Regulation of Ubiquitination-Mediated Protein Degradation by Survival Kinases in Cancer

The ubiquitin–proteasome system is essential for multiple physiological processes via selective degradation of target proteins and has been shown to plays a critical role in human cancer. Activation of oncogenic factors and inhibition of tumor suppressors have been shown to be essential for cancer development, and protein ubiquitination has been linked to the regulation of oncogenic factors and tumor suppressors. Three kinases, AKT, extracellular signal-regulated kinase, and IκB kinase, we refer to as oncokinases, are activated in multiple human cancers. We and others have identified several key downstream targets that are commonly regulated by these oncokinases, some of which are regulated directly or indirectly via ubiquitin-mediated proteasome degradation, including FOXO3, β-catenin, myeloid cell leukemia-1, and Snail. In this review, we summarize these findings from our and other groups and discuss potential future studies and applications in the clinic

The construction and performance of citizenship in contemporary China

Citizenship education has been an explicit part of the universal education system in contemporary China. Using data from an original nationwide survey conducted in 2018, this study tests the hypothesis that the longer the intensity of exposure to citizenship education, the more citizens are influenced by a state-led conception of citizenship characterized by passive obedience and loyalty to the state. The study finds mixed results in that citizenship education is effective at lower educational levels, but at higher levels it is not only less effective, but instead may foster (or at minimum, does not deter) more active conceptions of citizenship

Citizens’ expectations for crisis management and the involvement of civil society organizations in China

Chinese citizens are relatively happy with the state's management of national disasters and emergencies. However, they are increasingly concluding that the state alone cannot manage them. Leveraging the 2018 and 2020 Civic Participation in China Surveys, we find that more educated citizens conclude that the government has a leading role in crisis management, but there is ample room for civil society organisations (CSOs) to act in a complementary fashion. On a slightly diverging path, volunteers who have meaningfully interacted with CSOs are more skeptical than non-volunteers about CSOs’ organisational ability to fulfill this crisis management function. These findings imply that the political legitimacy of the Communist Party of China is not challenged by allowing CSOs a greater role in crisis management

Individual Differences in Dopamine Are Associated with Reward Discounting in Clinical Groups But Not in Healthy Adults.

Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: N = 144 males and females across 3 samples) and one meta-analytic (Study 2: N = 307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta-analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals but suggested that associations between individual differences in DA and reward discounting depend on clinical features. Addictions were characterized by negative correlations between DA and discounting, but other clinical conditions, such as Parkinson's disease, obesity, and attention-deficit/hyperactivity disorder, were characterized by positive correlations between DA and discounting. Together, the results suggest that trait differences in discounting in healthy adults do not appear to be strongly associated with individual differences in D2-like receptors. The difference in meta-analytic correlation effects between healthy controls and individuals with psychopathology suggests that individual difference findings related to DA and reward discounting in clinical samples may not be reliably generalized to healthy controls, and vice versa.SIGNIFICANCE STATEMENT Decisions to forgo large rewards for smaller ones due to increasing time delays, uncertainty, or physical effort have been linked to differences in dopamine (DA) function, which is disrupted in some forms of psychopathology. It remains unclear whether alterations in DA function associated with psychopathology also extend to explaining associations between DA function and decision making in healthy individuals. We show that individual differences in DA D2 receptor availability are not consistently related to monetary discounting of time, probability, or physical effort in healthy individuals across a broad age range. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of DA function and reward discounting behavior

Examining multiracial youth in context: ethnic identity development and mental health outcomes

Although multiracial individuals are the fastest growing population in the United States, research on the identity development of multiracial adolescents remains scant. This study explores the relationship between ethnic identity, its components (affirmation, exploration), and mental health outcomes (anxiety, depression) within the contexts of schools for multiracial adolescents. Participants were multiracial and monoracial minority and majority high school students (n=4,766). Using Analysis of Variance and Multiple Indicators Multiple Causes (MIMIC) models, results indicated that multiracial youth experience more exploration and less affirmation than African Americans, but more than Caucasians. In addition, multiracial youth were found to have higher levels of mental health issues than their monoracial minority and majority peers. Specifically, multiracial youth had higher levels of depression than their African American and Caucasian counterparts. Multiracial and Caucasian youth had similar levels of anxiety but these levels were significantly higher than African Americans. Results also show that school diversity can mitigate mental health outcomes finding that multiracial youth in more diverse schools are at lower risk for mental health issues

Gadolinium decreases inflammation related to myocardial ischemia and reperfusion injury

