Mild traumatic brain injury in Drosophila melanogaster alters reactive oxygen and nitrogen species in a sex-dependent manner.

Traumatic brain injury (TBI) is an outside force causing a modification in brain function and/or structural brain pathology that upregulates brain inducible nitric oxide synthase (iNOS), instigating increased levels of nitric oxide activity which is implicated in secondary pathology leading to behavioral deficits (Hall et al., 2012; Garry et al., 2015; Kozlov et al., 2017). In mammals, TBI-induced NO production activates an immune response and potentiates metabolic crisis through mitochondrial dysfunction coupled with vascular dysregulation; however, the direct influence on pathology is complicated by the activation of numerous secondary cascades and activation of other reactive oxygen species. Drosophila TBI models have demonstrated key features of mammalian TBI, including temporary incapacitation, disorientation, motor deficits, activation of innate immunity (inflammation), and autophagy responses observed immediately after injury (Katzenberger et al., 2013; Barekat et al., 2016; Simon et al., 2017; Anderson et al., 2018; Buhlman et al., 2021b). We hypothesized that acute behavioral phenotypes would be associated with deficits in climbing behavior and increased oxidative stress. Because flies lack mammalian-like cardiovascular and adaptive immune systems, we were able to make our observations in the absence of vascular disruption and adaptive immune system interference in a system where highly targeted interventions can be rapidly evaluated. To demonstrate the induction of injury, ten-day-old transgenic flies received an injury of increasing angles from a modified high impact trauma (HIT) device where angle-dependent increases occurred for acute neurological behavior assessments and twenty-four-hour mortality, and survival was significantly decreased. Injury caused sex-dependent effects on climbing activity and measures of oxidative stress. Specifically, after a single 60-degree HIT, female flies exhibited significant impairments in climbing activity beyond that observed in male flies. We also found that several measures of oxidative stress, including Drosophila NOS (dNOS) expression, protein nitration, and hydrogen peroxide production were significantly decreased in female flies. Interestingly, protein nitration was also decreased in males, but surpassed sham levels with a more severe injury. We also observed decreased autophagy demand in vulnerable dopaminergic neurons in female, but not male flies. In addition, mitophagy initiation was decreased in females. Collectively, our data suggest that TBI in flies induces acute behavioral phenotypes and climbing deficits that are analogous to mammalian TBI. We also observed that various indices of oxidative stress, including dNOS expression, protein tyrosine nitration, and hydrogen peroxide levels, as well as basal levels of autophagy, are altered in response to injury, an effect that is more pronounced in female flies.

Midterm outcomes of open repair versus endovascular descending thoracic aortic aneurysm repair.

Objective: The study objective was to evaluate the midterm outcome of thoracic endovascular aortic repair compared with open repair in patients with descending thoracic aortic aneurysm. Methods: From August 1993 to February 2023, 499 patients with descending thoracic aortic aneurysms underwent open repair (n = 221) or thoracic endovascular aortic repair (n = 278). Of these, 120 matched pairs were identified using propensity score matching based on age, sex, chronic lung disease, stroke, coronary artery disease, diabetes, ejection fraction, dialysis, peripheral vascular disease, prior cardiac surgery, connective tissue disease, and chronic dissection. Primary outcomes were postoperative paralysis, operative mortality, reoperation, and midterm survival. Results: After matching, the preoperative demographics and comorbidities were balanced in both groups. Intraoperatively, open repair had a lower temperature (18 °C vs 36 °C) and more patients required blood products (66% vs 8%), P < .001. Postoperatively, patients undergoing thoracic endovascular aortic repair had fewer strokes (2.5% vs 9.2%; P = .03), less dialysis (0% vs 3.3%; P = .04), and shorter length of stay (5 days vs 12 days, P < .001), but similar lower-extremity paralysis (2.5% vs 2.5%, P = 1.00) compared with open repair. Furthermore, thoracic endovascular aortic repair had higher 7-year incidence of first reoperation (16.1% vs 3.6%, P < .001) but similar operative mortality (0.8% vs 4.2%; P = .10) and 10-year survival outcome (56%; 95% CI, 43-72 vs 58%; 95% CI, 49-68; P = .55) compared with open aortic repair. The hazard ratio was 0.93 (P = .78) for thoracic endovascular aortic repair for midterm mortality and 6.87 (P < .001) for reoperation. Conclusions: Open repair could be the first option for patients with descending thoracic aortic aneurysms who were surgical candidates.

A subset of brain neurons controls regurgitation in adult Drosophila melanogaster.

Taste is essential for animals to evaluate food quality and make important decisions about food choice and intake. How complex brains process sensory information to produce behavior is an essential question in the field of sensory neurobiology. Currently, little is known about higher-order taste circuits in the brain as compared with those of other sensory systems. Here, we used the common vinegar fly, Drosophila melanogaster, to screen for candidate neurons labeled by different transgenic GAL4 lines in controlling feeding behaviors. We found that activation of one line (VT041723-GAL4) produces 'proboscis holding' behavior (extrusion of the mouthpart without withdrawal). Further analysis showed that the proboscis holding phenotype indicates an aversive response, as flies pre-fed with either sucrose or water prior to neuronal activation exhibited regurgitation. Anatomical characterization of VT041723-GAL4-labeled neurons suggests that they receive sensory input from peripheral taste neurons. Overall, our study identifies a subset of brain neurons labeled by VT041723-GAL4 that may be involved in a taste circuit that controls regurgitation.

Structural basis for the activation of PPARgamma by oxidized fatty acids.

The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) has important roles in adipogenesis and immune response as well as roles in both lipid and carbohydrate metabolism. Although synthetic agonists for PPARgamma are widely used as insulin sensitizers, the identity of the natural ligand(s) for PPARgamma is still not clear. Suggested natural ligands include 15-deoxy-delta12,14-prostaglandin J2 and oxidized fatty acids such as 9-HODE and 13-HODE. Crystal structures of PPARgamma have revealed the mode of recognition for synthetic compounds. Here we report structures of PPARgamma bound to oxidized fatty acids that are likely to be natural ligands for this receptor. These structures reveal that the receptor can (i) simultaneously bind two fatty acids and (ii) couple covalently with conjugated oxo fatty acids. Thermal stability and gene expression analyses suggest that such covalent ligands are particularly effective activators of PPARgamma and thus may serve as potent and biologically relevant ligands.