Opposing effects of an F-box protein and the HSP90 chaperone network on microtubule stability and neurite growth in Caenorhabditis elegans.

Molecular chaperones often work collaboratively with the ubiquitylation-proteasome system (UPS) to facilitate the degradation of misfolded proteins, which typically safeguards cellular differentiation and protects cells from stress. In this study, however, we report that the Hsp70/Hsp90 chaperone machinery and an F-box protein, MEC-15, have opposing effects on neuronal differentiation, and that the chaperones negatively regulate neuronal morphogenesis and functions. Using the touch receptor neurons (TRNs) of Caenorhabditis elegans, we find that mec-15(-) mutants display defects in microtubule formation, neurite growth, synaptic development and neuronal functions, and that these defects can be rescued by the loss of Hsp70/Hsp90 chaperones and co-chaperones. MEC-15 probably functions in a Skp-, Cullin- and F-box- containing complex to degrade DLK-1, which is an Hsp90 client protein stabilized by the chaperones. The abundance of DLK-1, and likely other Hsp90 substrates, is fine-tuned by the antagonism between MEC-15 and the chaperones; this antagonism regulates TRN development, as well as synaptic functions of GABAergic motor neurons. Therefore, a balance between the UPS and the chaperones tightly controls neuronal differentiation.

Laparoscopic Heller Myotomy and Dor Fundoplication.

INTRODUCTION: Achalasia is an esophageal motility disorder characterized by disordered esophageal peristalsis with failed relaxation of the lower esophageal sphincter resulting in a functional obstruction.Treatment can include medical, endoscopic, or surgical interventions. Although none of these are curative, they each offer methods to create esophageal outflow. MATERIALS AND METHODS: This article discusses our preferred surgical technique used for laparoscopic Heller myotomy with Dor fundoplication. This technique has been developed over the author's career. CONCLUSION: The technique discussed provides a safe and effective strategy to manage achalasia.

Is language a barrier in the management of acute appendicitis?

BACKGROUND: Language preference is a contributing factor for prolonged time from symptom onset to appendectomy within pediatrics, but is poorly characterized in adults. We aimed to investigate associations between language barriers and delays in assessment and treatment for adults with acute appendicitis. METHODS: In a multiethnic community, patients aged ≥18 years old who underwent appendectomy were identified between January 2017 and August 2022 at a single institution. Negative binomial regression was used to compare interval wait times to imaging, medication administration, and surgical evaluation between patients with limited English proficiency and those who are English proficient. RESULTS: Of the 1469 patients included, 48% (n = 699) were with limited English proficiency. Average age was higher for patients with limited English proficiency (45 vs 36, P < .001). Most of them were Asian (54%) and without private insurance (65%, P < .001). Symptom duration, incidence of septic shock, and date/time of presentation to the emergency department were similar. Patients with limited English proficiency presented more frequently with gangrenous appendicitis (20% vs 15%, P = .013) but not perforated (23% vs 20%, P = .065). They experienced longer wait times for surgical evaluation (376 vs 348 min, incidence rate ratio [IRR], 1.08; P = .002) but similar times for imaging, and medications administered. After controlling for demographics, triage acuity, and hospital factors, significantly longer wait times for surgical evaluation persisted (IRR adjusted, 1.07; P = .038). There was no significant difference in hospital length-of-stay, postoperative infection, or 30-day readmission rate. CONCLUSION: Adult patients with limited English proficiency may experience longer wait times for surgical evaluation for acute appendicitis, but this may not result in clinically significant delays in the initiation of treatment.

Epistatic, synthetic, and balancing interactions among tubulin missense mutations affecting neurite growth in Caenorhabditis elegans.

Mutations in tubulins affect microtubule (MT) dynamics and functions during neuronal differentiation and their genetic interaction provides insights into the regulation of MT functions. We previously used Caenorhabditis elegans touch receptor neurons to analyze the cellular impact of tubulin mutations and reported the phenotypes of 67 tubulin missense mutations, categorized into three classes: loss-of-function (lf), antimorphic (anti), and neomorphic (neo) alleles. In this study, we isolated 54 additional tubulin alleles through suppressor screens in sensitized backgrounds that caused excessive neurite growth. These alleles included 32 missense mutations not analyzed before, bringing the total number of mutations in our collection to 99. Phenotypic characterization of these newly isolated mutations identified three new types of alleles: partial lf and weak neo alleles of mec-7/ß-tubulin that had subtle effects and strong anti alleles of mec-12/α-tubulin. We also discovered complex genetic interactions among the tubulin mutations, including the suppression of neo mutations by intragenic lf and anti alleles, additive and synthetic effects between mec-7 neo alleles, and unexpected epistasis, in which weaker neo alleles masked the effects of stronger neo alleles in inducing ectopic neurite growth. We also observed balancing between neo and anti alleles, whose respective MT-hyperstablizing and -destabilizing effects neutralized each other.