What to expect from reliability and validity claims? A pragmatic conception of psychiatric nosology

The reliability and validity of psychiatric diagnoses have always been a major concern. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) reliability field trials yielded ambiguous results, with some diagnostic categories scoring well below par. We argue that the emphasis on the reliability of psychiatric diagnoses, which has dominated psychiatric nosology and guided the endeavor of improving the DSM in its consecutive editions, is misguided and lacks in structural validity. In this article, we defend a pragmatic view on psychiatric disease as the most fruitful approach to an understanding of what the categorical distinctions in the DSM (can) represent. Disorders in the DSM are descriptions of clinical pictures and do not necessarily correspond to an identified pathological substrate. Although this is a logical result of the nature of psychiatric disease, it bears important consequences. The various DSM disease categories are not uniform but should be regarded as representing different kinds of disorders, ranging from a separation from normal behavior based on practical grounds to the discrete kind of disorders envisioned by proponents of a strong realistic view. We argue that the explication of kinds of disorders outlined in this article provides interesting perspectives on the problems of reliability and validity that the DSM faces

The Development of RNA-KISS, a Mammalian Three-Hybrid Method to Detect RNA-Protein Interactions in Living Mammalian Cells

RNA-protein interactions are essential for the regulation of mRNA and noncoding RNA functions and are implicated in many diseases, such as cancer and neurodegenerative disorders. A method that can detect RNA-protein interactions in living mammalian cells on a proteome-wide scale will be an important asset to identify and study these interactions. Here we show that a combination of the mammalian two-hybrid protein-protein detection method KISS (kinase substrate sensor) and the yeast RNA three-hybrid method, utilizing the specific interaction between the MS2 RNA and MS2 coat protein, is capable of detecting RNA-protein interactions in living mammalian cells. For conceptional proof we used the subgenomic flavivirus RNA (sfRNA) of the dengue virus (DENV), a highly structured noncoding RNA derived from the DENV genome known to target host cell proteins involved in innate immunity and antiviral defense, as bait. Using RNA-KISS, we could confirm the previously established interaction between the RNA-binding domain of DDX6 and the DENV sfRNA. Finally, we performed a human proteome-wide screen for DENV sfRNA-binding host factors, identifying several known flavivirus host factors such as DDX6 and PACT, further validating the RNA-KISS method as a robust and high-throughput cell-based RNA-protein interaction screening tool.status: publishe

A nuclear receptor HR96-related gene underlies large trans-driven differences in detoxification gene expression in a generalist herbivore

Abstract The role, magnitude, and molecular nature of trans-driven expression variation underlying the upregulation of detoxification genes in pesticide resistant arthropod populations has remained enigmatic. In this study, we performed expression quantitative trait locus (eQTL) mapping (n = 458) between a pesticide resistant and a susceptible strain of the generalist herbivore and crop pest Tetranychus urticae. We found that a single trans eQTL hotspot controlled large differences in the expression of a subset of genes in different detoxification gene families, as well as other genes associated with host plant use. As established by additional genetic approaches including RNAi gene knockdown, a duplicated gene with a nuclear hormone receptor HR96-related ligand-binding domain was identified as causal for the expression differences between strains. The presence of a large family of HR96-related genes in T. urticae may enable modular control of detoxification and host plant use genes, facilitating this species’ known and rapid evolution to diverse pesticides and host plants

Intradiol ring cleavage dioxygenases from herbivorous spider mites as a new detoxification enzyme family in animals

Background Generalist herbivores such as the two-spotted spider mite Tetranychus urticae thrive on a wide variety of plants and can rapidly adapt to novel hosts. What traits enable polyphagous herbivores to cope with the diversity of secondary metabolites in their variable plant diet is unclear. Genome sequencing of T. urticae revealed the presence of 17 genes that code for secreted proteins with strong homology to "intradiol ring cleavage dioxygenases (DOGs)" from bacteria and fungi, and phylogenetic analyses show that they have been acquired by horizontal gene transfer from fungi. In bacteria and fungi, DOGs have been well characterized and cleave aromatic rings in catecholic compounds between adjacent hydroxyl groups. Such compounds are found in high amounts in solanaceous plants like tomato, where they protect against herbivory. To better understand the role of this gene family in spider mites, we used a multi-disciplinary approach to functionally characterize the various T. urticae DOG genes. Results We confirmed that DOG genes were present in the T. urticae genome and performed a phylogenetic reconstruction using transcriptomic and genomic data to advance our understanding of the evolutionary history of spider mite DOG genes. We found that DOG expression differed between mites from different plant hosts and was induced in response to jasmonic acid defense signaling. In consonance with a presumed role in detoxification, expression was localized in the mite's gut region. Silencing selected DOGs expression by dsRNA injection reduced the mites' survival rate on tomato, further supporting a role in mitigating the plant defense response. Recombinant purified DOGs displayed a broad substrate promiscuity, cleaving a surprisingly wide array of aromatic plant metabolites, greatly exceeding the metabolic capacity of previously characterized microbial DOGs. Conclusion Our findings suggest that the laterally acquired spider mite DOGs function as detoxification enzymes in the gut, disarming plant metabolites before they reach toxic levels. We provide experimental evidence to support the hypothesis that this proliferated gene family in T. urticae is causally linked to its ability to feed on an extremely wide range of host plants