Murine IRF8 Mutation Offers New Insight into Osteoclast and Root Resorption.

Interferon regulatory factor 8 (IRF8), a transcription factor expressed in immune cells, functions as a negative regulator of osteoclasts and helps maintain dental and skeletal homeostasis. Previously, we reported that a novel mutation in the IRF8 gene increases susceptibility to multiple idiopathic cervical root resorption (MICRR), a form of tooth root resorption mediated by increased osteoclast activity. The IRF8 G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. To investigate the molecular basis of MICRR and IRF8 function in osteoclastogenesis, we generated Irf8 knock-in (KI) mice using CRISPR/Cas9 technique modeling the human IRF8G388S mutation. The heterozygous (Het) and homozygous (Homo) Irf8 KI mice showed no gross morphological defects, and the development of hematopoietic cells was unaffected and similar to wild-type (WT) mice. The Irf8 KI Het and Homo mice showed no difference in macrophage gene signatures important for antimicrobial defenses and inflammatory cytokine production. Consistent with the phenotype observed in MICRR patients, Irf8 KI Het and Homo mice demonstrated significantly increased osteoclast formation and resorption activity in vivo and in vitro when compared to WT mice. The oral ligature-inserted Het and Homo mice displayed significantly increased root resorption and osteoclast-mediated alveolar bone loss compared to WT mice. The increased osteoclastogenesis noted in KI mice is due to the inability of IRF8G388S mutation to inhibit NFATc1-dependent transcriptional activation and downstream osteoclast specific transcripts, as well as its impact on autophagy-related pathways of osteoclast differentiation. This translational study delineates the IRF8 domain important for osteoclast function and provides novel insights into the IRF8 mutation associated with MICRR. IRF8G388S mutation mainly affects osteoclastogenesis while sparing immune cell development and function. These insights extend beyond oral health and significantly advance our understanding of skeletal disorders mediated by increased osteoclast activity and IRF8's role in osteoclastogenesis.

Phylogenetic relationships of living and recently extinct bandicoots based on nuclear and mitochondrial DNA sequences.

Bandicoots (Peramelemorphia) are a major order of australidelphian marsupials, which despite a fossil record spanning at least the past 25 million years and a pandemic Australasian range, remain poorly understood in terms of their evolutionary relationships. Many living peramelemorphians are critically endangered, making this group an important focus for biological and conservation research. To establish a phylogenetic framework for the group, we compiled a concatenated alignment of nuclear and mitochondrial DNA sequences, comprising representatives of most living and recently extinct species. Our analysis confirmed the currently recognised deep split between Macrotis (Thylacomyidae), Chaeropus (Chaeropodidae) and all other living bandicoots (Peramelidae). The mainly New Guinean rainforest peramelids were returned as the sister clade of Australian dry-country species. The wholly New Guinean Peroryctinae was sister to Echymiperinae. The poorly known and perhaps recently extinct Seram Bandicoot (Rhynchomeles) is sister to Echymipera. Estimates of divergence times from relaxed-clock Bayesian methods suggest that living bandicoots originated in the late Oligocene or early Miocene, much earlier than currently thought based on fossils. Subsequent radiations within Peramelemorphia probably took place on the Australian mainland during the Miocene, with diversification of rainforest taxa on the newly emergent New Guinean landmasses through the middle-late Miocene and complete establishment of modern lineages by the early Pliocene.

Aircraft gas turbine materials and processes.

Materials and processing innovations that have been incorporated into the manufacture of critical components for high-performance aircraft gas turbine engines are described. The materials of interest are the nickel- and cobalt-base superalloys for turbine and burner sections of the engine, and titanium alloys and composites for compressor and fan sections of the engine. Advanced processing methods considered include directional solidification, hot isostatic pressing, superplastic foring, directional recrystallization, and diffusion brazing. Future trends in gas turbine technology are discussed in terms of materials availability, substitution, and further advances in air-cooled hardware.