Search

Adiponectin (AdipoQ), a hormone abundantly secreted by adipose tissues, has multiple beneficial functions, including insulin sensitization as well as lipid and glucose metabolism. It has been reported that bone controls energy metabolism through an endocrine-based mechanism. In this study, we observed that bone also acts as an important endocrine source for AdipoQ, and its capacity in osteoblasts is controlled by the forkhead box P1 (FOXP1) transcriptional factor. Deletion of the Foxp1 gene in osteoblasts led to augmentation of AdipoQ levels accompanied by fueled energy expenditure in adipose tissues. In contrast, overexpression of Foxp1 in bones impaired AdipoQ secretion and restrained energy consumption. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis revealed that AdipoQ expression, which increases as a function of bone age, is directly controlled by FOXP1. Our results indicate that bones, especially aged bones, provide an important source of a set of endocrine factors, including AdipoQ, that control body metabolism. © 2021 American Society for Bone and Mineral Research (ASBMR).

Kiwifruit is loved by consumers for its unique taste and rich vitamin C content. Kiwifruit are very sensitive to adverse soil environments owing to fleshy and shallow roots, which limits the uptake of water and nutrients into the root system, resulting in low yield and poor fruit quality. Lateral roots are the key organs for plants to absorb water and nutrients. Improving water and fertilizer use efficiency by promoting lateral root development is a feasible method to improve yield and quality. Expansin proteins plays a major role in lateral root growth; hence, it is important to identify expansin protein family members, screen key genes, and explore gene function in root development. In this study, 41 expansin genes were identified based on the genome of kiwifruit (‘Hongyang’, Actinidia chinensis). By clustering with the Arabidopsis thaliana expansin protein family, the 41 AcExpansin proteins were divided into four subfamilies. The AcExpansin protein family was further analysed by bioinformatics methods and was shown to be evolutionarily diverse and conserved at the DNA and protein levels. Based on previous transcriptome data and quantitative real-time PCR assays, we screened the candidate gene AcEXPA23. Overexpression of AcEXPA23 in kiwifruit increased the number of kiwifruit lateral roots.

Kiwifruit is loved by consumers for its unique taste and rich vitamin C content. Kiwifruit are very sensitive to adverse soil environments owing to fleshy and shallow roots, which limits the uptake of water and nutrients into the root system, resulting in low yield and poor fruit quality. Lateral roots are the key organs for plants to absorb water and nutrients. Improving water and fertilizer use efficiency by promoting lateral root development is a feasible method to improve yield and quality. Expansin proteins plays a major role in lateral root growth; hence, it is important to identify expansin protein family members, screen key genes, and explore gene function in root development. In this study, 41 expansin genes were identified based on the genome of kiwifruit ('Hongyang'

Quiescent hair follicle stem cells (HFSCs) reside in specialized bulge niche where they undergo activation and differentiation upon sensing niche-dependent signals during hair follicle (HF) homeostasis and wound repair. The underlying mechanism of HFSCs and bulge niche maintenance is poorly understood. Our previous study has reported that a transcription factor, forkhead box P1 (Foxp1), functions to maintain the quiescence of HFSCs. Here, we further discovered that forkhead box P4 (Foxp4), a close family member of Foxp1, had similar expression profiles in various components of HFs and formed a complex with Foxp1 in vitro and in vivo. The HF-specific deficiency of Foxp4 resulted in the precocious activation of HFSCs during hair cycles. In contrast to single Foxp1 or Foxp4 conditional knockout (cKO) mice, Foxp1/4 double cKO exerted an additive effect in the spectrum and severity of phenotypes in HFSC activation, hair cycling acceleration and hair loss, coupled with remarkable downregulation of fibroblast growth factor 18 (Fgf18) and bone morphogenetic protein 6 (Bmp6) expression in bulge cells. In addition, the double KO of Foxp1/4 induced the apoptosis of K6-positive (K6+) inner bulge cells, a well-established stem cell (SC) niche, thus resulting in the destruction of the bulge SC niche and recurrent hair loss. Our investigation reveals the synergistic role of Foxp1/4 in sustaining K6+ niche cells for the quiescence of HFSCs.

