Making Sense of Adopted Children's Internal Reality Using Narrative Story Stem Techniques: A Mixed-Methods Synthesis

Background: Extant research on adopted children has consistently shown that early adverse experiences confer vulnerability to myriad developmental problems, which may be mitigated by the “natural intervention” of adoption itself and/or by treatment efforts. Narrative Story Stems Techniques (NSSTs) have been used in research and clinical practice to assess adopted children's developmental profiles in middle childhood. However, no study to date has systematically reviewed this body of literature.Objectives: This paper presents a systematic review of research using NSSTs to make sense of adopted children's internal reality (i.e., perceptions, experiences, and representations), in terms of exploring theoretical perspectives as well as critically synthesizing findings and discussing implications.Methods: State-of-the-art PRISMA guidelines were followed throughout, resulting in the identification of 18 records, comprising six qualitative, 10 quantitative, and two mixed-methods primary papers, reporting on seven unique studies. All records were assessed with regard to methodological quality. Data were extracted and synthesized narratively using an integrated design for mixed-methods synthesis.Results: The findings suggest that, although NSST research with adopted children is still in its infancy, there is relatively robust evidence supporting the use of these techniques to assess and track developmental change in adopted children's attachment representations. In this regard, the non-verbal (aside from the verbal) approach to children's complex internal reality, as well as a more fine-grained (aside from a categorical or dimensional) perspective on children's NSST responses, are highlighted as particularly valuable in tailoring treatment to a particular child's needs and vulnerabilities. Moreover, several promising avenues for future research and clinical application of NSSTs, including the extension to affect-regulatory and mentalizing perspectives, may further our knowledge and understanding of, and thus treatment efforts toward, these often vulnerable children. However, these findings should be interpreted with caution, due to the limited number of studies characterized by considerable methodological heterogeneity.Conclusions: In light of the findings of the present review, we strongly advocate future studies using NSSTs in theoretically and empirically consistent ways, in order to gain a better understanding of adopted children's internal reality in terms of attachment representations, affect-regulatory strategies, and mentalizing processes, and to track changes therein

Shape Shifting Leads to Small-Molecule Allosteric Drug Discovery

SummaryEnzymes that regulate their activity by modulating an equilibrium of alternate, nonadditive, functionally distinct oligomeric assemblies (morpheeins) constitute a recently described mode of allostery. The oligomeric equilibrium for porphobilinogen synthase (PBGS) consists of high-activity octamers, low-activity hexamers, and two dimer conformations. A phylogenetically diverse allosteric site specific to hexamers is proposed as an inhibitor binding site. Inhibitor binding is predicted to draw the oligomeric equilibrium toward the low-activity hexamer. In silico docking enriched a selection from a small-molecule library for compounds predicted to bind to this allosteric site. In vitro testing of selected compounds identified one compound whose inhibition mechanism is species-specific conversion of PBGS octamers to hexamers. We propose that this strategy for inhibitor discovery can be applied to other proteins that use the morpheein model for allosteric regulation

Homoprejudiced violence among Chinese men who have sex with men: a cross-sectional analysis in Guangzhou, China.

BACKGROUND: Homoprejudiced violence, defined as physical, verbal, psychological and cyber aggression against others because of their actual or perceived sexual orientation, is an important public health issue. Most homoprejudiced violence research has been conducted in high-income countries. This study examined homoprejudiced violence among men who have sex with men (MSM) in Guangzhou, China. METHODS: MSM in a large Chinese city, Guangzhou, completed an online survey. Data about experiencing and initiating homoprejudiced violence was collected. Multivariable logistic regression analyses, controlling for age, residence, occupation, heterosexual marriage, education and income, were carried out to explore associated factors. RESULTS: A total of 777 responses were analyzed and most (64.9%) men were under the age of 30. Three-hundred-ninety-nine (51.4%) men experienced homoprejudiced violence and 205 (25.9%) men perpetrated homoprejudiced violence against others. Men who identified as heterosexual were less (AOR = 0.6, 95% CI: 0.4-0.9) likely to experience homoprejudiced violence compared to men who identified as gay. Men who experienced homoprejudiced violence were more likely to initiate homoprejudiced violence (AOR = 2.44, 95% CI: 1.6-3.5). Men who disclosed their sexual orientation to other people were more likely to experience homoprejudiced violence (AOR = 1.8, 95% CI:1.3-2.5). CONCLUSIONS: These findings suggest the importance of further research and the implementation of interventions focused on preventing and mitigating the effects of homoprejudiced violence among MSM in China

Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression.

Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST

Variability of extragalactic X-ray jets on kiloparsec scales

Unexpectedly strong X-ray emission from extragalactic radio jets on kiloparsec scales has been one of the major discoveries of Chandra, the only X-ray observatory capable of sub-arcsecond-scale imaging. The origin of this X-ray emission, which appears as a second spectral component from that of the radio emission, has been debated for over two decades. The most commonly assumed mechanism is inverse Compton upscattering of the Cosmic Microwave Background (IC-CMB) by very low-energy electrons in a still highly relativistic jet. Under this mechanism, no variability in the X-ray emission is expected. Here we report the detection of X-ray variability in the large-scale jet population, using a novel statistical analysis of 53 jets with multiple Chandra observations. Taken as a population, we find that the distribution of p-values from a Poisson model is strongly inconsistent with steady emission, with a global p-value of 1.96e-4 under a Kolmogorov-Smirnov test against the expected Uniform (0,1) distribution. These results strongly imply that the dominant mechanism of X-ray production in kpc-scale jets is synchrotron emission by a second population of electrons reaching multi-TeV energies. X-ray variability on the time-scale of months to a few years implies extremely small emitting volumes much smaller than the cross-section of the jet.Comment: Published in Nature Astronomy 29 May 2023; Supplemental Information and Excel File include

Failure patterns in resected pancreas adenocarcinoma: lack of predicted benefit to SMAD4 expression.

OBJECTIVE: To determine whether SMAD4 expression is associated with recurrence pattern after resection for pancreatic ductal adenocarcinoma (PDA). BACKGROUND: SMAD4 expression status has been reported to be associated with patterns of failure in PDA, but studies have not examined recurrence patterns after resection. METHODS: A tissue microarray was constructed including 127 patients with resected PDA and either short-term (\u3c12 \u3emonths) or long-term (\u3e30 months) survival. SMAD4 expression was evaluated by immunohistochemistry and categorized as present or lost in tumor cells. Conventional pathologic features (lymph node metastases, positive resection margin, poor grade, and tumor size) were recorded, and disease-specific outcomes (eg, recurrence pattern and early cancer-specific mortality) were determined. RESULTS: Loss of SMAD4 expression in pancreatic adenocarcinoma was identified in 40 of 127 patients (32%). SMAD4 loss occurred in 27% of patients who experienced isolated local recurrence, 33% of patients with a distant recurrence, 33% of patients who experienced local and distant site recurrences, and 25% of patients who were without evidence of recurrence (Fisher exact, P = 0.9). In a multivariate analysis, the presence of regional lymph node metastases was the only factor associated with the development of distant metastases (odds ratio = 4.7, P = 0.02). SMAD4 was neither associated with recurrence pattern (odds ratio = 0.9, P = 0.9) nor associated with early death (odds ratio = 0.5, P = 0.15). CONCLUSIONS: Primary tumor SMAD4 expression status was not a predictor of recurrence pattern in a large cohort of patients with resected PDA