A novel mistranslating tRNA model in Drosophila melanogaster has diverse, sexually dimorphic effects.

Transfer RNAs (tRNAs) are the adaptor molecules required for reading the genetic code and producing proteins. Transfer RNA variants can lead to genome-wide mistranslation, the misincorporation of amino acids not specified by the standard genetic code into nascent proteins. While genome sequencing has identified putative mistranslating transfer RNA variants in human populations, little is known regarding how mistranslation affects multicellular organisms. Here, we create a multicellular model of mistranslation by integrating a serine transfer RNA variant that mistranslates serine for proline (tRNAUGG,G26ASer) into the Drosophila melanogaster genome. We confirm mistranslation via mass spectrometry and find that tRNAUGG,G26ASer misincorporates serine for proline at a frequency of ∼0.6% per codon. tRNAUGG,G26ASer extends development time and decreases the number of flies that reach adulthood. While both sexes of adult flies containing tRNAUGG,G26ASer present with morphological deformities and poor climbing performance, these effects are more pronounced in female flies and the impact on climbing performance is exacerbated by age. This model will enable studies into the synergistic effects of mistranslating transfer RNA variants and disease-causing alleles.

Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity.

Protein misfolding is a central feature of most neurodegenerative diseases. Molecular chaperones can modulate the toxicity associated with protein misfolding, but it remains elusive which molecular chaperones and co-chaperones interact with specific misfolded proteins. TDP-43 misfolding and inclusion formation are a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Using yeast and mammalian neuronal cells we find that Hsp90 and its co-chaperone Sti1 have the capacity to alter TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity. Our data also demonstrate that impaired Hsp90 function sensitizes cells to TDP-43 toxicity and that Sti1 specifically interacts with and strongly modulates TDP-43 toxicity in a dose-dependent manner. Our study thus uncovers a previously unrecognized tie between Hsp90, Sti1, TDP-43 misfolding, and cellular toxicity.

The Connection Between Thwarted Belongingness, Alcohol Consumption, Suicidal, and Homicidal Ideation in a Criminal Justice Sample.

BACKGROUND: To determine if thwarted belongingness in combination with frequent alcohol use increased suicidal and homicidal ideation when known predictors were controlled for (eg, depressive disorders, anxiety disorders, drug use, race, sex, age, and employment status). METHOD: This study utilized an archival database. Participants were 574 individuals at an outpatient substance abuse treatment facility who were under community corrections supervision. The average age was 34.5 (SD = 10.9) years; there were 371 (64.6%) men and 287 (50.0%) Black participants. Data were originally gathered from face-to-face interviews with the participants by their case manager or an intake specialist when they entered treatment. Self-reported suicidal and homicidal ideation was used as a dependent variable in unadjusted and adjusted binary logistic regressions to determine the influence of thwarted belongingness and frequent alcohol use. RESULTS: Thwarted belongingness alone (ie, without frequent alcohol use) was associated with risk for suicidal ideation, and was approaching significance for homicidal ideation. The combination of thwarted belongingness and frequent alcohol use was associated with the greatest risk for suicidal and homicidal ideation. Cocaine use and employment status were also identified as significant predictors for suicidal and homicidal ideation in the fully adjusted models. CONCLUSIONS: Thwarted belongingness in combination with frequent alcohol use seems to have a large and meaningful relationship with both suicidal and homicidal ideation. Additional research is needed to better understand the relationship between alcohol, thwarted belongingness, and outcomes such as suicide and homicide.

Cognitive risk profiles for anxiety disorders in a high-risk population.

The purpose of the present study was to identify subgroups of participants who may be at particularly high risk for anxiety pathology based on specific combinations of demographic characteristics and higher-order cognitive abilities in a population at disproportionate risk for deficits in cognitive abilities (i.e., smokers within the criminal justice system). Participants (N=495) provided demographic information, were administered a semi-structured diagnostic interview, and completed a number of measures assessing cognitive abilities. A receiver-operating characteristic (ROC) model using signal detection theory indicated that the strongest predictor of anxiety disorder diagnosis was race, with White participants having a 30.6% likelihood of diagnosis and participants in the non-White category (97% of which identified as Black/African American) having a 18.9% likelihood of diagnosis. Interestingly, the individual risk profile associated with the highest probability of having a current anxiety disorder was characterized by White participants with impaired response inhibition (58.6%), and the lowest probability of having a current anxiety disorder was among non-White males (13.9%). The findings, which indicated that White individuals with impaired response inhibition are at a disproportionately high risk for anxiety disorders, suggest a potential target for prevention and intervention.