β-Adrenergic receptor (β-AR) signaling is a pathway controlling adaptive thermogenesis in brown or beige adipocytes. Here we investigate the biological roles of the transcription factor Foxp1 in brown/beige adipocyte differentiation and thermogenesis. Adipose-specific deletion of Foxp1 leads to an increase of brown adipose activity and browning program of white adipose tissues. The Foxp1-deficient mice show an augmented energy expenditure and are protected from diet-induced obesity and insulin resistance. Consistently, overexpression of Foxp1 in adipocytes impairs adaptive thermogenesis and promotes diet-induced obesity. A robust change in abundance of the β3-adrenergic receptor (β3-AR) is observed in brown/beige adipocytes from both lines of mice. Molecularly, Foxp1 directly represses β3-AR transcription and regulates its desensitization behavior. Taken together, our findings reveal Foxp1 as a master transcriptional repressor of brown/beige adipocyte differentiation and thermogenesis, and provide an important clue for its targeting and treatment of obesity., Beta3-adrenergic receptor (b3-AR) signaling in response to cold activates adipose tissue thermogenesis. Here the authors identify the transcription factor FoxP1 as a direct negative regulator of b3-AR expression and show that loss of FoxP1 leads to enhanced development of thermogenic adipose tissue.

Hair follicle dermal sheath (DS) harbors hair follicle dermal stem cells (hfDSCs), which can be recruited to replenish DS and dermal papilla (DP). Cultured DS cells can differentiate into various cell lineages in vitro. However, it is unclear how its plasticity is modulated in vivo. Wnt/β-catenin signaling plays an important role in maintaining stem cells of various lineages and is required for HF development and regeneration. Here we report that activation of β-catenin in DS generates ectopic HF outgrowth (EF) by reprogramming HF epidermal cells and DS cells themselves, and endows DS cells with hair inducing ability. Epidermal homeostasis of pre-existing HFs is disrupted. Additionally, cell-autonomous progressive skin fibrosis is prominent in dermis, where the excessive fibroblasts largely originate from DS. Gene expression analysis of purified DS cells with activated β-catenin revealed significantly increased expression of Bmp, Fgf, and Notch ligands and administration of Bmp, Fgf, or Notch signaling inhibitor attenuates EF formation. In summary, our findings advance the current knowledge of high plasticity of DS cells and provide an insight into understanding how Wnt/β-catenin signaling controls DS cell behaviors.

Obesity is one of the main risk factors for type II diabetes and cardiovascular diseases, while Wnt signaling is one of the important signaling pathways implicated in multiple cellular differentiation and developmental processes. Here, we first describe adipose tissue formation, regulators for adipogenic differentiation, and the canonical and non-canonical Wnt signaling pathways. We then review the impact of Wnt signaling on adipose tissue formation as well as mitochondrial metabolism and inflammation, which are involved in obesity and diabetes development.

A hallmark of aged mesenchymal stem/progenitor cells (MSCs) in bone marrow is the pivot of differentiation potency from osteoblast to adipocyte coupled with a decrease in self-renewal capacity. However, how these cellular events are orchestrated in the aging progress is not fully understood. In this study, we have used molecular and genetic approaches to investigate the role of forkhead box P1 (FOXP1) in transcriptional control of MSC senescence. In bone marrow MSCs, FOXP1 expression levels declined with age in an inverse manner with those of the senescence marker p16INK4A. Conditional depletion of Foxp1 in bone marrow MSCs led to premature aging characteristics, including increased bone marrow adiposity, decreased bone mass, and impaired MSC self-renewal capacity in mice. At the molecular level, FOXP1 regulated cell-fate choice of MSCs through interactions with the CEBPβ/δ complex and recombination signal binding protein for immunoglobulin κ J region (RBPjκ), key modulators of adipogenesis and osteogenesis, respectively. Loss of p16INK4A in Foxp1-deficient MSCs partially rescued the defects in replication capacity and bone mass accrual. Promoter occupancy analyses revealed that FOXP1 directly represses transcription of p16INK4A. These results indicate that FOXP1 attenuates MSC senescence by orchestrating their cell-fate switch while maintaining their replicative capacity in a dose- and age-dependent manner.

