The recognition of helical BH3 domains by Bcl-2 homology (BH) receptors plays a central role in apoptosis. The residues that determine specificity or promiscuity in this interactome are difficult to predict from structural and computational data. Using a cell free split-luciferase system, we have generated a 276 pairwise interaction map for 12 alanine mutations at the binding interface for three receptors, Bcl-xL, Bcl-2, and Mcl-1, and interrogated them against BH3 helices derived from Bad, Bak, Bid, Bik, Bim, Bmf, Hrk, and Puma. This panel, in conjunction with previous structural and functional studies, starts to provide a more comprehensive portrait of this interactome, explains promiscuity, and uncovers surprising details; for example, the Bcl-xL R139A mutation disrupts binding to all helices but the Bad-BH3 peptide, and Mcl-1 binding is particularly perturbed by only four mutations of the 12 tested (V220A, N260A, R263A, and F319A), while Bcl-xL and Bcl-2 have a more diverse set of important residues depending on the bound helix.

Objective This study aims to assess early adverse events and patient factors associated with complications following mandible distraction osteogenesis (MDO). Materials and Methods The American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-Pediatric) database, years 2012 to 2019, was queried for patients undergoing mandible advancement via relevant Current Procedural Terminology and postoperative diagnosis codes. Thirty-day adverse events and co-morbidities are assessed. Results A total of 208 patients were identified with 17.3% (n = 36) experiencing an adverse event, reoperation (n = 14), and readmission (n = 11) being most common. Patients < 365 days old at the time of operation were more likely to experience an adverse event (26.1% vs 10.8%; P = .005). However, among patients less than 1 year of age, differences in the complication rates between patients  ≤ 28 days and >28 days (30.2% vs 22.2%; P = .47) and those weighing  ≤ 4 kg and >4 kg (31.7% vs 11.5%; P = .063) did not reach statistical significance. Conclusions Adverse events following mandible advancement are relatively common, though often minor. In our analysis of the NSQIP-Pediatric database, neonatal age ( ≤ 28 days) or weight  ≤ 4 kg did not result in a statistically significant increase in complications among patients less than 1 year of age. Providers should consider early intervention in patients who may benefit from MDO.

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The BCL‐2 protein homology plays a central role in regulating the intrinsic pathway of apoptosis. These proteins often hold the key to a cells decision to live or die following factors such as irreversible DNA damage. Not surprisingly, the anti‐apoptotic members of this family are over expressed in many cancers where they contribute to the formation, progression and chemo‐resistance of tumor cells. The promiscuous recognition of helical BH3 domains by the BCL‐2 class of proteins makes their exact roles in apoptosis difficult to determine and thus contribute to challenges in designing effective therapies. We seek to identify the molecular determinants of binding between the BCL‐2 homologs and their BH3 targets. Using in‐vitro translation and a luciferase based florescence assay we have examined the effects of mutations to the receptor pocket of BCL‐2 and MCL‐1 on interactions with 9 BH3 only proteins. Results from these experiments should formulate a picture of the role different members of this homology play in cell death. Moreover, these results will allow for the design of orthogonal receptor/ligand pairs, helpful for further interrogating this pathway. Grant Funding Source: Arnold and Mabel Beckman Foundation