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Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.

Oropouche orthobunyavirus (OROV; Peribunyaviridae ) is a mosquito-transmitted virus that causes widespread human febrile illness in South America, with occasional progression to neurologic effects. Host factors mediating the cellular entry of OROV are undefined. Here, we show that OROV uses the host protein low-density lipoprotein–related protein 1 (Lrp1) for efficient cellular infection. Cells from evolutionarily distinct species lacking Lrp1 were less permissive to OROV infection than cells with Lrp1. Treatment of cells with either the high-affinity Lrp1 ligand receptor-associated protein (RAP) or recombinant ectodomain truncations of Lrp1 significantly reduced OROV infection. In addition, chimeric vesicular stomatitis virus (VSV) expressing OROV glycoproteins (VSV-OROV) bound to the Lrp1 ectodomain in vitro. Furthermore, we demonstrate the biological relevance of the OROV-Lrp1 interaction in a proof-of-concept mouse study in which treatment of mice with RAP at the time of infection reduced tissue viral load and promoted survival from an otherwise lethal infection. These results with OROV, along with the recent finding of Lrp1 as an entry factor for Rift Valley fever virus, highlight the broader significance of Lrp1 in cellular infection by diverse bunyaviruses. Shared strategies for entry, such as the critical function of Lrp1 defined here, provide a foundation for the development of pan-bunyaviral therapeutics.

Polydopamine (PDA)-modified NaEr

8573 Background: The treatment mode of small cell lung cancer (SCLC) is mainly based on the comprehensive treatment of chemotherapy and radiotherapy. IMpower133 study, suggesting that immune checkpoint inhibitors combined with chemotherapy first-line treatment for advanced SCLC may bring new research directions of clinical benefit. Previous study suggested that the combination of anti-PD-1 antibody camrelizumab and VEGFR-2 inhibitor apatinib significantly improved antitumor effects. The aim of this study was to evaluate the efficacy and safety of camrelizumab combined with chemotherapy (irinotecan combined with platinum) followed by camrelizumab combined with apatinib in the first-line treatment of SCLC. Methods: Extensive-stage small cell lung cancer patients were enrolled in this single-center, single-arm study. During the induction treatment phase, Patients received camrelizumab (200mg q3w), irinotecan (65 mg/m2, q3w) and platinum (cisplatin: 30 mg/m2, carboplatin: AUC=4̃5), after 4-6 cycles, the patient entered the maintenance phase, and then patients received camrelizumab combined with apatinib until disease progression or unacceptable toxicity. Treatment efficacy was assessed every 3 cycles (6 weeks). The primary endpoint is progression-free survival (PFS). Secondary endpoints are objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and overall survival (OS), which are based on RECIST 1.1. Results: At data cut-off (Jan 10, 2022), 20 extensive-stage SCLC patients were enrolled in the study, of which 18 patients were evaluable. Median age was 64 years, male accounts for 85.0% (17/20). Median follow-up was 5.0 months (range 0.4̃17.6 months). Of 18 evaluable patients, no one achieved complete response Partial response was achieved by 17 (94.4%) patients and stable disease exhibited by 1 (5.6%) patient. The ORR and DCR were 94.4% and 100%, respectively. mPFS and mDoR have not been reached. In terms of adverse events (AEs), reactive cutaneous capillary hyperplasia (RCCEP) was observed in 10 (47.6%) patients 10 patients. Grade III-IV AEs were observed in 7 (35.0%) patients with neutropenia, thrombocytopenia, hemoglobin reduction, leukopenia, rash. The rest were grade I-II AEs. Conclusions: The treatment in this study showed impressive ORR and DCR, and acceptable toxicity, and may be a promising method as a first line treatment. Clinical trial information: NCT04453930.