Patients with classic fibrodysplasia ossificans progressiva, a disorder characterized by extensive extraskeletal endochondral bone formation, share a recurrent mutation (R206H) within the glycine/serine-rich domain of ACVR1/ALK2, a bone morphogenetic protein type I receptor. Through a series of in vitro assays using several mammalian cell lines and chick limb bud micromass cultures, we determined that mutant R206H ACVR1 activated BMP signaling in the absence of BMP ligand and mediated BMP-independent chondrogenesis that was enhanced by BMP. We further investigated the interaction of mutant R206H ACVR1 with FKBP1A, a glycine/serine domain-binding protein that prevents leaky BMP type I receptor activation in the absence of ligand. The mutant protein exhibited reduced binding to FKBP1A in COS-7 simian kidney cell line assays, suggesting that increased BMP pathway activity in COS-7 cells with R206H ACVR1 is due, at least in part, to decreased binding of this inhibitory factor. Consistent with these findings, in vivo analyses of zebrafish embryos showed BMP-independent hyperactivation of BMP signaling in response to the R206H mutant, resulting in increased embryonic ventralization. These data support the conclusion that the mutant R206H ACVR1 receptor in FOP patients is an activating mutation that induces BMP signaling in a BMP-independent and BMP-responsive manner to promote chondrogenesis, consistent with the ectopic endochondral bone formation in these patients. IntroductionFibrodysplasia ossificans progressiva (FOP; MIM 135100), a rare genetic disorder of progressive extraskeletal (heterotopic) ossification, is the most severe form of human heterotopic ossification known and results in profoundly decreased mobility of affected individuals (1). Patients with classic FOP have congenital malformation of the great toes and develop progressive heterotopic ossification within soft connective tissues in characteristic anatomic patterns (2, 3). Ectopic bone formation in FOP occurs through an endochondral pathway in which cartilage forms initially at the lesional site and is subsequently replaced by bone (4, 5). The genetic mutation in FOP is therefore a likely key regulator of cartilage and bone formation.The gene mutation for patients with the classic FOP clinical phenotype was mapped to chromosome 2q23-24, and mutations were identified in activin A receptor, type I (ACVR1; also known as ALK2), which encodes a bone morphogenetic protein (BMP) type I receptor (6). ACVR1 is expressed in several tissues, including cartilage and skeletal muscle, consistent with both the congenital skeletal malformations and the sites of postnatal endochondral het-

Bacterial communities associated with plant roots play an important role in the suppression of soil-borne pathogens, and multispecies probiotic consortia may enhance disease suppression efficacy. Here we introduced defined Pseudomonas species consortia into naturally complex microbial communities and measured the importance of Pseudomonas community diversity for their survival and the suppression of the bacterial plant pathogen Ralstonia solanacearum in the tomato rhizosphere microbiome. The survival of introduced Pseudomonas consortia increased with increasing diversity. Further, high Pseudomonas diversity reduced pathogen density in the rhizosphere and decreased the disease incidence due to both intensified resource competition and interference with the pathogen. These results provide novel mechanistic insights into elevated pathogen suppression by diverse probiotic consortia in naturally diverse plant rhizospheres. Ecologically based community assembly rules could thus play a key role in engineering functionally reliable microbiome applications.

Summary Plant roots exhibit diverse root functional traits to enable soil phosphorus (P) acquisition, including changes in root morphology, root exudation and mycorrhizal symbioses. Yet, whether these traits are differently coordinated among crop species to enhance P acquisition is unclear. Here, eight root functional traits for P acquisition were characterized in 16 major herbaceous crop species grown in a glasshouse under limiting and adequate soil P availability. We found substantial interspecific variation in root functional traits among species. Those with thinner roots showed more root branching and less first‐order root length, and had consistently lower colonization by arbuscular mycorrhizal fungi (AMF), fewer rhizosheath carboxylates and reduced acid phosphatase activity. In response to limiting soil P, species with thinner roots showed a stronger response in root branching, first‐order root length and specific root length of the whole root system, Conversely, species with thicker roots exhibited higher colonization by AMF and/or more P‐mobilizing exudates in the rhizosheath. We conclude that, at the species level, tradeoffs occur among the three groups of root functional traits we examined. Root diameter is a good predictor of the relative expression of these traits and how they change when P is limiting.

