Mechanical forces have been proposed to modulate organ growth, but a molecular mechanism that links them to growth regulation in vivo has been lacking. We report that increasing tension within the cytoskeleton increases Drosophila wing growth, whereas decreasing cytoskeletal tension decreases wing growth. These changes in growth can be accounted for by changes in the activity of Yorkie, a transcription factor regulated by the Hippo pathway. The influence of myosin activity on Yorkie depends genetically on the Ajuba LIM protein Jub, a negative regulator of Warts within the Hippo pathway. We further show that Jub associates with α-catenin, and that its localization to adherens junctions and association with α-catenin are promoted by cytoskeletal tension. Jub recruits Warts to junctions in a tension-dependent manner. Our observations delineate a mechanism that links cytoskeletal tension to regulation of Hippo pathway activity, providing a molecular understanding of how mechanical forces can modulate organ growth.

The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. Recent studies have provided new insights into the cellular organization of Hippo signaling, its relationship to cell-cell junctions, and how the cytoskeleton modulates Hippo signaling. Cell-cell junctions serve as platforms for Hippo signaling by localizing scaffolding proteins that interact with core components of the pathway. Interactions of Hippo pathway components with cell-cell junctions and the cytoskeleton also suggest potential mechanisms for the regulation of the pathway by cell contact and cell polarity. As our understanding of the complexity of Hippo signaling increases, a future challenge will be to understand how the diverse inputs into the pathway are integrated, and to define their respective contributions in vivo.

Hippo signalling controls organ growth and cell fate by regulating the activity of the kinase Warts. Multiple Hippo pathway components localize to apical junctions in epithelial cells, but the spatial and functional relationships among components have not been clarified, nor is it known where Warts activation occurs. We report here that Hippo pathway components in Drosophila wing imaginal discs are organized into distinct junctional complexes, including separate distributions for Salvador, Expanded, Warts and Hippo. These complexes are reorganized on Hippo pathway activation, when Warts shifts from associating with its inhibitor Jub to its activator Expanded, and Hippo concentrates at Salvador sites. We identify mechanisms promoting Warts relocalization, and using a phospho-specific antisera and genetic manipulations, identify where Warts activation occurs: at apical junctions where Expanded, Salvador, Hippo and Warts overlap. Our observations define spatial relationships among Hippo signalling components and establish the functional importance of their localization to Warts activation.

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ABSTRACT. Objective. To perform hearing screenings on all newborns before hospital discharge, using auditory brainstem evoked responses with analysis of time, cost, and failure rates to evaluate and determine the screening practicality.Method. Over a 3-year period from January 1, 1993 to December 31, 1995, auditory brainstem evoked response screenings were performed on 15 749 infants born at Saint Barnabas Medical Center, Livingston, New Jersey, before their hospital discharge by certified/licensed audiologists. The auditory brainstem evoked response screenings were conducted using the Nicolet Compass Evoked Potential System.Results. A 3-year experience of testing 15 749 infants proved to be a cost-effective program with costs less than $30.00/baby. To date, 46 babies have been identified with bilateral sensorineural hearing loss and 6 babies with unilateral sensorineural hearing loss.Conclusions. The universal newborn hearing screening program at Saint Barnabas Medical Center has proved to be effective, beneficial, and necessary for an institution with more than 5000 births, annually. Early identification of hearing loss has resulted in infants receiving early intervention, and the screening program has provided education and follow-up services to both parents and physicians. Pediatrics 1997;99(6). URL: http: //www.pediatrics.org/cgi/content/full/99/6/e4; auditory brainstem evoked responses, early hospital discharge of newborns, early identification of hearing loss, screening auditory brainstem evoked responses, universal newborn hearing screening.

Neonatal respiratory distress syndrome due to surfactant deficiency is associated with high morbidity and mortality in preterm infants, and the use of less invasive surfactant administration (LISA) has been increasingly studied. This meta-analysis found that LISA via thin catheter significantly reduced the need for mechanical ventilation within the first 72 hours (relative risk [RR] = 0.677; P = .021), duration of mechanical ventilation (difference in means [MD] = −39.302 hours; P < .001), duration of supplemental oxygen (MD = −68.874 hours; P < .001), and duration of nasal continuous positive airway pressure (nCPAP; MD = −28.423 hours; P = .010). A trend toward a reduction in the incidence of bronchopulmonary dysplasia was observed (RR = 0.656; P = .141). No significant difference in overall mortality, incidence of pneumothorax, or successful first attempts was observed. LISA via thin catheter significantly reduces the need for mechanical ventilation within the first 72 hours as well as the duration of mechanical ventilation, supplemental oxygen, and nCPAP. LISA via thin catheter appears promising in improving preterm infant outcomes.

Pancreatic cancer is a deadly disease with little response to standard therapies. Irreversible electroporation (IRE) has emerged as a novel ablative technique for the clinical treatment of pancreatic cancer. Combinations of IRE and immunotherapies, including anti-programmed death 1 (𝜶PD1) immune checkpoint blockade, have shown promising efficacy in both preclinical and clinical studies. However, tumor recurrence remains an obstacle that needs to be overcome. It herein is shown that IRE induces a substantial infiltration of neutrophils into pancreatic tumors. These neutrophils are then polarized into a protumor phenotype by immunosuppressive cues, in particular transforming growth factor 𝜷 (TGF-𝜷). Using glutathione-responsive degradable mesoporous silica nanoparticles loaded with SB525334, an inhibitor of TGF-𝜷1 receptor, it is demonstrated that local inhibition of TGF-𝜷 within the tumor microenvironment promotes neutrophil polarization into an antitumor phenotype, enhances pancreatic cancer response to combined IRE and 𝜶PD1 therapy, and induces long-term antitumor memory. The therapeutic efficacy is also attributed to tumor infiltration by CD8 + cytotoxic T cells, depletion of regulatory T cells, and maturation of antigen-presenting dendritic cells. Thus, modulating neutrophil polarization with nanomedicine is a promising strategy for treating pancreatic cancer.