The ARF Tumor Suppressor Regulates Bone Remodeling and Osteosarcoma Development in Mice

The ARF tumor suppressor regulates p53 as well as basic developmental processes independent of p53, including osteoclast activation, by controlling ribosomal biogenesis. Here we provide evidence that ARF is a master regulator of bone remodeling and osteosarcoma (OS) development in mice. Arf-/- mice displayed increased osteoblast (OB) and osteoclast (OC) activity with a significant net increase in trabecular bone volume. The long bones of Arf-/- mice had increased expression of OB genes while Arf-/- OB showed enhanced differentiation in vitro. Mice transgenic for the Tax oncogene develop lymphocytic tumors with associated osteolytic lesions, while Tax+Arf-/- mice uniformly developed spontaneous OS by 7 months of age. Tax+Arf-/- tumors were well differentiated OS characterized by an abundance of new bone with OC recruitment, expressed OB markers and displayed intact levels of p53 mRNA and reduced Rb transcript levels. Cell lines established from OS recapitulated characteristics of the primary tumor, including the expression of mature OB markers and ability to form mineralized tumors when transplanted. Loss of heterozygosity in OS tumors arising in Tax+Arf+/- mice emphasized the necessity of ARF-loss in OS development. Hypothesizing that inhibition of ARF-regulated bone remodeling would repress development of OS, we demonstrated that treatment of Tax+Arf-/- mice with zoledronic acid, a bisphosphonate inhibitor of OC activity and repressor of bone turnover, prevented or delayed the onset of OS. These data describe a novel role for ARF as a regulator of bone remodeling through effects on both OB and OC. Finally, these data underscore the potential of targeting bone remodeling as adjuvant therapy or in patients with genetic predispositions to prevent the development of OS

Intestinal antiviral signaling is controlled by autophagy gene Epg5 independent of the microbiota

Mutations in the macroautophagy/autophagy gen

The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling

The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12(–/–) OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12(–/–), OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent α(IIb)β(3) integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β(3) gene knockout (Itgb3(–/–)) OCs, but its effects were substantially blunted in P2ry12(–/–) OCs. In vivo, P2ry12(–/–) mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss

Characterization of <i>Pseudomonas</i> sp. En3, an Endophytic Bacterium from Poplar Leaf Endosphere with Plant Growth-Promoting Properties

Growth-promoting endophytic bacteria possess substantial potential for sustainable agriculture. Here, we isolated an endophytic bacterium, Pseudomonas sp. En3, from the leaf endosphere of Populus tomentosa and demonstrated its significant growth-promoting effects on both poplar and tomato seedlings. The phosphorus solubilization and nitrogen fixation abilities of strain En3 were confirmed via growth experiments on NBRIP and Ashby media, respectively. Salkowski staining and HPLC-MS/MS confirmed that En3 generated indole-3-acetic acid (IAA). The infiltration of En3 into leaf tissues of multiple plants did not induce discernible disease symptoms, and a successful replication of En3 was observed in both poplar and tobacco leaves. Combining Illumina and Nanopore sequencing data, we elucidated that En3 possesses a circular chromosome of 5.35 Mb, exhibiting an average G + C content of 60.45%. The multi-locus sequence analysis (MLSA) and genome average nucleotide identity (ANI) supported that En3 is a novel species of Pseudomonas and constitutes a distinct phylogenetic branch with P. rhizosphaerae and P. coleopterorum. En3 genome annotation analysis revealed the presence of genes associated with nitrogen fixation, phosphate solubilization, sulfur metabolism, siderophore biosynthesis, synthesis of IAA, and ethylene and salicylic acid modulation. The findings suggest that Pseudomonas sp. En3 exhibits significant potential as a biofertilizer for crop and tree cultivation

Polarization-sensitive optical Tamm state and its application in polarization-sensitive absorption

In conventional heterostructures consisting of metal layers and all-dielectric one-dimensional (1-D) photonic crystals (PCs), optical Tamm states (OTSs) shift toward shorter wavelengths (i.e., blueshift) as the incident angle increases for both transverse magnetic (TM) and transverse electric (TE) polarizations. Such celebrated polarization-insensitive characteristic of OTSs poses a great challenge in achieving polarization-sensitive absorption. Herein, we realize an anomalous OTS with polarization-sensitive characteristic in a heterostructure consisting of a metal layer and a 1-D PC containing hyperbolic metamaterials. As the incident angle increases, the designed OTS is redshifted for TM polarization while is blueshifted for TE polarization. The polarization-sensitive characteristic of the OTS can be explained by the phase analysis. Assisted by the designed OTS, polarization-sensitive absorption can be achieved. Our work provides a platform to engineer the angle-dependence of OTSs and would promote the development of absorption-based applications.Published versionThis work was supported by the National Natural Science Foundation of China (Grant Nos. 12104105, 61805064, 12104169 and 12104104), the Natural Science Foundation of Guangdong Province (Grant Nos. 2021A1515010050 and 2019A1515011499), the Guangdong Province University Youth Innovative Talents Program of China (Grant No. 2019KQNCX070), the Department of Education of Guangdong Province (Grant No. 2019KTSCX087), and the Start-up Funding of Guangdong Polytechnic Normal University (Grant No. 2021SDYKA033)

Significant Enhancement of Thermal Conductivity in Polymer Composite via Constructing Macroscopic Segregated Filler Networks

The low efficiency of thermal conductive filler is an unresolved issue in the area of thermal conductive polymer composites. Although it is known that minimizing phonon or electron interfacial scattering is the key for achieving high thermal conductivity, the enhancement is generally limited by preparation methods that can yield the ideal morphology and interfaces. Herein, low temperature expandable graphite (LTEG) is added into a commercial impact modifier (Elvaloy4170), which is then coated onto poly­(butylene terephthalate) (PBT) particles with various sizes at millimeter scale between their melting temperatures. Thus, macroscopic segregated filler networks with several considerations are constructed: high LTEG loading leads to a short distance between fillers and a robust filler network; continuous Elvaloy-LTEG phase leads to a continuous filler network; and good interaction among filler and matrix leads to good interfacial interaction. More importantly, the rather large size of PBT particles provides the filler networks with low specific interfacial area, which minimizes the interfacial scattering of phonons or electrons. Relative to homogeneous composites with an identical composition, the thermal conductivity is enhanced from 6.2 to 17.8 W/mK. Such an enhancement span is the highest compared with results reported in the literature. Due to possible “shortcut” behavior, much higher effectiveness can be achieved for the current system than found in literature results when the Elvaloy-LTEG phase is considered as filler, with the effectiveness even exceeding the upper limit of theoretical calculation for highly loaded Elvaloy-LTEG phase with relatively large PBT particle sizes. This could provide some guidelines for the fabrication of highly thermal conductive polymer composites as well as multifunctional polymer composites