The causative virus of the COVID-19 pandemic, SARS-CoV-2, uses its nonstructural protein 1 (Nsp1) to suppress cellular, but not viral, protein synthesis through yet unknown mechanisms. We show here that among all viral proteins, Nsp1 has the largest impact on host viability in the cells of human lung origin. Differential expression analysis of mRNA-seq data revealed that Nsp1 broadly alters the cellular transcriptome. Our cryo-EM structure of the Nsp1-40S ribosome complex shows that Nsp1 inhibits translation by plugging the mRNA entry channel of the 40S. We also determined the structure of the 48S preinitiation complex formed by Nsp1, 40S, and the cricket paralysis virus internal ribosome entry site (IRES) RNA, which shows that it is nonfunctional because of the incorrect position of the mRNA 3′ region. Our results elucidate the mechanism of host translation inhibition by SARS-CoV-2 and advance understanding of the impacts from a major pathogenicity factor of SARS-CoV-2.

Osteopontin (OPN), a glycosylated phosphoprotein that binds calcium, is present in bone extracellular matrix and has been reported to modulate both mineralization and bone resorption. Osteopontin (OPN)2 is a sialic acid-rich glycosylated phosphoprotein, comprising about 2% of the noncollagenous protein in bone (1, 2). OPN is produced by osteoblasts when they form bone matrix (1, 2). OPN is an extracellular matrix protein that contains arginine-glycineaspartate (RGD) integrin binding motifs and promotes attachment of bone cells to the bone surface through binding to OPN receptors such as the ␣ v ␤ 3 integrin and CD44 (1-3). OPN has been suggested to be involved in the attachment of osteoclasts during bone resorption, to play a role in osteogenesis by attachment of osteoblasts when they form bone matrix, and to act to regulate crystal size during bone mineralization (2). In addition, OPN has been suggested to be a mediator of bone remodeling in response to mechanical strain (4). OPN null mice are resistant to mineral loss and bone resorption upon estrogen deprivation and have impaired activation of osteoclasts (3, 5-7). Also, vascularization and resorption of bone discs have been reported to be significantly impaired in the absence of OPN (8). Although recent studies using OPN null mice have provided new insight into the role of OPN in vivo in bone metabolism, the factors that affect the regulation of OPN are not yet clearly defined. 1,25-Dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), the active form of vitamin D, is a major calcitropic hormone involved in calcium homeostasis (9). One of its functions in bone is to regulate the synthesis of the bone calcium-binding proteins osteocalcin (OC) and OPN (9). 1,25(OH) 2 D 3 modulates the expression of these genes through transcriptional regulation. The actions of 1,25(OH) 2 D 3 are mediated through the vitamin D receptor (VDR). Liganded VDR heterodimerizes with the retinoid X receptor and interacts with a vitamin D response element (VDRE). The VDRE in the mouse OPN promoter (at Ϫ757/ Ϫ743) is a perfect direct repeat of the motif GGTTCA spaced by three nucleotides (10). Transcription proceeds through the interaction of VDR with coactivators and coregulators, including SRC-1/NcoA1, SRC-2/GRIP-1 (GR-interacting protein)/NcoA2, SRC-3/ACTR, and the multisubunit DRIP (vitamin D receptor-interacting protein) complex (11). Although a VDRE has been identified in the mouse OPN promoter (10) and VDR null mice show marked inhibition of OPN expression in osteoblasts (12), the exact mechanisms, including proteinprotein and protein-DNA interactions, involved in 1,25(OH) 2 D 3 -regulated OPN transcription are not well understood.Runx2/Cbfa1 is a member of the runt/Cbfa family of transcription factors that was first identified as an osteoblast-specific transcription factor and a regulator of osteoblast differentiation (13,14). Runx2 Ϫ/Ϫ mice die shortly after birth and show a complete lack of mineralized bone tissue (13,14). Marked decreases in the expression of osteopontin and osteocalcin ar...