Myosin XV is a negative regulator of signaling filopodia during long-range lateral inhibition.

The self-organization of cells during development is essential for the formation of healthy tissues and requires the coordination of cell activities at local scales. Cytonemes, or signaling filopodia, are dynamic actin-based cellular protrusions that allow cells to engage in contact mediated signaling at a distance. While signaling filopodia have been shown to support several signaling paradigms during development, less is understood about how these protrusions are regulated. We investigated the role of the plus-end directed, unconventional MyTH4-FERM myosins in regulating signaling filopodia during sensory bristle patterning on the dorsal thorax of the fruit fly Drosophila melanogaster. We found that Myosin XV is required for regulating signaling filopodia dynamics and, as a consequence, lateral inhibition more broadly throughout the patterning epithelium. We found that Myosin XV is required for limiting the length and number of signaling filopodia generated by bristle precursor cells. Cells with additional and longer signaling filopodia due to loss of Myosin XV are not signaling competent, due to altered levels of Delta ligand and Notch receptor along their lengths. We conclude that Myosin XV acts to negatively regulate signaling filopodia, as well as promote the ability of signaling filopodia to engage in long-range Notch signaling. Since Myosin XV isoforms are present across several vertebrate and invertebrate systems, this may have significance for other long-range signaling mechanisms.

Myosin XV is a negative regulator of signaling filopodia during long-range lateral inhibition.

The self-organization of cells during development is essential for the formation of healthy tissues, and requires the coordination of cell activities at local scales. Cytonemes, or signaling filopodia, are dynamic actin-based cellular protrusions that allow cells to engage in contact mediated signaling at a distance. While signaling filopodia have been shown to support several signaling paradigms during development, less is understood about how these protrusions are regulated. We investigated the role of the plus-end directed, unconventional MyTH4-FERM myosins in regulating signaling filopodia during sensory bristle patterning on the dorsal thorax of the fruit fly Drosophila melanogaster. We found that Myosin XV is required for regulating signaling filopodia dynamics and, as a consequence, lateral inhibition more broadly throughout the patterning epithelium. We found that Myosin XV is required for limiting the length and number of signaling filopodia generated by bristle precursor cells. Cells with additional and longer signaling filopodia due to loss of Myosin XV are not signaling competent, due to altered levels of Delta ligand and Notch receptor along their lengths. We conclude that Myosin XV acts to negatively regulate signaling filopodia, as well as promote the ability of signaling filopodia to engage in long-range Notch signaling. Since Myosin XV is present across several vertebrate and invertebrate systems, this may have significance for other long-range signaling mechanisms.

The Value of Quantitative Faecal Immunochemical Testing as a Prioritisation Tool for the Endoscopic Investigation of Patients With Iron Deficiency.

Difficulty in providing endoscopy for patients with iron deficiency anaemia (IDA) during the COVID-19 pandemic has highlighted the requirement for a prioritisation tool. We aimed to test the validity of qFIT as a prioritisation tool in patients with iron deficiency and its ability to identify patients with advanced neoplastic lesions (ANLs). Data collected from patients referred with biochemically proven iron deficiency (ferritin ≤ 15 µg/L) and synchronous qFIT who underwent full gastrointestinal investigation within NHS Greater Glasgow and Clyde was analysed retrospectively. Patients who did not undergo full investigation, defined as gastroscopy and colonoscopy or CT colonography, were excluded. ANLs were defined as defined as upper GI cancer, colorectal adenoma ≥ 1 cm or colorectal cancer. Area under the curve (AUC) analysis was performed on qFIT results and outcome, defined as the presence of an ANL. AUC analysis guided cut-off scores for qFIT. Patients with a qFIT of <10, 10-200, >200, were allocated a score of 1, 2, and 3, respectively. A total of 575 patients met criteria for inclusion into the study. Overall, qFIT results strongly predicted the presence of ANLs (AUC 0.87, CI 0.81-0.92; P < 0.001). The prevalence of ANLs in patients with scores 1-3 was 1.2, 13.5, and 38.9% respectfully. When controlled for other significant variables, patients with a higher qFIT score were statistically more likely to have an ANL (qFIT score = 2; OR 12.8; P < 0.001, qFIT score = 3, OR 50.0; P < 0.001). A negative qFIT had a high NPV for the presence of ANLs (98.8%, CI 97.0-99.5%). These results strongly suggest that qFIT has validity as a prioritisation tool in patients with iron deficiency; both allowing for a more informed decision of investigation of patients with very low risk of malignancy, and in identifying higher risk patients who may benefit from more urgent endoscopy.