Summary Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are capable of differentiating into osteoblasts, chondrocytes, and adipocytes. Skewed differentiation of BM-MSCs contributes to the pathogenesis of osteoporosis. Yet how BM-MSC lineage commitment is regulated remains unclear. We show that ablation of p38α in Prx1+ BM-MSCs produced osteoporotic phenotypes, growth plate defects, and increased bone marrow fat, secondary to biased BM-MSC differentiation from osteoblast/chondrocyte to adipocyte and increased osteoclastogenesis and bone resorption. p38α regulates BM-MSC osteogenic commitment through TAK1-NF-κB signaling and osteoclastogenesis through osteoprotegerin (OPG) production by BM-MSCs. Estrogen activates p38α to maintain OPG expression in BM-MSCs to preserve the bone. Ablation of p38α in BM-MSCs positive for Dermo1, a later BM-MSC marker, only affected osteogenic differentiation. Thus, p38α mitogen-activated protein kinase (MAPK) in Prx1+ BM-MSCs acts to preserve the bone by promoting osteogenic lineage commitment and sustaining OPG production. This study thus unravels previously unidentified roles for p38α MAPK in skeletal development and bone remodeling., Highlights • p38α deletion in Prx1+ BM-MSCs led to osteoporosis and cartilage anomaly • p38α controls proliferation and tri-lineage differentiation of Prx1+ BM-MSCs • p38α regulates osteoclastogenesis through OPG production by BM-MSCs • The BM-MSC p38-OPG axis participates in estrogen deficiency-induced osteoporosis, In this article, Li, Liu, and colleagues reveal that p38α MAPK regulates Prx1+BM-MSC cell fate decision. p38α is required for proper BM-MSC osteogenic commitment, via the TAK1-NF-κB pathway, to maintain proper bone formation, and for OPG synthesis by BM-MSCs to constrain osteoclastogenesis and bone resorption. Moreover, estrogen appears to go through the p38-OPG pathway to preserve the bone.

Aims WD40 repeat and FYVE domain containing 3 (WDFY3) is an adaptor protein involved in selective degradation of protein aggregates by autophagy. Recent studies have revealed that Wdfy3 is critical in the regulation of brain development and osteoclastogenesis in vivo. However, the function of Wdfy3 in cardiac development remains completely unknown. In this study, we explore the role of Wdfy3 in cardiac morphogenesis using Wdfy3-deficient mice. Methods and results Wdfy3 was expressed in the developing heart in mice and peaked at embryonic day 12.5 (E12.5). Loss of Wdfy3 in mice led to embryonic and neonatal lethality. Wdfy3-deficient mice displayed various congenital heart defects including membranous ventricular septal defect (VSD), aortic overriding (AO), double outlet right ventricle (DORV), thinning of ventricular wall, ventricular dilation, and disorganized ventricular trabeculation at E14.5. Cell proliferation was reduced in the hearts from Wdfy3-deficient mice at E12.5 and E14.5, which was associated with enhanced p21 expression. Cardiomyocyte differentiation was diminished as demonstrated by reduced Myh6 and MLC2v in Wdfy3-deficient mice at E14.5. In addition, Nkx2-5 and Mef2c, two cardiac transcription factors regulating cardiomyocyte differentiation, were decreased in Wdfy3-deficient mice at E14.5. Apoptotic cell death remained unaltered. These data suggest that reduced cell proliferation and cardiomyocyte differentiation contribute to cardiac defects in Wdfy3-deficient mice. Mechanistically, loss of Wdfy3 led to a reduction in protein levels of Notch 1 intracellular domain and its downstream targets Hes1 and Hey1, which was accompanied with enhanced full-length Notch1 protein levels. In vitro luciferase assay showed that Wdfy3 deficiency induced activity of p21 promoter, while diminished activity of Hes1 promoter through modulation of Notch1 signalling. Moreover, Wdfy3 was co-localized with Notch1 in primary embryonic cardiomyocytes. Endogenous Wdfy3 physically interacted with full-length Notch1 in the developing heart. These results suggest that Notch1 signalling is perturbed in the hearts from Wdfy3-deficient mice. No alteration of autophagy was detected in the hearts from Wdfy3-deficient mice. Conclusion Taken together, our data suggest that Wdfy3 plays an essential role in cardiac development, which may be mediated by modulation of Notch1 signalling.

