Brachyury and Related Tbx Proteins Interact with the Mixl1 Homeodomain Protein and Negatively Regulate Mixl1 Transcriptional Activity

Mixl1 is a homeodomain transcription factor required for mesoderm and endoderm patterning during mammalian embryogenesis. Despite its crucial function in development, co-factors that modulate the activity of Mixl1 remain poorly defined. Here we report that Mixl1 interacts physically and functionally with the T-box protein Brachyury and related members of the T-box family of transcription factors. Transcriptional and protein analyses demonstrated overlapping expression of Mixl1 and Brachyury during embryonic stem cell differentiation. In vitro protein interaction studies showed that the Mixl1 with Brachyury associated via their DNA-binding domains and gel shift assays revealed that the Brachyury T-box domain bound to Mixl1-DNA complexes. Furthermore, luciferase reporter experiments indicated that association of Mixl1 with Brachyury and related T-box factors inhibited the transactivating potential of Mixl1 on the Gsc and Pdgfrα promoters. Our results indicate that the activity of Mixl1 can be modulated by protein-protein interactions and that T-box factors can function as negative regulators of Mixl1 activity

The Context of Current Content Analysis of Gender Roles: An Introduction to a Special Issue

The aim of this paper is to provide context for the quantitative content analyses of gender roles that are to be included in both parts of this special issue. First, a timeline of historical uses of the content analysis methodology is presented. Second, research objectives that frequently drive content analysis of gender roles are described; these include: to support feminist claims, to compare media with real life, to predict effects on audiences, and to detect effects of media producers on content. Third, previous content analyses published in Sex Roles and other gender-focused journals are reviewed and categorized in terms of medium, genre, time span, gender, and nationality. Finally, contributions of each of the articles in this special issue are outlined

Shake a tail feather: the evolution of the theropod tail into a stiff aerodynamic surface

Theropod dinosaurs show striking morphological and functional tail variation; e.g., a long, robust, basal theropod tail used for counterbalance, or a short, modern avian tail used as an aerodynamic surface. We used a quantitative morphological and functional analysis to reconstruct intervertebral joint stiffness in the tail along the theropod lineage to extant birds. This provides new details of the tail's morphological transformation, and for the first time quantitatively evaluates its biomechanical consequences. We observe that both dorsoventral and lateral joint stiffness decreased along the non-avian theropod lineage (between nodes Theropoda and Paraves). Our results show how the tail structure of non-avian theropods was mechanically appropriate for holding itself up against gravity and maintaining passive balance. However, as dorsoventral and lateral joint stiffness decreased, the tail may have become more effective for dynamically maintaining balance. This supports our hypothesis of a reduction of dorsoventral and lateral joint stiffness in shorter tails. Along the avian theropod lineage (Avialae to crown group birds), dorsoventral and lateral joint stiffness increased overall, which appears to contradict our null expectation. We infer that this departure in joint stiffness is specific to the tail's aerodynamic role and the functional constraints imposed by it. Increased dorsoventral and lateral joint stiffness may have facilitated a gradually improved capacity to lift, depress, and swing the tail. The associated morphological changes should have resulted in a tail capable of producing larger muscular forces to utilise larger lift forces in flight. Improved joint mobility in neornithine birds potentially permitted an increase in the range of lift force vector orientations, which might have improved flight proficiency and manoeuvrability. The tail morphology of modern birds with tail fanning capabilities originated in early ornithuromorph birds. Hence, these capabilities should have been present in the early Cretaceous, with incipient tail-fanning capacity in the earliest pygostylian birds

HIV-1 Nef Targets MHC-I and CD4 for Degradation Via a Final Common β-COP–Dependent Pathway in T Cells

To facilitate viral infection and spread, HIV-1 Nef disrupts the surface expression of the viral receptor (CD4) and molecules capable of presenting HIV antigens to the immune system (MHC-I). To accomplish this, Nef binds to the cytoplasmic tails of both molecules and then, by mechanisms that are not well understood, disrupts the trafficking of each molecule in different ways. Specifically, Nef promotes CD4 internalization after it has been transported to the cell surface, whereas Nef uses the clathrin adaptor, AP-1, to disrupt normal transport of MHC-I from the TGN to the cell surface. Despite these differences in initial intracellular trafficking, we demonstrate that MHC-I and CD4 are ultimately found in the same Rab7+ vesicles and are both targeted for degradation via the activity of the Nef-interacting protein, β-COP. Moreover, we demonstrate that Nef contains two separable β-COP binding sites. One site, an arginine (RXR) motif in the N-terminal α helical domain of Nef, is necessary for maximal MHC-I degradation. The second site, composed of a di-acidic motif located in the C-terminal loop domain of Nef, is needed for efficient CD4 degradation. The requirement for redundant motifs with distinct roles supports a model in which Nef exists in multiple conformational states that allow access to different motifs, depending upon which cellular target is bound by Nef

Estimates of burden and consequences of infants born small for gestational age in low and middle income countries with INTERGROWTH-21 st standard: Analysis of CHERG datasets

Objectives To estimate small for gestational age birth prevalence and attributable neonatal mortality in low and middle income countries with the INTERGROWTH-21 st birth weight standard. Design Secondary analysis of data from the Child Health Epidemiology Reference Group (CHERG), including 14 birth cohorts with gestational age, birth weight, and neonatal follow-up. Small for gestational age was defined as infants weighing less than the 10th centile birth weight for gestational age and sex with the multiethnic, INTERGROWTH-21 st birth weight standard. Prevalence of small for gestational age and neonatal mortality risk ratios were calculated and pooled among these datasets at the regional level. With available national level data, prevalence of small for gestational age and population attributable fractions of neonatal mortality attributable to small for gestational age were estimated. Setting CHERG birth cohorts from 14 population based sites in low and middle income countries. Main outcome measures In low and middle income countries in the year 2012, the number and proportion of infants born small for gestational age; number and proportion of neonatal deaths attributable to small for gestational age; the number and proportion of neonatal deaths that could be prevented by reducing the prevalence of small for gestational age to 10%. Results In 2012, an estimated 23.3 million infants (uncertainty range 17.6 to 31.9; 19.3% of live births) were born small for gestational age in low and middle income countries. Among these, 11.2 million (0.8 to 15.8) were term and not low birth weight (≥2500 g), 10.7 million (7.6 to 15.0) were term and low birth weight (<2500 g) and 1.5 million (0.9 to 2.6) were preterm. In low and middle income countries, an estimated 606 500 (495 000 to 773 000) neonatal deaths were attributable to infants born small for gestational age, 21.9% of all neonatal deaths. The largest burden was in South Asia, where the prevalence was the highest (34%); about 26% of neonatal deaths were attributable to infants born small for gestational age. Reduction of the prevalence of small for gestational age from 19.3% to 10.0% in these countries could reduce neonatal deaths by 9.2% (254 600 neonatal deaths; 164 800 to 449 700). Conclusions In low and middle income countries, about one in five infants are born small for gestational age, and one in four neonatal deaths are among such infants. Increased efforts are required to improve the quality of care for and survival of these high risk infants in low and middle income countries