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Because no rigorously validated, simple yet accurate continuous delirium assessment instrument exists, we developed the Nursing Delirium Screening Scale (Nu-DESC). The Nu-DESC is an observational five-item scale that can be completed quickly. To test the validity of the Nu-DESC, 146 consecutive hospitalized patients from a prospective cohort study were continuously assessed for delirium symptoms by bedside nurses using the Nu-DESC. Psychometric properties of Nu-DESC screening were established using 59 blinded Confusion Assessment Method (CAM) ratings made by research nurses and psychiatrists. DSM-IV criteria and the Memorial Delirium Assessment Scale (MDAS) were rated along with CAM assessments. Analysis of these data showed that the Nu-DESC is psychometrically valid and has a sensitivity and specificity of 85.7% and 86.8%, respectively. These values are comparable to those of the MDAS, a longer instrument. Nu-DESC and DSM-IV sensitivities were similar. The Nu-DESC appears to be well-suited for widespread clinical use in busy oncology inpatient settings and shows promise as a research instrument.

The present study aims to sensitize SLA researchers to the importance of documenting and controlling for their participants’ proficiency in the target language, with the goal of establishing more robust proficiency assessment standards in experimental research. First, this article presents a survey of recent (2000–2008) foreign and second-language (L2) acquisition studies that show that such standards have yet to be met. Second, it demonstrates the validity, reliability, and practicality of a cloze (i.e., fill-in-the-blank) test designed to discriminate among L2 learners of French at different proficiency levels. Subject and item analyses are performed on the cloze test scores of 169 L2 learners of French from various language backgrounds. The relationship between these scores and the learners’ language background is examined. Cutoff points between proficiency levels are identified in the data. The test then is shared with scholars so that those working with a similar population of L2 learners of French can also use it.

The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering with MYOD1 and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy.

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Estrogen-related receptor a (ERRa) and proliferatoractivated receptor g coactivator-1a (PGC-1a) play central roles in the transcriptional control of energy homeostasis, but little is known about factors regulating their activity. Here we identified the homeobox protein prospero-related homeobox 1 (Prox1) as one such factor. Prox1 interacts with ERRa and PGC-1a, occupies promoters of metabolic genes on a genome-wide scale, and inhibits the activity of the ERRa/PGC-1a complex. DNA motif analysis suggests that Prox1 interacts with the genome through tethering to ERRa and other factors. Importantly, ablation of Prox1 and ERRa have opposite effects on the respiratory capacity of liver cells, revealing an unexpected role for Prox1 in the control of energy homeostasis. Regulation of energy homeostasis involves elaborate biochemical pathways that have evolved to react to the metabolic needs of the organism in response to specific physiological states. While homeostatic regulation is generally under hormonal control and achieved through allosteric control and post-translational modifications of metabolic enzymes for immediate needs, organ-specific requirements and lasting adaptation require regulation of metabolic genes at the transcriptional level via the action of diverse classes of transcription factors and coregulatory proteins (Desvergne et al. 2006;Feige and Auwerx 2007). Among those factors, the orphan nuclear receptor estrogenrelated receptor a (ERRa, NR3B1) and the coregulator peroxisome proliferator-activated receptor g coactivator1a (PGC-1a) have been shown to play a predominant role in controlling several aspects of energy metabolism, most notably mitochondrial biogenesis and oxidative phosphorylation (Oxphos) (Lin et al. 2005;Giguè re 2008).

A eukaryotic protein is often subject to regulation by multiple modifications like phosphorylation, acetylation, ubiquitination, and sumoylation. How these modifications are coordinated in vivo is an important issue that is poorly understood but is relevant to many biological processes. We recently showed that human MEF2D (myocyte enhancer factor 2D) is sumoylated on Lys-439. Adjacent to the sumoylation motif is Ser-444, which like Lys-439 is highly conserved among MEF2 proteins from diverse species. Here we presented several lines of evidence to demonstrate that Ser-444 of MEF2D is required for sumoylation of Lys-439. Histone deacetylase 4 (HDAC4) stimulated this modification by acting through Ser-444. In addition, phosphorylation of Ser-444 by Cdk5, a cyclin-dependent kinase known to inhibit MEF2 transcriptional activity, stimulated sumoylation. Opposing the actions of HDAC4 and Cdk5, calcineurin (also known as protein phosphatase 2B) dephosphorylated Ser-444 and inhibited sumoylation of Lys-439. This phosphatase, however, exerted minimal effects on the phosphorylation catalyzed by ERK5, an extracellular signal-regulated kinase known to activate MEF2D. These results identified an essential role for Ser-444 in MEF2D sumoylation and revealed a novel mechanism by which calcineurin selectively "edits" phosphorylation at different sites, thereby reiterating that interplay between different modifications represents a general mechanism for coordinated regulation of eukaryotic protein functions in vivo.In higher eukaryotes, each cell type has a unique gene expression pattern that is ultimately determined by a specific network of transcription factors. The question how cell signaling regulates activities of transcription factors is thus of central importance to many biological processes. The MEF2 3 family of transcription factors comprises four members in mammals, MEF2A, -B, -C, and -D. They were originally identified as major transcriptional activators for muscle differentiation (1, 2). Indeed, some of them were subsequently shown to be important for cardiac myogenesis; null mutation of the murine MEF2A or MEF2C gene led to cardiac death (3-5), and a mutation on the human MEF2A gene was recently suggested to play a role in coronary artery disease (6). MEF2 proteins also have important roles in non-muscle cells by regulating growth factor response, viral gene expression, neuronal survival, T-cell apoptosis, and tumorigenesis (7-12). Consistent with this, the human MEF2D gene is rearranged in pre-B acute lymphoblastic leukemia (13,14), and large scale retrovirus-mediated insertion mutagenesis identified the mouse MEF2D gene as a potential oncogene (15, 16). Therefore, MEF2 transcription factors are key players in diverse cellular programs.At the molecular level, MEF2 is composed of a highly conserved N-terminal domain responsible for DNA recognition and a C-terminal domain with trans-acting function. Regulation of MEF2 function is complex and occurs at multiple levels, including tissue-specific expression (1, 5), altern...

The mouse heart has become a widely used model for genetic studies of heart diseases. Thus, understanding gender differences in mouse cardiac repolarization is crucial to the interpretation of such studies. The objective of this study was to evaluate whether there are gender differences in cardiac repolarization in mouse ventricle and to gain insights into the ionic and molecular mechanisms underlying these differences. Action potential durations (APDs) and K(+) currents in male and female ventricular myocytes were compared using a patch-clamp technique. APD(20), APD(50), and APD(90) were found to be significantly longer in females than males. Examination of the different K(+) currents revealed that a significantly lower current density exists in female ventricular myocytes compared with male myocytes for the ultrarapid delayed rectifier K(+) current, I(Kur) (at +30 mV, male, 33.2+/-2.9 pA/pF [n= 22]; female, 20.9+/-1.73 pA/pF [n= 19], P<0.001). Consistent with these findings were the results of the ribonuclease protection assay, Western blots, and confocal analysis that showed a significantly lower expression level of Kv1.5 (coding for I(Kur)) in female compared with male ventricle. The additional K(+) currents present in mouse ventricle exhibited no gender differences. In agreement with these electrophysiological data, no differences in the expression levels for the K(+) channels underlying these currents were detected between both sexes. This study demonstrates that adult mice exhibit gender differences in cardiac repolarization. The expression of Kv1.5 and of its corresponding K(+) current, I(Kur), is significantly lower in female mouse ventricle, and as a result, the APD is lengthened.