Fundamental human traits, such as language and bipedalism, are associated with a range of anatomical adaptations in craniofacial shaping and skeletal remodeling. However, it is unclear how such morphological features arose during hominin evolution. FOXP2 is a brain-expressed transcription factor implicated in a rare disorder involving speech apraxia and language impairments. Analysis of its evolutionary history suggests that this gene may have contributed to the emergence of proficient spoken language. In the present study, through analyses of skeleton-specific knockout mice, we identified roles of Foxp2 in skull shaping and bone remodeling. Selective ablation of Foxp2 in cartilage disrupted pup vocalizations in a similar way to that of global Foxp2 mutants, which may be due to pleiotropic effects on craniofacial morphogenesis. Our findings also indicate that Foxp2 helps to regulate strength and length of hind limbs and maintenance of joint cartilage and intervertebral discs, which are all anatomical features that are susceptible to adaptations for bipedal locomotion. In light of the known roles of Foxp2 in brain circuits that are important for motor skills and spoken language, we suggest that this gene may have been well placed to contribute to coevolution of neural and anatomical adaptations related to speech and bipedal locomotion.

The roles of the Wnt cargo receptor Wntless (Wls) during hair follicle (HF) induction and postnatal HF cycling in skin have been elucidated. However, whether Wls regulates postnatal HF morphogenesis remains unclear. In this study, we found that Wls is expressed in developing HF during the morphogenesis stage after birth. By knocking out Wls in mouse skin epithelia with hypomorphic K14-cre, we found that Wls is required for normal HF morphogenesis. Wls-deficient HFs prematurely regressed, which was possibly caused by abnormally activated TGF-β/JNK pathway. Although Wls was reported to be a direct target of the Wnt/β-catenin pathway, we found that epithelial β-catenin was not necessary to maintain Wls expression. Therefore, other signals are involved in regulating Wls transcription in mouse skin.

Through the Three Gorges well network, we examine different coseismic changes in water temperature caused by local earthquakes since 2008, and offer a mechanistic explanation. The relations between the coseismic changes in water temperature and the parameters of distant and local earthquakes are deduced.

In mouse, continuous growth of the postnatal incisor is coordinated by two populations of multipotent progenitor cells, the dental papilla mesenchymal cells and dental epithelial stem cells, residing at the proximal end of the incisor, yet the molecular mechanism underlying the cooperation between mesenchymal and epithelial cells is largely unknown. Here, transforming growth factor-β (TGF-β) type II receptor (Tgfbr2) was specifically deleted within the postnatal dental papilla mesenchyme. The Tgfbr2-deficient mice displayed malformed incisors with wavy mineralized structures at the labial side as a result of increased differentiation of dental epithelial stem cells. We found that mesenchymal Tgfbr2 disruption led to upregulated expression of Wnt5a and downregulated expression of Fgf3/10 in the mesenchyme, both of which synergistically enhanced Lrp5/6-β-catenin signaling in the cervical loop epithelium. In accord with these findings, mesenchyme-specific depletion of the Wnt transporter gene Wls abolished the aberrant mineralized structures caused by Tgfbr2 deletion. Thus, mesenchymal TGF-β signaling provides a unifying mechanism for the homeostasis of dental epithelial stem cells via a Wnt signaling-mediated mesenchymal-epithelial cell interaction. Stem Cells 2014;32:2939–2948

