Formation of proper neuromuscular connections is a process coordinated by both motoneuron-intrinsic and target-dependent programs. Under these programs, motoneurons innervate target muscles, escape programmed cell death during fetal development, and form neuromuscular junctions (NMJ). Although a number of studies have revealed molecules involved in axon guidance to target muscles and NMJ formation, little is known about the molecular mechanisms linking intramuscular innervation and target-derived trophic factordependent prevention of motoneuron apoptosis. Here we studied the physiological function of CLAC-P/collagen XXV, a transmembranetype collagen originally identified as a component of senile plaque amyloid of Alzheimer's disease brains, by means of generating Col25a1-deficient (KO) mice. Col25a1 KO mice died immediately after birth of respiratory failure. In Col25a1 KO mice, motor axons projected properly toward the target muscles but failed to elongate and branch within the muscle, followed by degeneration of axons. Failure of muscular innervation in Col25a1 KO mice led to excessive apoptosis during development, resulting in almost complete and exclusive loss of spinal motoneurons and immaturity in skeletal muscle development. Bax deletion in Col25a1 KO mice rescued motoneurons from apoptosis, although motor axons remained halted around the muscle entry site. Furthermore, these motoneurons were positive for phosphorylated c-Jun, an indicator of insufficient supply of target-derived survival signals. Together, these observations indicate that CLAC-P/collagen XXV is a novel essential factor that regulates the initial phase of intramuscular motor innervation, which is required for subsequent target-dependent motoneuron survival and NMJ formation during development.

Many flowering plants exhibit self-incompatibility (SI) to prevent inbreeding and promote outcrossing. This self/non-self discrimination mechanism is controlled by the S locus, which contains separate genes for pistil and pollen specificities. In the gametophytic SI (GSI) of Rosaceae, Solanaceae and Plantaginaceae, the pistil S determinant, S-RNase, encodes extracellular ribonuclease which is thought to act as a cytotoxin to the self pollen tube, while the pollen S determinant is the F-box gene called SLF/SFB/SFBB. In Petunia (Solanaceae), SLF is reported to be a component of the noncanonical E3 ubiquitin ligase complex with S-RNase binding protein1 (SBP1) and Cullin1 (CUL1), and interact with non-self S-RNases to ubiquitinate them for degradation. Here, we isolated an apple (Malus×domestica) homolog of SBP1 (MdSBP1) from pollen RNA by RT-PCR. MdSBP1 included a RING-HC domain required for E3 ubiquitin ligase activity, and showed 64.0-68.2% amino acid identities with solanaceous SBP1 proteins. Expression analysis showed that MdSBP1 was expressed in all the organs analyzed. We detected an interaction between recombinant MdSBP1 protein and S-RNase of apple using a pull-down assay.Key words: Self-incompatibility, S-RNase binding protein, pollen, apple, Rosaceae.Self-incompatibility (SI) is a mechanism adopted by many flowering plants to prevent inbreeding and promote outcrossing. The S-RNase-based gametophytic self-incompatibility (GSI) of Rosaceae, Solanaceae and Plantaginaceae is controlled by a single multiallelic S locus which contains separate genes for pistil and pollen specificities. When the S haplotype of a pollen matches one of the two S haplotypes of the diploid pistil, the pollen is recognized as self and rejected (de et al. 1986;McClure et al. 1989;Sassa et al. 1996Sassa et al. , 1997Tao et al. 1997;Xue et al. 1996) which is thought to be taken up by pollen tubes and act as a cytotoxin to self pollen (Goldraij et al. 2006;Luu et al. 2000). In Petunia of Solanaceae and species of Rosaceae tribe Pyreae, i.e., apples (Malus×domestica) and pears (Pyrus spp.), multiple F-box genes SLFs/SFBBs are implicated in pollen-part specificity (De Franceschi et al. 2011;Kubo et al. 2010;Kakui et al. 2011;Minamikawa et al. 2010;Saito et al. 2012;Sassa et al. 2007).SLF has been predicted to act as a component of the E3 ubiquitin ligase complex and interact with non-self S-RNases to ubiquitinate them for degradation (Huang et al. 2006;Qiao et al. 2004aQiao et al. , 2004bSijacic et al. 2004). Canonical E3 complex comprises Skp1, Cullin1, F-box protein and Rbx1 (Cardozo and Pagano 2004). In Petunia inflata, however, SLF-containing E3 ubiquitin ligase is reported to be a noncanonical SCF-like complex which includes S-RNase binding protein1 ( Abbreviations: GSI, Gametophytic self-incompatibility; RNase, ribonuclease; SBP1, S-RNase binding protein1; MBP, maltose binding protein.† These authors contributed equally to this work. This article can be found at

We build a tractable SIR-macro-model with time-varying parameters and use it to explore various policy questions such as when to lift the state of emergency (SOE). An earlier departure from the SOE results in smaller output loss and more deaths in the short run. However, if the SOE is lifted too early, the number of new cases will surge and another SOE may need to be issued in the future, possibly resulting in both larger output loss and more deaths. That is, the tradeoff between output and infection that exists in the short run does not necessarily exist in the long run. Our model-based analysis—updated weekly since January 2021, frequently reported by media, and presented to policymakers on many occasions—has played a unique role in the policy response to the COVID-19 crisis in Japan.