<p>Abstract</p> <p>Background</p> <p>The lanthanide cation, gadolinium (GdCl₃) protects the myocardium against infarction following ischemia and reperfusion. Neutrophils and macrophages are the main leukocytes responsible for infarct expansion after reperfusion. GdCl₃interferes with macrophage and neutrophil function in the liver by decreasing macrophage secretion of inflammatory cytokines and neutrophil infiltration. We hypothesized that GdCl₃protects against ischemia and reperfusion injury by decreasing inflammation. We determined the impact of GdCl₃treatment for reperfusion injury on 1) circulating monoctye and neutrophil counts, 2) secretion of inflammatory cytokines, and 3) influx of monocytes and neutrophils into the myocardium.</p> <p>Methods</p> <p>Rats (n = 3-6/gp) were treated with saline or GdCl₃(20 μmol/kg) 15 min prior to a 30 min period of regional ischemia and 120 min reperfusion. Sham rats were not subject to ischemia. Blood was collected either after 30 min ischemia or 120 min reperfusion and hearts were harvested at 120 min reperfusion for tissue analysis. Blood was analyzed for leukocytes counts and cytokines. Tissue was analyzed for cytokines and markers of neutrophil and monocyte infiltration by measuring myeloperoxidase (MPO) and α-naphthyl acetate esterase (ANAE).</p> <p>Results</p> <p>GdCl₃did not affect the number of circulating neutrophils prior to ischemia. Two hours reperfusion resulted in a 2- and 3- fold increase in circulating monocytes and neutrophils, respectively. GdCl₃decreased the number of circulating monocytes and neutrophils during reperfusion to levels below those present prior to ischemia. Furthermore, after 120 min of reperfusion, GdCl₃decreased ANAE and MPO activity in the myocardium by 1.9-fold and 6.5-fold respectively. GdCl₃decreased MPO activity to levels below those measured in the Sham group. Serum levels of the major neutrophil chemoattractant cytokine, IL-8 were increased from pre-ischemic levels during ischemia and reperfusion in both control and GdCl₃treated rats. Likewise, IL-8 levels increased throughout the 3 hour time period in the Sham group. There was no difference in IL-8 detected in the myocardium after 120 min reperfusion between groups. In contrast, after 120 min reperfusion GdCl₃decreased the myocardial tissue levels of macrophage secreted cytokines, GM-CSF and IL-1.</p> <p>Conclusion</p> <p>GdCl₃treatment prior to ischemia and reperfusion injury decreased circulating monocytes and neutrophils, macrophage secreted cytokines, and leukocyte infiltration into injured myocardium. These results suggest GdCl₃decreased monoctye and neutrophil migration and activation and may be a novel treatment for inflammation during ischemia and reperfusion.</p

Metagenomic next-generation sequencing of samples from pediatric febrile illness in Tororo, Uganda.

Febrile illness is a major burden in African children, and non-malarial causes of fever are uncertain. In this retrospective exploratory study, we used metagenomic next-generation sequencing (mNGS) to evaluate serum, nasopharyngeal, and stool specimens from 94 children (aged 2-54 months) with febrile illness admitted to Tororo District Hospital, Uganda. The most common microbes identified were Plasmodium falciparum (51.1% of samples) and parvovirus B19 (4.4%) from serum; human rhinoviruses A and C (40%), respiratory syncytial virus (10%), and human herpesvirus 5 (10%) from nasopharyngeal swabs; and rotavirus A (50% of those with diarrhea) from stool. We also report the near complete genome of a highly divergent orthobunyavirus, tentatively named Nyangole virus, identified from the serum of a child diagnosed with malaria and pneumonia, a Bwamba orthobunyavirus in the nasopharynx of a child with rash and sepsis, and the genomes of two novel human rhinovirus C species. In this retrospective exploratory study, mNGS identified multiple potential pathogens, including 3 new viral species, associated with fever in Ugandan children

A Detailed Study of Spitzer-IRAC Emission in Herbig-Haro Objects (I): Morphology and Flux Ratios of Shocked Emission

We present a detailed analysis of Spitzer-IRAC images obtained toward six Herbig-Haro objects (HH 54/211/212, L 1157/1448, BHR 71). Our analysis includes: (1) comparisons in morphology between the four IRAC bands (3.6, 4.5, 5.8 and 8.0 um), and H2 1-0 S(1) at 2.12 um for three out of six objects; (2) measurements of spectral energy distributions (SEDs) at selected positions; and (3) comparisons of these results with calculations of thermal H2 emission at LTE (207 lines in four bands) and non-LTE (32-45 lines, depending on particle for collisions). We show that the morphologies observed at 3.6 and 4.5 um are similar to each other, and to H2 1-0 S(1). This is well explained by thermal H2 emission at non-LTE if the dissociation rate is significantly larger than 0.002-0.02, allowing thermal collisions to be dominated by atomic hydrogen. In contrast, the 5.8 and 8.0 um emission shows different morphologies from the others in some regions. This emission appears to be more enhanced at the wakes in bow shocks, or less enhanced in patchy structures in the jet. These tendencies are explained by the fact that thermal H2 emission in the 5.8 and 8.0 um band is enhanced in regions at lower densities and temperatures. Throughout, the observed similarities and differences in morphology between four bands and 1-0 S(1) are well explained by thermal H2 emission. The observed SEDs are categorized into:- (A) those in which the flux monotonically increases with wavelength; and (B) those with excess emission at 4.5-um. The type-A SEDs are explained by thermal H2 emission, in particular with simple shock models with a power-law cooling function. Our calculations suggest that the type-B SEDs require extra contaminating emission in the 4.5-um band. The CO vibrational emission is the most promising candidate, and the other contaminants discussed to date are not likely to explain the observed SEDs.Comment: 35 pages, 21 figures, 6 tables, accepted by Astrophysical Journa

MicroRNA-223 Suppresses the Canonical NF-kB Pathway in Basal Keratinocytes to Dampen Neutrophilic Inflammation

MicroRNA-223 is known as a myeloid-enriched anti-inflammatory microRNA that is dysregulated in numerous inflammatory conditions. Here, we report that neutrophilic inflammation (wound response) is augmented in miR-223-deficient zebrafish, due pri- marily to elevated activation of the canonical nuclear factor kB (NF-kB) pathway. NF-kB over-activation is restricted to the basal layer of the surface epithelium, although miR-223 is detected throughout the epithe- lium and in phagocytes. Not only phagocytes but also epithelial cells are involved in miR-223-medi- ated regulation of neutrophils’ wound response and NF-kB activation. Cul1a/b, Traf6, and Tab1 are iden- tified as direct targets of miR-223, and their levels rise in injured epithelium lacking miR-223. In addi- tion, miR-223 is expressed in cultured human bron- chial epithelial cells, where it also downregulates NF-kB signaling. Together, this direct connection between miR-223 and the canonical NF-kB pathway provides a mechanistic understanding of the multi- faceted role of miR-223 and highlights the relevance of epithelial cells in dampening neutrophil activation