repeated measures approach (MMRM) was specified as the primary analysis in the Phase III clinical trials of duloxetine for the treatment of major depressive disorder (MDD). Analysis of covariance using the last observation carried forward approach to impute missing values (LOCF_ANCOVA) was specified as a secondary analysis. Previous research has shown that MMRM and LOCF_ANCOVA yield identical endpoint results when no data are missing, while MMRM is more robust to biases from missing data and thereby provides superior control of Type I and Type II error compared with LOCF_ANCOVA. We compared results from MMRM and LOCF_ANCOVA analyses across eight clinical trials of duloxetine in order to investigate how the choice of primary analysis may influence interpretations of efficacy. METHODS: Results were obtained from the eight acute-phase clinical trials that formed the basis of duloxetine's New Drug Application for the treatment of MDD. All 202 mean change analyses from the 20 rating scale total scores and subscales specified a priori in the various protocols were included in the comparisons. RESULTS: In 166/202 comparisons (82.2%), MMRM and LOCF_ANCOVA agreed with regard to the statistical significance of the differences between duloxetine and placebo. In 25/202 cases (12.4%), MMRM yielded a significant difference when LOCF_ANCOVA did not, while in 11/202 cases (5.4%), LOCF_ANCOVA produced a significant difference when MMRM did not. In 110/202 comparisons (54.4%) the p-value from MMRM was lower than that from LOCF_ANCOVA, while in 69/202 comparisons (34.2%), the p-value from LOCF_ANCOVA was lower than that from MMRM. In the remaining 23 comparisons (11.4%), the p-values from LOCF_ANCOVA and MMRM were equal when rounded to the 3(rd )decimal place (usually as a result of both p-values being < .001). For the HAMD(17 )total score, the primary outcome in all studies, MMRM yielded 9/12 (75%) significant contrasts, compared with 6/12 (50%) for LOCF_ANCOVA. The expected success rate was 80%. CONCLUSIONS: Important differences exist between MMRM and LOCF_ANCOVA. Empirical research has clearly demonstrated the theoretical advantages of MMRM over LOCF_ANCOVA. However, interpretations regarding the efficacy of duloxetine in MDD were unaffected by the choice of analytical technique

Les derniers rennes de Dordogne

Dans le cadre d’une étude régionale sur les modalités chronologiques et environnementales de la disparition du Renne (Rangifer tarandus) et de l’expansion du Cerf (Cervus elaphus) et du Chevreuil (Capreolus capreolus), une série d’analyses isotopiques en isotopes stables (13C, 15N) et de datations 14C par SMA sur collagène a été réalisée sur des cervidés des sites du Tardiglaciaire du Moulin du Roc (Saint-Chamassy) et de La Gare de Couze (Lalinde) situés en Dordogne. Les résultats des datations directes confirment la cohabitation du Renne et du Chevreuil au cours du Tardiglaciaire. Des cerfs datés des couches du Magdalénien supérieur de La Gare de Couze et du Magdalénien final du Moulin du Roc s’avèrent contemporains de la fin du Dryas récent ou GS-1. De plus, la couche brune-bigarrée du Moulin du Roc a livré un reste de Renne daté de 11860 ± 60 ans BP (13480-13860 ans cal BP, GrA-44537) qui situe ce spécimen au début de l’Alleröd ou GI-1c. Cette donnée confirme la présence du Renne en Dordogne après 12000 ans BP (ca. 13800 ans cal BP), alors que cette espèce semble avoir déjà disparu dans la région montagneuse des Pyrénées françaises et de la plaine septentrionale du Bassin parisien. Les teneurs en 13C des rennes de Dordogne montrent une légère diminution attribuable à la baisse de la disponibilité du lichen probablement liée au réchauffement climatique du début du Bölling. Cette tendance ne semble pas se confirmer avec le Renne de l’Alleröd du Moulin du Roc dont les teneurs isotopiques sont semblables à celles de ses congénères du Dryas ancien. Par ailleurs, les rennes du sud-ouest de la France présentent une teneur moyenne en 15N plus élevée que celles des rennes du Poitou, du Bassin parisien et des Alpes du Nord et Jura entre 12100 et 13400 ans BP (ca. 14000-16600 ans cal BP). Ce résultat pourrait refléter la reprise plus précoce de la pédogénèse dans le territoire du sud-ouest qui n’a pas subi la proximité d’un front glaciaire ou l’emprise directe d’un permafrost continu au cours du Dernier Maximum Glaciaire, à la différence des régions du Bassin parisien et du Jura. Les derniers rennes de Dordogne ont ainsi persisté au-delà de 12 000 ans BP dans un milieu où la production végétale s’était déjà intensifiée, permettant la coexistence de différentes espèces de cervidés. Nous présentons l’hypothèse qu’il pourrait s’agir d’une adaptation temporaire aux changements climatiques de l’interstade du Tardiglaciaire par des rennes sédentaires dans le sud-ouest de la France, tandis que les groupes plus mobiles des régions septentrionales ont changé leurs aires de répartition en modifiant leur schéma de déplacement

