Interleukin-17A upregulates receptor activator of NF-κB on osteoclast precursors

Introduction  

The interaction between the immune and skeletal systems is evidenced by the bone loss observed in autoimmune diseases such as rheumatoid arthritis. In this paper we describe a new mechanism by which the immune cytokine IL-17A directly affects osteoclastogenesis.     

Thermal Properties of Tree Cavities During Winter in a Northern Hardwood Forest

ABSTRACT Tree cavities likely vary in their thermal quality for cavity-nesting animals, which could be especially important during winter. We conducted a winter field experiment to test whether cavities vary either in their buffering capacity or in their mean temperature according to predictable characteristics. We found that cavities buffered temperature and that there was a lag effect in temperature that appeared to be related to heating and cooling. Diameter at breast height was the most important variable influencing cavity temperature during the day, with smaller trees warming up more. During the night, diameter at breast height and tree decay class were important, such that larger, live trees cooled down less. Maintaining live trees with cavities in managed forests should be considered in addition to snag retention, because live trees appear to provide warmer structures during winter.     

Modeling the Spatial and Temporal Dependence in fMRI Data

Summary Functional magnetic resonance imaging (fMRI) data sets are large and characterized by complex dependence structures driven by highly sophisticated neurophysiology and aspects of the experimental designs. Typical analyses investigating task‐related changes in measured brain activity use a two‐stage procedure in which the first stage involves subject‐specific models and the second‐stage specifies group (or population) level parameters. Customarily, the first‐level accounts for temporal correlations between the serial scans acquired during one scanning session. Despite accounting for these correlations, fMRI studies often include multiple sessions and temporal dependencies may persist between the corresponding estimates of mean neural activity. Further, spatial correlations between brain activity measurements in different locations are often unaccounted for in statistical modeling and estimation. We propose a two‐stage, spatio‐temporal, autoregressive model that simultaneously accounts for spatial dependencies between voxels within the same anatomical region and for temporal dependencies between a subject's estimates from multiple sessions. We develop an algorithm that leverages the special structure of our covariance model, enabling relatively fast and efficient estimation. Using our proposed method, we analyze fMRI data from a study of inhibitory control in cocaine addicts.     

Alpine plants show species-level differences in the uptake of organic and inorganic nitrogen

As an estimate of species-level differences in the capacity to take up different forms of N, we measured plant uptake of ¹⁵N-NH₄ ⁺, ¹⁵N-NO₃ ^– and ¹⁵N, [1]-¹³C glycine within a set of herbaceous species collected from three alpine community types. Plants grown from cuttings in the greenhouse showed similar growth responses to the three forms of N but varied in the capacity to take up NH₄ ⁺, NO₃ ^– and glycine. Glycine uptake ranged from approximately 42% to greater than 100% of NH₄ ⁺ uptake; however, four out of nine species showed significantly greater uptake of either NH₄ ⁺ or NO₃ ^– than of glycine. Relative concentrations of exchangeable N at the sites of plant collection did not correspond with patterns of N uptake among species; instead, species from the same community varied widely in the capacity to take up NH₄ ⁺, NO₃ ^–, and glycine, suggesting the potential for differentiation among species in resource (N) use.     

The rho-guanine nucleotide exchange factor domain of obscurin regulates assembly of titin at the Z-disk through interactions with Ran binding protein 9

Obscurin is an approximately 800-kDa protein composed of structural and signaling domains that organizes contractile structures in striated muscle. We have studied the Rho-GEF domain of obscurin to understand its roles in morphogenesis and signaling. We used adenoviral overexpression of this domain, together with ultrastructural and immunofluorescence methods, to examine its effect on maturing myofibrils. We report that overexpression of the Rho-GEF domain specifically inhibits the incorporation of titin into developing Z-disks and disrupts the structure of the Z-disk and Z/I junction, and alters features of the A/I junction. The organization of other sarcomeric markers, including alpha-actinin, was not affected. We identified Ran binding protein 9 (RanBP9) as a novel ligand of the Rho-GEF domain and showed that binding is specific, with an apparent binding affinity of 1.9 muM. Overexpression of the binding region of RanBP9 also disrupted the incorporation of titin into developing Z-disks. Immunofluorescence localization during myofibrillogenesis indicated that the Rho-GEF domain assembles into sarcomeres before RanBP9, which first occurs in myonuclei and later in development translocates to the myoplasm, where it colocalizes with obscurin. Both the Rho-GEF domain and its binding region on RanBP9 bind directly to the N-terminal Ig domains of titin, which flank the Z-disk. Our results suggest that the Rho-GEF domain interacts with RanBP9 and that both can interact with the N-terminal region of titin to influence the formation of the Z-disk and A/I junction.     

