Hypothesis test on a mixture forward-incubation-time epidemic model with application to COVID-19 outbreak

The distribution of the incubation period of the novel coronavirus disease that emerged in 2019 (COVID-19) has crucial clinical implications for understanding this disease and devising effective disease-control measures. Qin et al. (2020) designed a cross-sectional and forward follow-up study to collect the duration times between a specific observation time and the onset of COVID-19 symptoms for a number of individuals. They further proposed a mixture forward-incubation-time epidemic model, which is a mixture of an incubation-period distribution and a forward time distribution, to model the collected duration times and to estimate the incubation-period distribution of COVID-19. In this paper, we provide sufficient conditions for the identifiability of the unknown parameters in the mixture forward-incubation-time epidemic model when the incubation period follows a two-parameter distribution. Under the same setup, we propose a likelihood ratio test (LRT) for testing the null hypothesis that the mixture forward-incubation-time epidemic model is a homogeneous exponential distribution. The testing problem is non-regular because a nuisance parameter is present only under the alternative. We establish the limiting distribution of the LRT and identify an explicit representation for it. The limiting distribution of the LRT under a sequence of local alternatives is also obtained. Our simulation results indicate that the LRT has desirable type I errors and powers, and we analyze a COVID-19 outbreak dataset from China to illustrate the usefulness of the LRT.Comment: 34 pages, 2 figures, 2 table

Inactivation of Fam20C in Cells Expressing Type I Collagen Causes Periodontal Disease in Mice

FAM20C is a kinase that phosphorylates secretory proteins. Previous studies have shown that FAM20C plays an essential role in the formation and mineralization of bone, dentin and enamel. The present study analyzed the loss-of-function effects of FAM20C on the health of mouse periodontal tissues.By crossbreeding 2.3 kb Col 1a1-Cre mice with Fam20Cfl/fl mice, we created 2.3 kb Col 1a1-Cre;Fam20Cfl/fl (cKO) mice, in which Fam20C was inactivated in the cells that express Type I collagen. We analyzed the periodontal tissues in the cKO mice using X-ray radiography, histology, scanning electron microscopy and immunohistochemistry approaches.The cKO mice underwent a remarkable loss of alveolar bone and cementum, along with inflammation of the periodontal ligament and formation of periodontal pockets. The osteocytes and lacuno-canalicular networks in the alveolar bone of the cKO mice showed dramatic abnormalities. The levels of bone sialoprotein, osteopontin, dentin matrix protein 1 and dentin sialoprotein were reduced in the Fam20C-deficient alveolar bone and/or cementum, while periostin and fibrillin-1 were decreased in the periodontal ligament of the cKO mice.Loss of Fam20C function leads to periodontal disease in mice. The reduced levels of bone sialoprotein, osteopontin, dentin matrix protein 1, dentin sialoprotein, periostin and fibrillin-1 may contribute to the periodontal defects in the Fam20C-deficient mice

Water use strategies of Nitraria tangutorum in the lake-basin region of the Badain Jaran Desert

Information regarding plant water-use strategies is essential for understanding the hydrological processes and plant survival adaptation mechanisms in desert lake basin regions. To examine the water use strategies of plants in desert lake basin areas, water uptake patterns, water use efficiency, and water potential of Nitraria tangutorum were investigated at different distances from the lake duringhe growing seasons in the lake basin regions of the Badain Jaran Desert. The results indicate that N. tangutorum primarily absorbed groundwater in May (63.8%) and August (53.5%), relied on deep soil water in June (75.1%), and uniformly absorbed soil water from different layers in July. These observations could be explained by periodic fluctuations in the groundwater level and the consequent decrease in soil water availability, as well as plant root adjustments. As soil water availability decreases, N. tangutorum adapts to water variation by increasing its water use efficiency (WUE) and reducing its leaf water potential (Ψ). With intensified water stress, N. tangutorum gradually shifted from adventurous anisohydric regulation to conservative isohydric regulation. Thus, N. tangutorum responds to diverse degrees of environmental changes by altering its water-use strategy. A better understanding of the adaptive water use strategies developed by desert plants under varying water availability conditions provides insight into the diversity of species’ reactions to long-term drought and quantifies the hydrological cycle of desert ecosystems against the background of worldwide climate warming

Distinct mechanisms define murine B cell lineage immunoglobulin heavy chain (IgH) repertoires

Processes that define immunoglobulin repertoires are commonly presumed to be the same for all murine B cells. However, studies here that couple high-dimensional FACS sorting with large-scale quantitative IgH deep-sequencing demonstrate that B-1a IgH repertoire differs dramatically from the follicular and marginal zone B cells repertoires and is defined by distinct mechanisms. We track B-1a cells from their early appearance in neonatal spleen to their long-term residence in adult peritoneum and spleen. We show that de novo B-1a IgH rearrangement mainly occurs during the first few weeks of life, after which their repertoire continues to evolve profoundly, including convergent selection of certain V(D)J rearrangements encoding specific CDR3 peptides in all adults and progressive introduction of hypermutation and class-switching as animals age. This V(D)J selection and AID-mediated diversification operate comparably in germ-free and conventional mice, indicating these unique B-1a repertoire-defining mechanisms are driven by antigens that are not derived from microbiota

Specific ablation of mouse Fam20C in cells expressing type I collagen leads to skeletal defects and hypophosphatemia