Defects of the ventral body wall are prevalent birth anomalies marked by deficiencies in body wall closure, hypoplasia of the abdominal musculature and multiple malformations across a gamut of organs. However, the mechanisms underlying ventral body wall defects remain elusive. Here, we investigated the role of Wnt signaling in ventral body wall development by inactivating Wls or β-catenin in murine abdominal ectoderm. The loss of Wls in the ventral epithelium, which blocks the secretion of Wnt proteins, resulted in dysgenesis of ventral musculature and genito-urinary tract during embryonic development. Molecular analyses revealed that the dermis and myogenic differentiation in the underlying mesenchymal progenitor cells was perturbed by the loss of ectodermal Wls. The activity of the Wnt-Pitx2 axis was impaired in the ventral mesenchyme of the mutant body wall, which partially accounted for the defects in ventral musculature formation. In contrast, epithelial depletion of β-catenin or Wnt5a did not resemble the body wall defects in the ectodermal Wls mutant. These findings indicate that ectodermal Wnt signaling instructs the underlying mesodermal specification and abdominal musculature formation during ventral body wall development, adding evidence to the theory that ectoderm-mesenchyme signaling is a potential unifying mechanism for the origin of ventral body wall defects.

The role of Wnt signaling is extensively studied in skeletal development and postnatal bone remodeling, mostly based on the genetic approaches of β-catenin manipulation. However, given their independent function, a requirement for β-catenin is not the same as that for Wnt. Here, we investigated the effect of Wnt proteins in both tissues through generating cartilage- or bone-specific Wls null mice, respectively. Depletion of Wls by Col2-Cre, which would block Wnt secretion in the chondrocytes and perichondrium, delayed chondrocyte hypertrophy in the growth plate and impaired perichondrial osteogenesis. Loss of Wls in chondrocytes also disturbed the proliferating chondrocyte morphology and division orientation, which was similar to the defect observed in Wnt5a null mice. On the other hand, inactivation of Wls in osteoblasts by Col1-Cre resulted in a shorter hypertrophic zone and an increase of TRAP positive cell number in the chondro-osseous junction of growth plate, coupled with a decrease in bone mass. Taken together, our studies reveal that Wnt proteins not only modulate differentiation and cellular communication within populations of chondrocytes, but also mediate the cross regulation between the chondrocytes and osteoblasts in growth plate.

Online multi-label learning is an efficient classification paradigm in machine learning. However, traditional online multi-label methods often need requesting all class labels of each incoming sample, which is often human cost and time-consuming in labeling classification problem. In order to tackle these problems, in this paper, we present online multi-label passive aggressive active (MLPAA) learning algorithm by combining binary relevance (BR) decomposition strategy with online passive aggressive active (PAA) method. The proposed MLPAA algorithm not only uses the misclassified labels to update the classifier, but also exploits correctly classified examples with low prediction confidence. We perform extensive experimental comparison for our algorithm and the other methods using nine benchmark data sets. The encouraging results of our experiments validate the effectiveness of our proposed method.

Generation of germ cells from pluripotent stem cellsin vitrocould have great application for treating infertility and provides an excellent model for uncovering molecular mechanisms controlling gametogenesis. In this study, we explored the differentiation potential of mouse induced pluripotent stem (iPS) cells towards male germ cells. Embryoid body formation and retinoic acid/testosterone induction were applied to promote differentiation of mouse iPS cells into male germ cellsin vitro. Quantitative RT-PCR and immunoflourescence were performed to characterize the iPS cell differentiation process, and notably there were different temporal expression profiles of male germ cell-associated genes. The expression of proteins, including MVH, CDH1, and SCP3, was remarkably increased. mRNA expression ofStra8,Odf2,Act, andPrm1was upregulated in iPS cells by retinoic acid or testosterone induction, whereasOct-4transcription was reduced in these cells compared to the controls. Hormones were also measured in the EB medium. DNA content analysis by flow cytometry revealed that iPS cells could differentiate into haploid cells through retinoic acid or testosterone treatment. Collectively, our results suggest that mouse iPS cells possess the potency to differentiate into male germ cellsin vitrothrough embryoid body formation and retinoic acid or testosterone induction.

