alpha-klotho was identified as a gene associated with premature aging-like phenotypes characterized by short lifespan. In mice, we found the molecular association of alpha-Klotho (alpha-Kl) and Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) and provide evidence for an increase of abundance of Na+,K+-ATPase at the plasma membrane. Low concentrations of extracellular free calcium ([Ca2+]e) rapidly induce regulated parathyroid hormone (PTH) secretion in an alpha-Kl- and Na+,K+-ATPase-dependent manner. The increased Na+ gradient created by Na+,K+-ATPase activity might drive the transepithelial transport of Ca2+ in cooperation with ion channels and transporters in the choroid plexus and the kidney. Our findings reveal fundamental roles of alpha-Kl in the regulation of calcium metabolism.

IgA regulates the composition and function of gut microbiota. Nakajima et al. show that a heavily glycosylated monoclonal IgA coats B. theta and induces Mucus-Associated Functional Factor in vivo to enhance symbiotic interactions with commensal bacteria to maintain gut homeostasis.

Oxidative stresses such as UV irradiation to mammalian cells triggers a variety of oxistress responses including activation of transcription factors. Recently, activation of nuclear factor-B (NF-B) has been shown to be under oxidoreduction (redox) regulation controlled by thioredoxin (TRX), which is one of major endogenous redox-regulating molecules with thiol reducing activity. In order to elucidate where in the cellular compartment TRX participates in NF-B regulation, we investigated the intracellular localization of TRX. UVB irradiation induced translocation of TRX from the cytoplasm into the nucleus. In our in vitro diamide-induced cross-linking study, we showed that TRX can associate directly with NF-B p50. Overexpression of wild-type TRX suppressed induction of luciferase activity under NF-Bbinding sites in response to UV irradiation compared with the mock transfectant. In contrast, overexpression of nuclear-targeted TRX enhanced the luciferase activity. Thus, TRX seems to play dual and opposing roles in the regulation of NF-B. In the cytoplasm, it interferes with the signals to IB kinases and blocks the degradation of IB. In the nucleus, however, TRX enhances NF-B transcriptional activities by enhancing its ability to bind DNA. This two-step TRX-dependent regulation of the NF-B complex may be a novel activation mechanism of redox-sensitive transcription factors.

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Reconstruction of a severed mammalian spinal cord with restoration of function has so far not been achieved, although structural and functional restitution after spinal transection has been successful in some lower vertebrates. In quail-chick and chick-chick chimaeras, spinal cord segments were found to be functional after replacement by isotopic and isochronic grafting of the neural tube. Here we achieve such a replacement in neonatal rats under less restricted topological and temporal conditions than were necessary for the avian chimaeras. The replaced segments united with the host spinal cord and promoted robust growth and regrowth of axons across the graft, enabling neural connections to be reconstructed that were hardly distinguishable from normal. The animals with replaced segments could walk, run and climb with almost normal hind-forelimb coordination. This functional restoration in these animals appeared to be permanent, raising the possibility of therapeutic application in humans.