The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism.

The mosquito protein AEG12 is up-regulated in response to blood meals and flavivirus infection though its function remained elusive. Here, we determine the three-dimensional structure of AEG12 and describe the binding specificity of acyl-chain ligands within its large central hydrophobic cavity. We show that AEG12 displays hemolytic and cytolytic activity by selectively delivering unsaturated fatty acid cargoes into phosphatidylcholine-rich lipid bilayers. This property of AEG12 also enables it to inhibit replication of enveloped viruses such as Dengue and Zika viruses at low micromolar concentrations. Weaker inhibition was observed against more distantly related coronaviruses and lentivirus, while no inhibition was observed against the nonenveloped virus adeno-associated virus. Together, our results uncover the mechanistic understanding of AEG12 function and provide the necessary implications for its use as a broad-spectrum therapeutic against cellular and viral targets.

Should All Patients With Pulmonary Hypertension Undergoing Non-Cardiac Surgery Be Managed by Cardiothoracic Fellowship-Trained Anesthesiologists?

OBJECTIVES: To identify differences in practice patterns and outcomes related to the induction of general anesthesia for patients with pulmonary hypertension (PH) performed by anesthesiologists who have completed a cardiothoracic fellowship (CTA group) vs those who have not (non-CTA group). DESIGN: Retrospective study with propensity score matching. SETTING: Operating room. PARTICIPANTS: All adult patients with PH undergoing general anesthesia requiring intubation at a single academic center over 5 years. INTERVENTIONS: Patient baseline characteristics, peri-induction management variables, post-induction mean arterial pressure (MAP), and other outcomes were compared between CTA and non-CTA groups. METHODS AND MAIN RESULTS: Following propensity scoring matching, 402 patients were included in the final model, 100 in the CTA group and 302 in the non-CTA group. Also following matching, only cases of mild to moderate PH without right ventricular dysfunction remained in the analysis. Matched groups were overall statistically similar with respect to baseline characteristics; however, there was a greater incidence of higher ASA class (P = .025) and cardiology and thoracic procedures (P < .001) being managed by the CTA group. No statistical differences were identified in practice patterns or outcomes related to the induction of anesthesia between groups, except for longer hospital length of stay in the CTA group (P = .008). CONCLUSIONS: These results provide early evidence to suggest the induction of general anesthesia of patients with non-severe PH disease can be comparably managed by either anesthesiologists with or without a cardiothoracic fellowship. However, these findings should be confirmed in a prospective study.

Predictors of Post-induction Hypotension for Patients With Pulmonary Hypertension.

Purpose The purpose is to identify predictors of post-induction hypotension (PIH) during general anesthesia in a population of patients with varying degrees of pulmonary hypertension (PH). Methods This is a single-center, retrospective, observational study of perioperative data obtained via electronic health records from patients with PH undergoing surgery over a five-year period. Baseline patient characteristics, peri-induction management variables, and pre-induction mean arterial pressure (MAP) were statistically analyzed using Kruskal-Wallis rank sum tests, Pearson's chi-squared tests, and logistic regression analysis to identify risk factors for PIH. We further assessed the relationship between PH and PIH using propensity score matching. Primary outcomes include a percent decrease in post-induction blood pressure as well as a post-induction nadir with a threshold of 55 mm Hg. Results Eight hundred fifty-seven patients in the cohort stratified by severity of PH reveal that advanced age (p < 0.001), higher BMI (P = 0.002), higher American Society of Anesthesiologists (ASA) score (P = 0.001), and renal and cardiac comorbidities (P < 0.001) are associated with PH severity. None of our tested parameters were significantly predictive for PIH in patients with PH. Right heart failure was found to be weakly and non-significantly predictive of PIH in patients with PH (P = 0.052, odds ratio [OR] = 1.116). Diabetes (P = 0.007, OR = 0.919) and maintenance of spontaneous ventilation (P = 0.012, OR = 0.925) were associated with decreased rates of PIH. Conclusion Hypotension after induction of general anesthesia in patients with PH is a serious problem, yet statistically significant risk factors were not identified. History of diabetes and preservation of spontaneous ventilation had a significant but weak effect of decreasing rates of PIH. This pilot study was limited by retrospective design and warrants further analysis with a prospective cohort.

Hydrophobic ligands influence the structure, stability, and processing of the major cockroach allergen Bla g 1.

The cockroach allergen Bla g 1 forms a novel fold consisting of 12 amphipathic alpha-helices enclosing an exceptionally large hydrophobic cavity which was previously demonstrated to bind a variety of lipids. Since lipid-dependent immunoactivity is observed in numerous allergens, understanding the structural basis of this interaction could yield insights into the molecular determinants of allergenicity. Here, we report atomic modelling of Bla g 1 bound to both fatty-acid and phospholipids ligands, with 8 acyl chains suggested to represent full stoichiometric binding. This unusually high occupancy was verified experimentally, though both modelling and circular dichroism indicate that the general alpha-helical structure is maintained regardless of cargo loading. Fatty-acid cargoes significantly enhanced thermostability while inhibiting cleavage by cathepsin S, an endosomal protease essential for antigen processing and presentation; the latter of which was found to correlate to a decreased production of known T-cell epitopes. Both effects were strongly dependent on acyl chain length, with 18-20 carbons providing the maximal increase in melting temperature (~20 °C) while completely abolishing proteolysis. Diacyl chain cargoes provided similar enhancements to thermostability, but yielded reduced levels of proteolytic resistance. This study describes how the biophysical properties of Bla g 1 ligand binding and digestion may relate to antigen processing, with potential downstream implications for immunogenicity.