Rare codons generally arrest translation due to rarity of their cognate tRNAs. This property of rare codons can be utilized to regulate protein expression. In this study, a linear relationship was found between expression levels of genes and copy numbers of rare codons inserted within them. Based on this discovery, we constructed a molecular device in Escherichia coli using the rare codon AGG, its cognate tRNA (tRNAArg (CCU)), modified tRNAAsp (GUC → CCU), and truncated aspartyl-tRNA synthetase (TDRS) to switch the expression of reporter genes on or off as well as to precisely regulate their expression to various intermediate levels. To underscore the applicability of our work, we used the rare codon device to alter the expression levels of four genes of the fatty acid synthesis II (FASII) pathway (i.e. fabZ, fabG, fabI, and tesA’) in E. coli to optimize steady-state kinetics, which produced nearly two-fold increase in fatty acid yield. Thus, the proposed method has potential applications in regulating target protein expression at desired levels and optimizing metabolic pathways by precisely tuning in vivo molar ratio of relevant enzymes.

MiR-140 is a microRNA specially involved in chondrogenesis and osteoarthritis pathogenesis. However, its transcriptional regulation and target genes in cartilage development are not fully understood. Here we detected that miR-140 was uniquely expressed in chondrocyte and suppressed by Wnt/β-catenin signalling. The miR-140 primary transcript was an intron-retained RNA co-expressed with Wwp2-C isoform, which was directly induced by Sox9 through binding to the intron 10 of Wwp2 gene. Knockdown of miR-140 in limb bud micromass cultures resulted in arrest of chondrogenic proliferation. Sp1, the activator of the cell cycle regulator p15INK4b, was identified as a target of miR-140 in maintaining the chondrocyte proliferation. Collectively, our findings expand our understanding of the transcriptional regulation and the chondrogenic role of miR-140 in chondrogenesis.

N-ethyl-N-nitrosourea (ENU) mutagenesis has led to the elucidation of several regulator genes for melanocyte and skin development. Here we characterized a mutant from ENU mutagenesis with similar phenotype as that of Splotch mutant, including exencephaly, spina bifida and abnormal limbs in homozygotes as well as white belly spotting and occasionally loop-tail in heterozygotes. This novel mutant was named as Sp(xG). Through genome-wide linkage analysis in backcross progenies with microsatellite markers, the Sp(xG) was confined to a region between D1MIT415 and D1MIT7 on chromosome 1, where notable Pax3 gene was located. Direct sequencing revealed that Sp(xG) carried a nucleotide A894G missense transition in exon 6 of Pax3 gene that resulted in Asn to Asp substitution at amino acid 269 within the highly-conserved homeodomain (HD) DNA recognition module, which was the first point mutation found in this domain in mice. This N269D mutation impaired the transactivation capacity of Pax3 protein, but exerted no effect on Pax3 protein translation. The characterization of the new mutation expanded our understanding the transactivation and DNA-binding structure of Pax3 protein.

Influenza is a cause of hospitalization and mortality in infants. γδ T cells are the first T cells to develop during embryogenesis and are a significant component of the neonatal immune system. In the neonatal period, conventional αβ T cell responses are functionally less prominent. γδ T cells play critical regulatory and effector roles, but their relevance in neonatal influenza remains to be investigated. In our neonatal infection model, we found γδ T cells were protective against mortality associated with neonatal influenza infection. Infection induced the accumulation of γδ T cells, which transiently expressed IL-17a, rather than IFN-γ. Subsequently, this led to stronger Type 2 immune responses than the TCRδ-deficient animals, particularly in IL-33 production and amphiregulin-mediated tissue repair. Loss of γδ T cells did not alter viral clearance or conventional anti-viral responses. We also observed an association between IL-17a levels and clinical outcomes. Thus, our results identify a specific requirement for γδ T cells in influenza-infected neonates for initiating Type 2 immune responses, mediating tissue homeostasis, and promoting lung integrity, which may provide a new therapeutic target for pediatric influenza treatment.

