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Borderline personality disorder (BPD) is a debilitating psychiatric illness whose symptoms frequently emerge during adolescence. Critically, self-injury and suicide attempts in BPD are often precipitated by interpersonal discord. Initial studies in adults suggest that the interpersonal difficulties common in BPD may emerge from disrupted processing of socioemotional stimuli. Less is known about these processes in adolescents with BPD symptoms, despite substantial changes in socioemotional processing during this developmental period. Eighty-six adolescents and young adults with and without BPD symptoms completed an emotional interference task involving the identification of a facial emotion expression in the presence of a conflicting or congruent emotion word. We used hierarchical drift diffusion modeling to index speed of processing and decision boundary. Using Bayesian multilevel regression, we characterized age-related differences in facial emotion processing. We examined whether BPD symptom dimensions were associated with alterations in facial emotion processing. To determine the specificity of our effects, we analyzed behavioral data from a corresponding nonemotional interference task. Emotion-related impulsivity, but not negative affectivity or interpersonal dysfunction, predicted inefficient processing when presented with conflicting negative emotional stimuli. Across both tasks, emotion-related impulsivity in adolescents, but not young adults, was further associated with a lower decision boundary - resulting in fast but inaccurate decisions. Impulsive adolescents with BPD symptoms are prone to making errors when appraising facial emotion expressions, which may potentiate or worsen interpersonal conflicts. Our findings highlight the role of lower-level social cognitive processes in interpersonal difficulties among vulnerable youth during a sensitive developmental window.

Borderline personality disorder (BPD) is a debilitating psychiatric illness whose symptoms frequently emerge during adolescence. Initial studies in adults suggest that the interpersonal difficulties common in BPD may emerge from disrupted processing of social and emotional stimuli. Less is known about these processes in adolescents with BPD symptoms, despite substantial changes in socioemotional processing during this developmental period. 86 adolescents and young adults with and without BPD symptoms completed an emotional interference task involving the identification of a facial emotion expression in the presence of a conflicting or congruent emotion word. We used hierarchical drift diffusion modeling to index speed of processing and decision boundary. Using Bayesian multilevel regression, we characterized age-related differences in facial emotion processing. We then examined whether BPD symptom dimensions were associated with facial emotion processing on this task. To determine the specificity of our effects, we analyzed behavioral data from a corresponding nonemotional interference task. Impulsivity, but not negative affectivity or interpersonal dysfunction, predicted inefficient processing when presented with conflicting negative emotional stimuli. Across both tasks, impulsivity in adolescents was further associated with a lower decision boundary. Impulsive adolescents were especially likely to make fast, but inaccurate decisions about another person's emotional state. Impulsive adolescents with BPD symptoms are prone to making errors when appraising facial expressions of emotions, which may potentiate or worsen interpersonal conflicts. Our findings highlight the role of lower-level social cognitive processes in interpersonal difficulties among vulnerable youth during a sensitive developmental window.

The aim of this study was to describe the complex relationships among patient safety culture, nurse demographics, advocacy, and patient outcomes. Why has healthcare lagged behind other industries in improving quality? Little nursing research exists that explores the multifactorial relationships that impact quality. A convenience sample of 1045 nurses from 40 medical/surgical units was analyzed using a correlational cross-sectional design with secondary data analysis. Data sources included survey results for patient safety culture, nurse perceptions of patient advocacy, and patient experience and fall and pressure ulcer rates. Significant findings included a positive correlation between patient safety culture and advocacy and a negative correlation between safety culture, advocacy, and years of experience as a nurse. No significant correlations were found between safety culture and patient outcomes or advocacy and patient outcomes. Newer nurses were more positive about safety culture and advocacy, whereas experienced nurses were overall less positive.

Julie Williams, Michael Owen and colleagues report staged follow-up and meta-analyses of genome-wide association studies for Alzheimer's disease from the GERAD+ consortium. They identify common variants at ABCA7 and MS4A6A/MS4A4E associated with Alzheimer's disease and support for several additional susceptibility loci. We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10 −5 . We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10 −17 ; including ADGC data, meta P = 5.0 × 10 −21 ) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10 −14 ; including ADGC data, meta P = 1.2 × 10 −16 ) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10 −4 ; including ADGC data, meta P = 8.6 × 10 −9 ), CD33 (GERAD+, P = 2.2 × 10 −4 ; including ADGC data, meta P = 1.6 × 10 −9 ) and EPHA1 (GERAD+, P = 3.4 × 10 −4 ; including ADGC data, meta P = 6.0 × 10 −10 ).

High-throughput screening systems that better mimic the physiological complexity of diseased tissues may aid the discovery of more efficacious compounds. A co-culture system that mimics the microenvironment of leukemia stem cells (LSCs) in bone marrow enables the discovery of compounds, including lovastatin, that selectively kill LSCs. Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo . We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.

