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Summary Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3−/− mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.

A new measurement of the reactor antineutrino flux and energy spectrum by the Daya Bay reactor neutrino experiment is reported. The antineutrinos were generated by six 2.9 GWth nuclear reactors and detected by eight antineutrino detectors deployed in two near (560 m and 600 m flux-weighted baselines) and one far (1640 m flux-weighted baseline) underground experimental halls. With 621 days of data, more than 1.2 million inverse beta decay (IBD) candidates were detected. The IBD yield in the eight detectors was measured, and the ratio of measured to predicted flux was found to be 0.946±0.020 (0.992±0.021) for the Huber+Mueller (ILL+Vogel) model. A 2.9σ deviation was found in the measured IBD positron energy spectrum compared to the predictions. In particular, an excess of events in the region of 4–6 MeV was found in the measured spectrum, with a local significance of 4.4σ. A reactor antineutrino spectrum weighted by the IBD cross section is extracted for model-independent predictions.

Microelectromechanical system (MEMS) actuators essentially have movable silicon structures where the mechanical motion can be activated electronically. The microscanner is one of the most successfully commercialized MEMS devices which are widely used for collecting optical information, manipulating light, and displaying images. While silicon is abundant, it is also brittle and stiff and when microprocessed, defects are not uncommon. These defects result in weakness under torsional stress and this has been the key factor limiting the scanning performance of the microscanner. Here a metallic glass (MG)-based microscanner is reported with MG as the material for the moving torsion bars. The low elastic modulus, high fracture toughness, and high strength of MG offers, for the first time, an ultralarge rotating angle of 146 degrees with power consumption lowered to the microwatt range, and a smaller driving force and better actuation performance, than conventional single crystal silicon and polycrystalline silicon. The high spatial resolution and large scanning field of the MG-based microscanner are demonstrated in the tomographic imaging of a human finger. This development of an MG-based MEMS possibly opens a new field of low-powered MEMS devices with extreme actuation and enhanced sensing.

This work presents novel diamond-based nanostructures formed by a fluorescent nanodiamond core coated with a gold shell (ND@Au). Gold shell was grown on silicon-doped nanodiamonds in water by controlled reduction of gold chloride. The resulting gold-coated nanodiamond samples were characterized by means of scanning electron microscopy, UV-visible, Raman and luminescence spectroscopies. These gold-coated nanodiamonds showed a strong resonance absorption in the visible and near-infrared (NIR) range. When excited with green laser, the silicon doped nanodiamonds emit a stable fluorescence peaked at about 740 nm due to the SiV centers with no photobleaching and photoblinking. In this work we demonstrate that optical properties of the silicon-doped nanodiamonds are retained after the formation of the gold shell.

Objective. Inflammatory diseases often coincide with reduced bone mass. Mechanoresponsive osteocytes regulate bone mass by maintaining the balance between bone formation and resorption. Despite its biologic significance, the effect of inflammation on osteocyte mechanoresponsiveness is not understood. To fill this gap, we investigated whether the inflammatory cytokines tumor necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 beta) modulate the osteocyte response to mechanical loading. Methods. MLO-Y4 osteocytes were incubated with TNF alpha (0.5-30 ng/ml) or IL-1 beta (0.1-10 ng/ml) for 30 minutes or 24 hours, or with calcium inhibitors for 30 minutes. Cells were subjected to mechanical loading by pulsatile fluid flow (mean +/- amplitude 0.7 +/- 0.3 Pa, 5 Hz), and the response was quantified by measuring nitric oxide (NO) production using Griess reagent and by measuring intracellular calcium concentration ([Ca2+](i)) using Fluo-4/AM. Focal adhesions and filamentous actin (F-actin) were visualized by immunostaining, and apoptosis was quantified by measuring caspase 3/7 activity. Cell-generated tractions were quantified using traction force microscopy, and cytoskeletal stiffness was quantified using optical magnetic twisting cytometry. Results. Pulsatile fluid flow increased [Ca2+](i) within seconds (in 13% of cells) and NO production within 5 minutes (4.7-fold). TNF alpha and IL-1 beta inhibited these responses. Calcium inhibitors decreased pulsatile fluid flow-induced NO production. TNF alpha and IL-1 beta affected cytoskeletal stiffness, likely because 24 hours of incubation with TNF alpha and IL-1 beta decreased the amount of F-actin. Incubation with IL-1 beta for 24 hours stimulated osteocyte apoptosis. Conclusion. Our results suggest that TNF alpha and IL-1 beta inhibit mechanical loading-induced NO production by osteocytes via abrogation of pulsatile fluid flow-stimulated [Ca2+](i), and that IL-1 beta stimulates osteocyte apoptosis. Since both NO and osteocyte apoptosis affect osteoclasts, these findings provide a mechanism by which inflammatory cytokines might contribute to bone loss and consequently affect bone mass in rheumatoid arthritis.