Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory ...effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor gamma coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.
Adiponectin exerts multiple regulatory functions in the body and in the hypothalamus primarily through activation of its two receptors, adiponectin receptor1 and adiponectin receptor 2. Recent ...studies have shown that adiponectin receptors are widely expressed in other areas of the brain including the hippocampus. However, the functions of adiponectin in brain regions other than the hypothalamus are not clear. Here, we report that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Adiponectin reduced the level of reactive oxygen species, attenuated apoptotic cell death, and also suppressed activation of caspase-3 induced by KA. Pretreatment of hippocampal primary neurons with an AMPK inhibitor, compound C, abolished adiponectin-induced neuronal protection. The AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, attenuated KA-induced caspase-3 activity. These findings suggest that the AMPK pathway is critically involved in adiponectin-induced neuroprotection and may mediate the antioxidative and anti-apoptotic properties of adiponectin.
The performance and predictive capability of support vector machine (SVM) and radial basis function neural network (RBFNN) for classification problems in QSAR/QSPR were investigated and compared with ...several other classification methods such as linear discriminant analysis (LDA) and nonlinear discriminate analysis (NLDA). In the present study, two different data sets are evaluated. The first one involves the classification of four action modes of 221 phenols and the second investigation deals with the classification of the three narcosis mechanism of aquatic toxicity for 194 organic compounds. In both cases, the predictive ability of the SVM model is comparable or superior to those obtained by LDA, NLDA and RBFNN. The obtained results indicate that the SVM model with the RBF kernel function can be used as an alternative tool for classification problems in QSAR/QSPR.
Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain ...insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68–0.81, p = 3.08 × 10−11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26–1.60, p = 1.62 × 10−8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.
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We performed a large-scale genetic association study of nasopharyngeal carcinoma (NPC) followed by high-throughput profiling of cis-regulatory elements and experimental validation. We identified two NPC susceptibility genes, PHF2 at locus 9q22.33 and CDKN2B-AS1 at locus 9p21.3, which helps to uncover the genetic etiology of NPC development.
To explore the risk factors of malnutrition in infants with congenital heart disease within one year after surgery.
This retrospective cohort study selected 502 infants with congenital heart disease ...who underwent surgical treatment in Guangzhou Women and Children's Medical Center from February 2018 to January 2019. Their basic information and clinical data were analyzed, and their nutrition status after the surgery was followed up by questionnaire survey. Weight-for-age Z score (WAZ)≤-2 one year after operation was defined as malnutrition group, and WAZ>-2 was non-malnutrition group. The perioperative indicators and complementary food advancement were compared between the two groups by chi-square test,
-test, and Kruskal-Wallis test. The risk factors of malnutrition were analyzed by Logistic regression.
A total of 502 infants were selected, including 301 males and 201 females, with the age of 4.1 (2.0, 6.8) months. There were 90 cases in malnutrition group and 412 cases in non-malnutrition group. The body len
•Chinese citizens tend to conflate procedural-based trust and outcome-based trust.•Expressive concerns play a more important role than instrumental concern.•The effects of expressive variables are ...most evident among villagers and urbanites.•The instrumental variable, victimization, only affects migrant workers’ perceptions.•Media influence affects trust in the police.
While the past decade has witnessed the burgeoning of research on public assessments of the police in China, marginalized social groups have rarely been considered in this line of inquiry. Using data collected from migrant workers, rural villagers, and urban dwellers, this study assesses whether Chinese perceptions of the police are distinguishable along procedural-based trust and outcome-based trust and whether expressive concerns and instrumental concerns are predictive of trust in the police. Findings show that Chinese citizens tend to conflate procedural-based trust and outcome-based trust. Expressive concerns play a more important role than instrumental concerns, with such expressive variables as trust in neighborhood residents committee, perceived law and order, and quality of life influencing trust in the police. Public perceptions of police trustworthiness are also significantly linked to media influence. Directions for future research are discussed.
This article presents a metal-dielectric hybrid structure, namely a hexagonal periodic structure formed by self-assembly silica microsphere deposited on thin metal film substrate. Theoretical ...simulation and experimental results indicate that this structure can achieve strong (greater than 90 %) and broad absorption at atmospheric transparency window from 8 to 13μm.
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