AbstractFAM20C mutations in humans cause Raine syndrome and our previous studies showed that global inactivation of mouse Fam20C led to bone and dental defects. By crossbreeding 2.3  kb Col 1a1-Cre mice with Fam20C flox/flox mice, we created 2.3  kb Col 1a1-Cre;Fam20C foxl/flox (cKO) mice, in which Fam20C was inactivated in cells expressing Type I collagen. This study showed that the long bones of cKO mice were shorter and had a lower level of mineralization compared to the normal mice. The collagen fibrils in Fam20C-deficient bone were disorganized and thicker while the growth plate cartilage in cKO mice was disorganized and wider compared to the normal mice. The Fam20C-deficient bone had a lower level of dentin matrix protein 1, and higher levels of osteopontin and bone sialoprotein than the normal. The blood of cKO mice had an elevated level of fibroblast growth factor 23 and reduced level of phosphorus. These findings indicate that inactivation of Fam20C in cells expressing type I collagen led to skeletal defects and hypophosphatemia. The altered levels of dentin matrix protein 1 and osteopontin in Fam20C-deficient bone may be significant contributors to the mineralized tissue defects in human patients and animals suffering from the functional loss of FAM20C.</jats:p

Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression

Amelogenesis Imperfecta (AI) can be caused by the deficiencies of enamel matrix proteins, molecules responsible for the transportation and secretion of enamel matrix components, and proteases processing enamel matrix proteins. In the present study, we discovered the double deletion of bone morphogenetic protein 2 (Bmp2) and bone morphogenetic protein 4 (Bmp4) in the dental epithelium by K14-cre resulted in hypoplastic enamel and reduced density in X-ray radiography as well as shortened enamel rods under scanning electron microscopy. Such enamel phenotype was consistent with the diagnosis of hypoplastic amelogenesis imperfecta. Histological and molecular analyses revealed that the removal of matrix proteins in the mutant enamel was drastically delayed, which was coincided with the greatly reduced expression of matrix metalloproteinase 20 (MMP20) and kallikrein 4 (KLK4). Although the expression of multiple enamel matrix proteins was down-regulated in the mutant ameloblasts, the cleavage of ameloblastin was drastically impaired. Therefore, we attributed the AI primarily to the reduction of MMP20 and KLK4. Further investigation found that BMP/Smad4 signaling pathway was down-regulated in the K14-cre;Bmp2(f/f);Bmp4(f/f)ameloblasts, suggesting that the reduced MMP20 and KLK4 expression may be due to the attenuated epithelial BMP/Smad4 signaling

Inactivation of a Novel FGF23 Regulator, FAM20C, Leads to Hypophosphatemic Rickets in Mice

Family with sequence similarity 20,-member C (FAM20C) is highly expressed in the mineralized tissues of mammals. Genetic studies showed that the loss-of-function mutations in FAM20C were associated with human lethal osteosclerotic bone dysplasia (Raine Syndrome), implying an inhibitory role of this molecule in bone formation. However, in vitro gain- and loss-of-function studies suggested that FAM20C promotes the differentiation and mineralization of mouse mesenchymal cells and odontoblasts. Recently, we generated Fam20c conditional knockout (cKO) mice in which Fam20c was globally inactivated (by crossbreeding with Sox2-Cre mice) or inactivated specifically in the mineralized tissues (by crossbreeding with 3.6 kb Col 1a1-Cre mice). Fam20c transgenic mice were also generated and crossbred with Fam20c cKO mice to introduce the transgene in the knockout background. In vitro gain- and loss-of-function were examined by adding recombinant FAM20C to MC3T3-E1 cells and by lentiviral shRNA–mediated knockdown of FAM20C in human and mouse osteogenic cell lines. Surprisingly, both the global and mineralized tissue-specific cKO mice developed hypophosphatemic rickets (but not osteosclerosis), along with a significant downregulation of osteoblast differentiation markers and a dramatic elevation of fibroblast growth factor 23 (FGF23) in the serum and bone. The mice expressing the Fam20c transgene in the wild-type background showed no abnormalities, while the expression of the Fam20c transgene fully rescued the skeletal defects in the cKO mice. Recombinant FAM20C promoted the differentiation and mineralization of MC3T3-E1 cells. Knockdown of FAM20C led to a remarkable downregulation of DMP1, along with a significant upregulation of FGF23 in both human and mouse osteogenic cell lines. These results indicate that FAM20C is a bone formation “promoter” but not an “inhibitor” in mouse osteogenesis. We conclude that FAM20C may regulate osteogenesis through its direct role in facilitating osteoblast differentiation and its systemic regulation of phosphate homeostasis via the mediation of FGF23

Inactivation of Fam20B in Joint Cartilage Leads to Chondrosarcoma and Postnatal Ossification Defects

During endochondral ossification, chondrocytes embed themselves in a proteoglycan-rich matrix during the proliferation-maturation transition. Accumulating evidence shows that proteoglycans are essential components for chondrocyte proliferation and differentiation. When we conditionally inactivated FAM20B (Family with sequence similarity 20 member-B), which is a newly identified xylose kinase essential for glycosaminoglycan (GAG) formation on the protein core of proteoglycans, from the dental mesenchyme using Osr2-Cre, which is also strongly expressed in joint cartilage, we found chondrosarcoma in the knee joint and remarkable defects of postnatal ossification in the long bones. Mechanistic analysis revealed that the defects were associated with gain of function in multiple signaling pathways in the epiphyseal chondrocytes, such as those derived by WNT, BMP, and PTHrP/IHH molecules, suggesting that the FAM20B-catalyzed proteoglycans are critical mediators for a signaling balance in the regulatory network controlling chondrocyte differentiation and proliferation. In particular, we demonstrated that the WNT inhibitor was able to rescue part of the bone defects in Osr2-Cre;Fam20B(fl/fl) mice, indicating that FAM20B-catalyzed proteoglycans regulate postnatal endochondral ossification partially through the mediation of WNT signaling