Particle Dynamics in a Mass-Conserving Coalescence Process

We consider a fully asymmetric one-dimensional model with mass-conserving coalescence. Particles of unit mass enter at one edge of the chain and coalescence while performing a biased random walk towards the other edge where they exit. The conserved particle mass acts as a passive scalar in the reaction process $A+A\to A$, and allows an exact mapping to a restricted ballistic surface deposition model for which exact results exist. In particular, the mass- mass correlation function is exactly known. These results complement earlier exact results for the $A+A\to A$ process without mass. We introduce a comprehensive scaling theory for this process. The exact anaytical and numerical results confirm its validity.Comment: 5 pages, 6 figure

A new testudinoid turtle from the middle to late Eocene of Vietnam

Testudinoidea is a major clade of turtles that has colonized different ecological environments across the globe throughout the Tertiary. Aquatic testudinoids have a particularly rich fossil record in the Tertiary of the northern hemisphere, but little is known about the evolutionary history of the group, as the phylogenetic relationships of most fossils have not been established with confidence, in part due to high levels of homoplasy and polymorphism.Methods: We here focus on describing a sample of 30 testudinoid shells, belonging to a single population that was collected from lake sediments from the middle to late Eocene (35–39 Ma) Na Duong Formation in Vietnam. The phylogenetic placement of this new material is investigated by integrating it and 11 other species of putative geoemydids from the Eocene and Oligocene to a recently published matrix of geoemydid turtles, that embraces the use of polymorphic characters, and then running a total-evidence analysis.Results: The new material is highly polymorphic, but can be inferred with confidence to be a new taxon, Banhxeochelys trani gen. et sp. nov. It shares morphological similarities with other southeastern Asian testudinoids, Isometremys lacuna and Guangdongemys pingi, but is placed phylogenetically at the base of Pan-Testuguria when fossils are included in the analysis, or as a stem geoemydid when other fossils are deactivated from the matrix. The vast majority of other putative fossil geoemydids are placed at the base of Pan-Testuguria as well.Discussion: The phylogenetic placement of fossil testudinoids used in the analysis is discussed individually and each species compared to Banhxeochelys trani gen. et sp. nov. The high levels of polymorphism observed in the new taxon is discussed in terms of ontogenetic and random variability. This is the first time that a large sample of fossil testudinoids has its morphological variation described in detail

Body image and pregnancy : a matter of restraint?

iii, 66 leaves ; 28 cm. --Body image is a significant aspect of the pregnancy experience, and impacts the physical and psychological health of both the mother and baby. Dietary restraint is proposed as a construct by which to understand the change and continuity of women’s body image throughout pregnancy and postpartum, contributing to the experience of weight gain and body changes. Published literature is reviewed and analyzed to demonstrate connections between salient physical and psychological aspects of dietary restraint, body image prior to and during pregnancy, and disordered eating. Conclusion suggests the utility of dietary restraint for understanding the body image trajectory of individual women during this life transition

Did Ebola emerge in West Africa by a policy-driven phase change in agroecology? Ebola's social context

SCOPUS: no.jinfo:eu-repo/semantics/publishe

Middle Miocene Climate and Stable Oxygen Isotopes in Europe Based on Numerical Modeling

The Middle Miocene (15.99–11.65 Ma) of Europe witnessed major climatic, environmental, and vegetational change, yet we are lacking detailed reconstructions of Middle Miocene temperature and precipitation patterns over Europe. Here, we use a high-resolution (∼0.75°) isotope-enabled general circulation model (ECHAM5-wiso) with time-specific boundary conditions to investigate changes in temperature, precipitation, and δ18O in precipitation (δ18Op). Experiments were designed with variable elevation configurations of the European Alps and different atmospheric CO2 levels to examine the influence of Alpine elevation and global climate forcing on regional climate and δ18Op patterns. Modeling results are in agreement with available paleobotanical temperature data and with low-resolution Middle Miocene experiments of the Miocene Model Intercomparison Project (MioMIP1). However, simulated precipitation rates are 300–500 mm/yr lower in the Middle Miocene than for pre-industrial times for central Europe. This result is consistent with precipitation estimates from herpetological fossil assemblages, but contradicts precipitation estimates from paleobotanical data. We attribute the Middle Miocene precipitation change in Europe to shifts in large-scale pressure patterns in the North Atlantic and over Europe and associated changes in wind direction and humidity. We suggest that global climate forcing contributed to a maximum δ18Op change of ∼2‰ over high elevation (Alps) and ∼1‰ over low elevation regions. In contrast, we observe a maximum modeled δ18Op decrease of 8‰ across the Alpine orogen due to Alpine topography. However, the elevation-δ18Op lapse rate shallows in the Middle Miocene, leading to a possible underestimation of paleotopography when using present-day δ18Op—elevation relationships data for stable isotope paleoaltimetry studies