Measuring persistence of implementation: QUERI Series

Background

We describe how we used the framework of the U.S. Department of Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) to develop a program to improve rates of diagnostic testing for the Human Immunodeficiency Virus (HIV). This venture was prompted by the observation by the CDC that 25% of HIV-infected patients do not know their diagnosis – a point of substantial importance to the VA, which is the largest provider of HIV care in the United States.

Methods

Following the QUERI steps (or process), we evaluated: 1) whether undiagnosed HIV infection is a high-risk, high-volume clinical issue within the VA, 2) whether there are evidence-based recommendations for HIV testing, 3) whether there are gaps in the performance of VA HIV testing, and 4) the barriers and facilitators to improving current practice in the VA. Based on our findings, we developed and initiated a QUERI step 4/phase 1 pilot project using the precepts of the Chronic Care Model. Our improvement strategy relies upon electronic clinical reminders to provide decision support; audit/feedback as a clinical information system, and appropriate changes in delivery system design. These activities are complemented by academic detailing and social marketing interventions to achieve provider activation.

Results

Our preliminary formative evaluation indicates the need to ensure leadership and team buy-in, address facility-specific barriers, refine the reminder, and address factors that contribute to inter-clinic variances in HIV testing rates. Preliminary unadjusted data from the first seven months of our program show 3–5 fold increases in the proportion of at-risk patients who are offered HIV testing at the VA sites (stations) where the pilot project has been undertaken; no change was seen at control stations.

Discussion

This project demonstrates the early success of the application of the QUERI process to the development of a program to improve HIV testing rates. Preliminary unadjusted results show that the coordinated use of audit/feedback, provider activation, and organizational change can increase HIV testing rates for at-risk patients. We are refining our program prior to extending our work to a small-scale, multi-site evaluation (QUERI step 4/phase 2). We also plan to evaluate the durability/sustainability of the intervention effect, the costs of HIV testing, and the number of newly identified HIV-infected patients. Ultimately, we will evaluate this program in other geographically dispersed stations (QUERI step 4/phases 3 and 4).     

The political gender gap: gender bias in facial inferences that predict voting behavior

Background

Throughout human history, a disproportionate degree of political power around the world has been held by men. Even in democracies where the opportunity to serve in top political positions is available to any individual elected by the majority of their constituents, most of the highest political offices are occupied by male leaders. What psychological factors underlie this political gender gap? Contrary to the notion that people use deliberate, rational strategies when deciding whom to vote for in major political elections, research indicates that people use shallow decision heuristics, such as impressions of competence solely from a candidate''s facial appearance, when deciding whom to vote for. Because gender has previously been shown to affect a number of inferences made from the face, here we investigated the hypothesis that gender of both voter and candidate affects the kinds of facial impressions that predict voting behavior.

Methodology/Principal Finding

Male and female voters judged a series of male and female political candidates on how competent, dominant, attractive and approachable they seemed based on their facial appearance. Then they saw a series of pairs of political candidates and decided which politician they would vote for in a hypothetical election for President of the United States. Results indicate that both gender of voter and candidate affect the kinds of facial impressions that predict voting behavior. All voters are likely to vote for candidates who appear more competent. However, male candidates that appear more approachable and female candidates who appear more attractive are more likely to win votes. In particular, men are more likely to vote for attractive female candidates whereas women are more likely to vote for approachable male candidates.

Conclusions/Significance

Here we reveal gender biases in the intuitive heuristics that voters use when deciding whom to vote for in major political elections. Our findings underscore the impact of gender and physical appearance on shaping voter decision-making and provide novel insight into the psychological foundations underlying the political gender gap.     

