Chemokine CXCL12 promotes growth and metastasis of more than 20 different human cancers, as well as pathogenesis of other common diseases. CXCL12 binds two different receptors, CXCR4 and CXCR7, both of which recruit and signal through the cytosolic adapter protein β-arrestin 2. Differences in CXCL12-dependent recruitment of β-arrestin 2 in cells expressing one or both receptors remain poorly defined. To quantitatively investigate parameters controlling association of β-arrestin 2 with CXCR4 or CXCR7 in cells co-expressing both receptors, we used a systems biology approach combining real-time, multi-spectral luciferase complementation imaging with computational modeling. Cells expressing only CXCR4 maintain low basal association with β-arrestin 2, and CXCL12 induces a rapid, transient increase in this interaction. In contrast, cells expressing only CXCR7 have higher basal association with β-arrestin 2 and exhibit more gradual, prolonged recruitment of β-arrestin 2 in response to CXCL12. We developed and fit a data-driven computational model for association of either CXCR4 or CXCR7 with β-arrestin 2 in cells expressing only one type of receptor. We then experimentally validated model predictions that co-expression of CXCR4 and CXCR7 on the same cell substantially decreases both the magnitude and duration of CXCL12-regulated recruitment of β-arrestin 2 to CXCR4. Co-expression of both receptors on the same cell only minimally alters recruitment of β-arrestin 2 to CXCR7. In silico experiments also identified β-arrestin 2 as a limiting factor in cells expressing both receptors, establishing that CXCR7 wins the “competition” with CXCR4 for CXCL12 and recruitment of β-arrestin 2. These results reveal how competition for β-arrestin 2 controls integrated responses to CXCL12 in cells expressing both CXCR4 and CXCR7. These results advance understanding of normal and pathologic functions of CXCL12, which is critical for developing effective strategies to target these pathways therapeutically.

Objectives Nonautologous graft materials may solve several dilemmas in tympanoplasty by obviating the need for graft harvest, facilitating consistent wound healing, and permitting graft placement in the clinical setting. Prior studies of nonautologous grafts in humans have shown variable outcomes. In this systematic review, we aim to 1) summarize clinical outcomes and 2) discuss limitations in the literature regarding nonautologous grafts for tympanoplasty in humans. Methods A literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) recommendations. The study size, etiology and duration of perforation, type of nonautologous graft, and postoperative closure rate were assessed. Results The PRISMA approach yielded 61 articles, including 3,247 ears that met inclusion criteria. Studies evaluated nonautologous grafts including paper patch, gelatin sponge, growth factors, porcine small‐intestinal submucosa, among others. Traumatic perforations (62.3%) were most commonly studied, whereas postinfectious perforations (31.9%) and other etiologies (5.8%) comprised a minority of cases. Acute perforations of <8 weeks duration constituted just over half of all treated ears. Overall closure rate was 82.1%, with significantly higher closure rates in acute (89.9%) versus chronic perforations (64.9%, P < .01), regardless of material. A median postoperative air‐bone gap of 5.6 dB was found in the 23% of studies reporting this metric. Conclusions The majority of publications reviewing nonautologous materials in tympanoplasty evaluate acute or traumatic perforations, and few rigorously report hearing outcomes. Given available data, porcine submucosa and basic fibroblast growth factor may hold promise for chronic perforation closure. Future studies should report closure rates and hearing outcomes in perforations >8 weeks duration. Laryngoscope, 131:392–400, 2021

Objectives Conventional reporting of posttympanoplasty hearing outcomes use a pure-tone averaged air-bone gap (ABG) largely representing a low-frequency sound conduction. Few studies report high-frequency conductive hearing outcomes. Herein, we evaluate high-frequency ABG in patients following temporalis fascia total drum replacement. Study Design Case series with chart review. Setting Tertiary care center. Subjects and Methods All patients who underwent type 1 tympanoplasty using a lateral graft total drum replacement technique between August 2016 and February 2019 were identified. Patients with pre- and postoperative audiograms were included. Low-frequency ABG was calculated as the mean ABG at 250, 500, and 1000 Hz. High-frequency ABG was calculated at 4 KHz. Pre- and postoperative ABGs were compared. Results Twenty-three patients were included, and the mean age at surgery was 44 years (range, 9-68 years). Perforation etiology was from trauma (n = 14) or chronic otitis media (n = 9). Preoperative mean low-frequency ABG was 27.8 ± 12.6 dB and mean high-frequency ABG was 21.5 ± 15.1 dB ( P = .044). Postoperatively, the mean low-frequency ABG was significantly reduced by 15.5 ± 13.3 dB ( P < .001) while the mean high-frequency ABG insignificantly changed (reduced by 2.6 ± 16.2 dB, P = .450). Conclusion In a series of patients undergoing temporalis fascia total drum replacement, low-frequency ABG improved; however, high-frequency conductive hearing loss persists. Conventional methods of reporting ABG may not identify persistent high-frequency ABG. These results merit further study across a range of tympanoplasty graft materials and surgical techniques.

Objective: The aim of this study was to determine whether downstream [peroxisome proliferator-activated-receptor alpha (PPARα) and the G-protein coupled receptor, GPR119] and upstream (a fatty acid translocase, CD36) signaling targets of N-oleoylethanolamide (OEA) were necessary for weight loss, metabolic improvements, and diet preference following vertical sleeve gastrectomy (VSG). Summary Background Data: OEA is an anorectic N-acylethanolamine produced from dietary fats within the intestinal lumen that can modulate lipid metabolism, insulin secretion, and energy expenditure by activating targets such as PPARα and GPR119. Methods: Diet-induced obese mice, including wild-type or whole body knockout (KO) of PPARα, GPR119, and CD36, were stratified to either VSG or sham surgery before body weight, body composition, diet preference, and glucose and lipid metabolic endpoints were assessed. Results: We found increased duodenal production of OEA and expression of both GPR119 and CD36 were upregulated in wild-type mice after VSG. However, weight loss and glucose tolerance were improved in response to VSG in PPARαKO, GPR119KO, and CD36KO mice. In fact, VSG corrected hepatic triglyceride dysregulation in CD36KO mice, and circulating triglyceride and cholesterol levels in PPARαKO mice. Lastly, we found PPARα-mediated signaling contributes to macronutrient preference independent of VSG, while removal of CD36 signaling blunts the VSG-induced shift toward carbohydrate preference. Conclusions: In the search for more effective and less invasive therapies to help reverse the global acceleration of obesity and obesity-related disease OEA is a promising candidate; however, our data indicate that it is not an underlying mechanism of the effectiveness of VSG.