Temperament and Personality Traits as Predictors of Preschool ODD Symptoms, Longitudinal Course, and Impairment

Oppositional Defiant Disorder (ODD) is commonly conceptualized as a disorder of negative affect and low effortful control. Currently, it is unclear whether temperament and personality traits associated with negative affect and effortful control can be useful assessment tools for identifying ODD early during development. This study examined the relationship between temperament and personality traits and ODD in a clinical sample of preschoolers. Results suggest that, at this age, temperament and personality traits of negative affect and neuroticism and effortful control and conscientiousness/agreeableness are not associated with one another. High negative affect, low conscientiousness, and low agreeableness were all specifically associated with the angry/irritable (vs. argumentative/defiant, vindictive) ODD symptom domain; however, the traits did not predict change in symptoms over time. Lastly, low conscientiousness predicted ODD-related impairment, while negative affect and agreeableness interacted to predict impairment such low agreeableness appears to be a primary pathway to impairment, and high negative affect appears to be a secondary pathway. Overall, this study suggests high negative affect, low conscientiousness, and low agreeableness are associated with ODD. Early assessment of these traits may be clinically useful in identifying children at risk for ODD, given that they may be early markers for ODD symptoms and impairment

An Ionization Cone in the Dwarf Starburst Galaxy NGC 5253

There are few observational constraints on how the escape of ionizing photons from starburst galaxies depends on galactic parameters. Here, we report on the first major detection of an ionization cone in NGC 5253, a nearby starburst galaxy. This high-excitation feature is identified by mapping the emission-line ratios in the galaxy using [S III] lambda 9069, [S II] lambda 6716, and H_alpha narrow-band images from the Maryland-Magellan Tunable Filter at Las Campanas Observatory. The ionization cone appears optically thin, which is suggestive of the escape of ionizing photons. The cone morphology is narrow with an estimated solid angle covering just 3% of 4pi steradians, and the young, massive clusters of the nuclear starburst can easily generate the radiation required to ionize the cone. Although less likely, we cannot rule out the possibility of an obscured AGN source. An echelle spectrum along the minor axis shows complex kinematics that are consistent with outflow activity. The narrow morphology of the ionization cone supports the scenario that an orientation bias contributes to the difficulty in detecting Lyman continuum emission from starbursts and Lyman break galaxies.Comment: 5 pages, 4 figures, Accepted to ApJ Letter

The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor.

Arrestin domain-containing protein 3 (ARRDC3) is a member of the mammalian α-arrestin family, which is predicted to share similar tertiary structure with visual-/β-arrestins and also contains C-terminal PPXY motifs that mediate interaction with E3 ubiquitin ligases. Recently, ARRDC3 has been proposed to play a role in regulating the trafficking of G protein-coupled receptors, although mechanistic insight into this process is lacking. Here, we focused on characterizing the role of ARRDC3 in regulating the trafficking of the β2-adrenergic receptor (β2AR). We find that ARRDC3 primarily localizes to EEA1-positive early endosomes and directly interacts with the β2AR in a ligand-independent manner. Although ARRDC3 has no effect on β2AR endocytosis or degradation, it negatively regulates β2AR entry into SNX27-occupied endosomal tubules. This results in delayed recycling of the receptor and a concomitant increase in β2AR-dependent endosomal signaling. Thus, ARRDC3 functions as a switch to modulate the endosomal residence time and subsequent intracellular signaling of the β2AR

Protective Effects of the Novel Phytonutrient S7 Against Intestinal Tight Junction Disruption: Composition Matters