BMP and Wnt specify hematopoietic fate by activation of the Cdx-Hox pathway

The formation of blood in the embryo is dependent on bone morphogenetic protein (BMP), but how BMP signaling intersects with other regulators of hematopoietic development is unclear. Using embryonic stem (ES) cells, we show that BMP4 first induces ventral-posterior (V-P) mesoderm and subsequently directs mesodermal cells toward blood fate by activating Wnt3a and upregulating Cdx and Hox genes. When BMP signaling is blocked during this latter phase, enforced expression of either Cdx1 or Cdx4 rescues hematopoietic development, thereby placing BMP4 signaling upstream of the Cdx-Hox pathway. Wnt signaling cooperates in BMP-induced hemogenesis, and the Wnt effector LEF1 mediates BMP4 activation of Cdx genes. Our data suggest that BMP signaling plays two distinct and sequential roles during blood formation, initially as an inducer of mesoderm, and later to specify blood via activation of Wnt signaling and the Cdx-Hox pathway.     

Prokaryotic Metabolic Activity and Community Structure in Antarctic Continental Shelf Sediments

The prokaryote community activity and structural characteristics within marine sediment sampled across a continental shelf area located off eastern Antarctica (66°S, 143°E; depth range, 709 to 964 m) were studied. Correlations were found between microbial biomass and aminopeptidase and chitinase rates, which were used as proxies for microbial activity. Biomass and activity were maximal within the 0- to 3-cm depth range and declined rapidly with sediment depths below 5 cm. Most-probable-number counting using a dilute carbohydrate-containing medium recovered 1.7 to 3.8% of the sediment total bacterial count, with mostly facultatively anaerobic psychrophiles cultured. The median optimal growth temperature for the sediment isolates was 15°C. Many of the isolates identified belonged to genera characteristic of deep-sea habitats, although most appear to be novel species. Phospholipid fatty acid (PLFA) and isoprenoid glycerol dialkyl glycerol tetraether analyses indicated that the samples contained lipid components typical of marine sediments, with profiles varying little between samples at the same depth; however, significant differences in PLFA profiles were found between depths of 0 to 1 cm and 13 to 15 cm, reflecting the presence of a different microbial community. Denaturing gradient gel electrophoresis (DGGE) analysis of amplified bacterial 16S rRNA genes revealed that between samples and across sediment core depths of 1 to 4 cm, the community structure appeared homogenous; however, principal-component analysis of DGGE patterns revealed that at greater sediment depths, successional shifts in community structure were evident. Sequencing of DGGE bands and rRNA probe hybridization analysis revealed that the major community members belonged to delta proteobacteria, putative sulfide oxidizers of the gamma proteobacteria, Flavobacteria, Planctomycetales, and Archaea. rRNA hybridization analyses also indicated that these groups were present at similar levels in the top layer across the shelf region.     

FMRFamide-like peptides encoded on the flp-18 precursor gene activate two isoforms of the orphan Caenorhabditis elegans G-protein-coupled receptor Y58G8A.4 heterologously expressed in mammalian cells

Two alternatively spliced variants of an orphan Caenorhabditis elegans G-protein-coupled receptors (GPCRs; Y58G8A.4a and Y58G8A.4b) were cloned and functionally expressed in Chinese hamster ovary (CHO) cells. The Y58G8A.4a and Y58G8A.4b proteins (397 and 433 amino acid residues, respectively) differ both in amino acid sequence and length of the C-terminal tail of the receptor. A calcium mobilization assay was used as a read-out for receptor function. Both receptors were activated, with nanomolar potencies, by putative peptides encoded by the flp-18 precursor gene, leading to their designation as FLP-18R1a (Y58G8A.4a) and FLP-18R1b (Y58G8A.4b). Three Ascaris suum neuropeptides AF3, AF4, and AF20 all sharing the same FLP-18 C-terminal signature, -PGVLRF-NH(2), were also potent agonists. In contrast to other previously reported C. elegans GPCRs expressed in mammalian cells, both FLP-18R1 variants were fully functional at 37 degrees C. However, a 37 to 28 degrees C temperature shift improved their activity, an effect that was more pronounced for FLP-18R1a. Despite differences in the C-terminus, the region implicated in distinct G-protein recognition for many other GPCRs, the same signaling pathways were observed for both Y58G8A.4 isoforms expressed in CHO cells. Gq protein coupling seems to be the main but not the exclusive signaling pathway, because pretreatment of cells with U-73122, a phospholipase inhibitor, attenuated but did not completely abolish the Ca(2+) signal. A weak Gs-mediated receptor activation was also detected as reflected in an agonist-triggered concentration-dependent cAMP increase. The matching of the FLP-18 peptides with their receptor(s) allows for the evaluation of the pharmacology of this system in the worm in vivo.