The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity. Inflammation is used by the immune system to protect and repair tissues after an injury or infection. However, if inflammation is too strong, or goes on for too long, it can damage tissues. This is seen in autoimmune diseases such as inflammatory bowel disease and type 1 diabetes. Therefore, precise regulation of the inflammatory response is essential for maintaining human health. White blood cells known as T cells are central regulators of tissue inflammation. To achieve this goal, they develop into subtypes with specialized roles. For example, some T helper cells release chemical signals that trigger inflammation and other immune responses. Regulatory T (Treg) cells then shut down these immune responses once they are no longer needed. Many autoimmune and other inflammatory diseases are thought to arise—at least partially—because Treg cells fail to stop the inflammatory response. Boosting the number or the activity of Treg cells could therefore help to treat these diseases. However, technical difficulties have made it difficult to investigate the genes and molecular pathways that control how this subtype of white blood cells develops. Khor et al. thought that discovering new chemicals that increase the number of Treg cells without harming them could help to identify the pathways that control their development. Khor et al. screened over 3000 chemicals, many of which are drugs currently approved for use in humans, for their effect on immature T cells that were taken from mice and grown in the laboratory. This ‘unbiased chemical biology’ approach identified several chemicals that both encouraged the T cells to develop into Treg cells and reduced the numbers that became inflammation-promoting T helper cells. Khor et al. then focused on one of these chemicals, called harmine. Tests in mice showed that harmine reduces the extent of experimentally induced inflammatory reactions. Treg cells generated by treating immature T cells with harmine had the same effect. Further experiments showed that harmine exerts these effects, at least in part, by inhibiting the activity of a protein called DYRK1A. When DYRK1A was removed from maturing mouse T cells grown in the laboratory, the T cells tended to develop into anti-inflammatory Treg cells. These findings therefore identify DYRK1A as part of a pathway that suppresses the development of Treg cells. It remains to be discovered how it does this, and whether other DYRK protein family members have similar roles.

Antisense oligonucleotides (ASOs) designed to lower prion protein (PrP) expression in the brain through RNase H1-mediated degradation of PrP RNA are in development as prion disease therapeutics. ASOs were previously reported to sequence-independently interact with PrP and inhibit prion accumulation in cell culture, yet in vivo studies using a new generation of ASOs found that only PrP-lowering sequences were effective at extending survival. Cerebrospinal fluid (CSF) PrP has been proposed as a pharmacodynamic biomarker for trials of such ASOs, but is only interpretable if PrP lowering is indeed the relevant mechanism of action in vivo and if measurement of PrP is unconfounded by any PrP–ASO interaction. Here, we examine the PrP-binding and antiprion properties of ASOs in vitro and in cell culture. Binding parameters determined by isothermal titration calorimetry were similar across all ASOs tested, indicating that ASOs of various chemistries bind full-length recombinant PrP with low- to mid-nanomolar affinity in a sequence-independent manner. Nuclear magnetic resonance, dynamic light scattering, and visual inspection of ASO–PrP mixtures suggested, however, that this interaction is characterized by the formation of large aggregates, a conclusion further supported by the salt dependence of the affinity measured by isothermal titration calorimetry. Sequence-independent inhibition of prion accumulation in cell culture was observed. The inefficacy of non-PrP-lowering ASOs against prion disease in vivo may be because their apparent activity in vitro is an artifact of aggregation, or because the concentration of ASOs in relevant compartments within the central nervous system (CNS) quickly drops below the effective concentration for sequence-independent antiprion activity after bolus dosing into CSF. Measurements of PrP concentration in human CSF were not impacted by the addition of ASO. These findings support the further development of PrP-lowering ASOs and of CSF PrP as a pharmacodynamic biomarker.

Andrew Singleton, Thomas Gasser and colleagues report results of a genome-wide association study of Parkinson's disease among individuals of European ancestry. They find genome-wide significant associations at two loci, SNCA and MAPT , and provide supporting evidence for a new risk locus on 1q32. We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding α-synuclein ( SNCA ; rs2736990, OR = 1.23, P = 2.24 × 10 −16 ) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 × 10 −16 ). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS 1 , confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort ( PARK16 , rs823128, OR = 0.66, P = 7.29 × 10 −8 ) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 × 10 −5 ). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

Radionuclide-stimulated dynamic therapy (RaST) utilizes Cerenkov-radiating radiopharmaceuticals to activate light-sensitive drugs and materials, generating reactive oxygen species (ROS) that inhibit cancer progression. However, the underlying cell death mechanisms are not fully understood. Using ROS-regenerative nanophotosensitizers coated with a tumor-targeting transferrin-titanocene complex and radiolabeled 2-fluorodeoxyglucose, we found that RaST induced apoptosis and necroptosis, characterized by the activation of RIPK-1, RIPK-3, nuclear factor kappa B, and mixed lineage kinase domain-like pseudokinase, leading to membrane permeabilization, cytokine release, and the expression of immunogenic damage-associated molecular patterns. In immune-deficient breast tumor-bearing mice with adequate stroma and growth factors, RaST did not prevent tumor growth or lung metastasis. However, in immunocompetent models, RaST induced a partial and complete response (CR) with no metastasis, driven by the recruitment of CD11b+, CD11c+, and CD8b+ effector immune cells. A cancer-imaging agent, LS301, identified latent minimal residual disseminated tumors in the lymph nodes of the CR group. Although cancer cells in CR mice enhanced protumor cytokines and immune checkpoints over time, RaST maintained cancer control through dynamic redistribution of ROS-regenerative titanium dioxide nanoparticles from bones to spleen and lymph nodes, supporting sustained immunity. This study highlights how RaST reprograms tumor immunity, overcoming apoptosis resistance by activating complementary necroptosis. RaST activates complementary apoptotic, necroptotic, and immune pathways to eliminate tumors, prevent metastasis, and achieve long term cancer remission.