The prevalence of intestinal inflammatory diseases is increasing, and pharmacologic agents for intervention are currently limited. Preserving epithelial tight junction (TJ) integrity and preventing underlying immune cell activation by intestinal bacteria are key targets for abrogating the perpetual inflammatory cycle that plagues these diseases. Phytonutrients have shown promise for their ability to reduce cellular inflammation, but the extent of their efficacy in an intestinal model of inflammation is not well understood. Here, we hypothesized that S7, a novel phytonutrient derived from extracts rich in curcuminoids and catechins, would reduce immune cell inflammation and preserve TJ integrity in an in vitro co-culture model of intestinal inflammation. We further investigated whether a curcumin-containing formulation (S7-C) or its metabolite, tetrahydrocurcumin (S7-THC) would similarly preserve TJ integrity. An in vitro intestinal co-culture model was established by seeding Caco-2 epithelial cells on semipermeable transwell inserts 21 days prior to the addition of RAW264.7 macrophages in the basolateral chamber. Macrophages were next stimulated with 10 ng/ml lipopolysaccharide (LPS) to induce inflammation, and subsequent TJ disruption in the co-cultured Caco-2 cells was assessed by transepithelial electrical resistance (TEER) using epithelial ohmmeter chopstick electrodes. We found that administration of S7-THC containing 1-5 μM THC produced dose dependent mitigation of LPS-induced decreases in TEER and approached the efficacy of the pharmacologic agent, budesonide. However, S7-C at 5 μM curcumin was unable to preserve TEER, suggesting that the specific combination of phytonutrients is important for preventing inflammation-induced TJ disruption. We also found that, though apical application (Caco-2 only) of budesonide was sufficient for preserving TEER in our model, S7-THC required both apical (Caco-2) and basolateral (RAW264.7) treatment, suggesting that reducing macrophage inflammation is important for limiting epithelial TJ disruption in this context. Interestingly, S7-C was more effective than S7-THC or budesonide at reducing inflammatory basolateral nitric oxide (NO) production as determined by the Griess assay. This suggests that, though S7-C more effectively reduces this aspect of inflammation, another inflammatory mediator is responsible for conveying TJ disruption and is governed differentially by S7-THC. Further support of this comes from our finding that S7-THC, but not S7-C, ameliorated the LPS-induced increase in myosin light chain kinase (MLCK) expression in Caco-2 cells as determined by Western blot. Together, these findings suggest that phytonutrients such as S7-THC have prophylactic potential in the preservation of TJ integrity, and the specific composition of these phytonutrients matters

Regulation of Opioid Receptor Trafficking and Morphine Tolerance by Receptor Oligomerization

AbstractThe utility of morphine for the treatment of chronic pain is hindered by the development of tolerance to the analgesic effects of the drug. Morphine is unique among opiates in its ability to activate the mu opioid receptor (MOR) without promoting its desensitization and endocytosis. Here we demonstrate that [D-Ala2-MePhe4-Gly5-ol] enkephalin (DAMGO) can facilitate the ability of morphine to stimulate MOR endocytosis. As a consequence, rats treated chronically with both drugs show reduced analgesic tolerance compared to rats treated with morphine alone. These results demonstrate that endocytosis of the MOR can reduce the development of tolerance, and hence suggest an approach for the development of opiate analogs with enhanced efficacy for the treatment of chronic pain

Seeking critical nodes in digraphs

The Critical Node Detection Problem (CNDP) consists in finding the set of nodes, defined critical, whose removal maximally degrades the graph. In this work we focus on finding the set of critical nodes whose removal minimizes the pairwise connectivity of a direct graph (digraph). Such problem has been proved to be NP-hard, thus we need efficient heuristics to detect critical nodes in real-world applications. We aim at understanding which is the best heuristic we can apply to identify critical nodes in practice, i.e., taking into account time constrains and real-world networks. We present an in-depth analysis of several heuristics we ran on both real-world and on synthetic graphs. We define and evaluate two different strategies for each heuristic: standard and iterative. Our main findings show that an algorithm recently proposed to solve the CNDP and that can be used as heuristic for the general case provides the best results in real-world graphs, and it is also the fastest. However, there are few exceptions that are thoroughly analyzed and discussed. We show that among the heuristics we analyzed, few of them cannot be applied to very large graphs, when the iterative strategy is used, due to their time complexity. Finally, we suggest possible directions to further improve the heuristic providing the best results

[S IV] in the NGC 5253 Supernebula: Ionized Gas Kinematics at High Resolution

The nearby dwarf starburst galaxy NGC 5253 hosts a deeply embedded radio-infrared supernebula excited by thousands of O stars. We have observed this source in the 10.5{\mu}m line of S+3 at 3.8 kms-1 spectral and 1.4" spatial resolution, using the high resolution spectrometer TEXES on the IRTF. The line profile cannot be fit well by a single Gaussian. The best simple fit describes the gas with two Gaussians, one near the galactic velocity with FWHM 33.6 km s-1 and another of similiar strength and FWHM 94 km s-1 centered \sim20 km s-1 to the blue. This suggests a model for the supernebula in which gas flows towards us out of the molecular cloud, as in a "blister" or "champagne flow" or in the HII regions modelled by Zhu (2006).Comment: Accepted for publication in the Astrophysical Journal 4 June 201

Reaction-Based Probes for Imaging Mobile Zinc in Live Cells and Tissues

Chelatable, or mobile, forms of zinc play critical signaling roles in numerous biological processes. Elucidating the action of mobile Zn(II) in complex biological environments requires sensitive tools for visualizing, tracking, and manipulating Zn(II) ions. A large toolbox of synthetic photoinduced electron transfer (PET)-based fluorescent Zn(II) sensors are available, but the applicability of many of these probes is limited by poor zinc sensitivity and low dynamic ranges owing to proton interference. We present here a general approach for acetylating PET-based probes containing a variety of fluorophores and zinc-binding units. The new sensors provide substantially improved zinc sensitivity and allow for incubation of live cells and tissue slices with nM probe concentrations, a significant improvement compared to the μM concentrations that are typically required for a measurable fluorescence signal. Acetylation effectively reduces or completely quenches background fluorescence in the metal-free sensor. Binding of Zn(II) selectively and quickly mediates hydrolytic cleavage of the acetyl groups, providing a large fluorescence response. An acetylated blue coumarin-based sensor was used to carry out detailed analyses of metal binding and metal-promoted acetyl hydrolysis. Acetylated benzoresorufin-based red-emitting probes with different zinc-binding sites are effective for sensing Zn(II) ions in live cells when applied at low concentrations (∼50–100 nM). We used green diacetylated Zinpyr1 (DA-ZP1) to image endogenous mobile Zn(II) in the molecular layer of mouse dorsal cochlear nucleus (DCN), confirming that acetylation is a suitable approach for preparing sensors that are highly specific and sensitive to mobile zinc in biological systems.National Institutes of Health (U.S.) (NIH grant GM065519)National Institutes of Health (U.S.) (NIH grant R01-DC007905)National Institutes of Health (U.S.) (NIH Fellowship (F32- EB019243))National Institutes of Health (U.S.) (NIH Fellowship (T32-DC011499))National Institutes of Health (U.S.) (NIH Fellowship (F32-DC013734)

Occurrence of testicular microlithiasis in androgen insensitive hypogonadal mice

<b>Background</b>: Testicular microliths are calcifications found within the seminiferous tubules. In humans, testicular microlithiasis (TM) has an unknown etiology but may be significantly associated with testicular germ cell tumors. Factors inducing microlith development may also, therefore, act as susceptibility factors for malignant testicular conditions. Studies to identify the mechanisms of microlith development have been hampered by the lack of suitable animal models for TM.<BR/> <b>Methods</b>: This was an observational study of the testicular phenotype of different mouse models. The mouse models were: cryptorchid mice, mice lacking androgen receptors (ARs) on the Sertoli cells (SCARKO), mice with a ubiquitous loss of androgen ARs (ARKO), hypogonadal (hpg) mice which lack circulating gonadotrophins, and hpg mice crossed with SCARKO (hpg.SCARKO) and ARKO (hpg.ARKO) mice.<BR/> <b>Results</b>: Microscopic TM was seen in 94% of hpg.ARKO mice (n=16) and the mean number of microliths per testis was 81 +/- 54. Occasional small microliths were seen in 36% (n=11) of hpg testes (mean 2 +/- 0.5 per testis) and 30% (n=10) of hpg.SCARKO testes (mean 8 +/- 6 per testis). No microliths were seen in cryptorchid, ARKO or SCARKO mice. There was no significant effect of FSH or androgen on TM in hpg.ARKO mice.<BR/> <b>Conclusions</b>: We have identified a mouse model of TM and show that lack of endocrine stimulation is a cause of TM. Importantly, this model will provide a means with which to identify the mechanisms of TM development and the underlying changes in protein and gene expression