The lung extracellular matrix (ECM) is extensively remodeled following respiratory viral infection. This remodeling occurs during inflammation when immune cells migrate to the site of infection and during repair as the ECM is modified to regenerate damaged tissue. Matrix proteases, including the A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) gene family, play a critical role in these remodeling processes. The immune mechanisms that regulate matrix protease activity and their effect on host responses to lung infection have not been well characterized. Previously, we found that ADAMTS-4 knockout mice exhibited improved survival following lethal influenza A (IAV) challenge and signs of reduced immunopathology, including fewer numbers of inflammatory T cells. Here, by flow cytometric sorting of immune and stromal cell populations, we identified fibroblasts as the main producers of ADAMTS-4 in the lung during severe IAV infection, with ~50-fold higher levels of mRNA compared to other lung cell populations. Stimulation of primary lung fibroblasts in vitro with a wide range of inflammatory cytokines demonstrated that only IL-1β and IL-1α induced expression of ADAMTS-4. Co-stimulation of lung fibroblasts with IL-1 cytokines and TNF-α resulted in a synergistic effect and an increase of ADAMTS-4 expression to greater than 6-fold above baseline levels. IL-1 treatment of lung fibroblasts also induced expression of the lung ECM proteoglycan versican (VCAN), a major enzymatic target of ADAMTS-4. These results suggest a role for IL-1 cytokines in regulating lung ECM remodeling, and highlight the potential of modulating the IL-1/ADAMTS-4 pathway to reduce immunopathology following severe respiratory infection.

Reduced mechanical stress leads to bone loss, as evidenced by disuse osteoporosis in bedridden patients and astronauts. Osteocytes have been identified as major cells responsible for mechanotransduction; however, the mechanism underlying the response of bone to mechanical unloading remains poorly understood. In this study, we found that mechanical unloading of wildtype mice caused decrease of Wnt/beta-catenin signaling activity accompanied by upregulation of Sost. To further analyze the causal relationship among these events, Sost gene targeting mice were generated. We showed that sclerostin selectively inhibited Wnt/beta-catenin in vivo, and sclerostin suppressed the activity of osteoblast and viability of osteoblasts and osteocytes. Interestingly, Sost(-/-) mice were resistant to mechanical unloading-induced bone loss. Reduction in bone formation in response to unloading was also abrogated in the mutant mice. Moreover, in contrast to wildtype mice, Wnt/beta-catenin signaling was not altered by unloading in Sost(-/-) mice. Those data implied that sclerostin played an essential role in mediating bone response to mechanical unloading, likely through Wnt/beta-catenin signaling. Our findings also indicated sclerostin is a promising target for preventing disuse osteoporosis.

In the developing limb bud, digit pattern arises from anterior-posterior (A-P) positional information which is provided by the concentration gradient of SHH. However, the mechanisms of translating early asymmetry into morphological form are still unclear. Here, we examined the ability of IHH and FGF8 signaling to regulate digital chondrogenesis, by implanting protein-loaded beads in the interdigital space singly and in combination. We found that IHH protein induced an elongated digit and that FGF8 protein blocked the terminal phalange formation. Molecular marker analysis showed that IHH expanded Sox9 expression in mesenchymal cells possibly through up-regulated FGF8 expression. Application of both IHH and FGF8 protein induced a large terminal phalange. These results suggest that both enhanced IHH and FGF8 signaling are required for the development of additional cartilage element in limbs. IHH and FGF8 maybe play different roles and act synergistically to promote chondrogenesis during digit primordia elongation.

Wnt/β-catenin signaling has been reported to contribute to the development of bone fibrous dysplasia. However, it remains unclear whether fibrocytes and immune cells are involved in this β-catenin-mediated bone marrow fibrosis. In this study, we showed that constitutive activation of β-catenin by Col1a1-Cre (3.6-kb) exhibited bone marrow fibrosis, featured with expanded populations of fibrocytes, myofibroblasts and osteoprogenitors. Lineage tracing and IHC examinations showed that Col3.6-Cre display Cre recombinase activity not only in osteoprogenitors, but also in monocyte-derived fibrocytes in the endosteal niches of bones. Additionally, β-catenin stimulated the secretion of cytokines and pro-fibrotic signals in bone marrow, including GM-CSF, TGFβ1 and VEGF. Consequently, the frequency of differentiated immature monocyte-derived dendritic cells and naive T cells was markedly increased in the mutant bone marrow. These phenotypes were quite different from those following β-catenin activation in mature osteoblasts driven by Col1a1-Cre (2.3-kb). Our findings suggested that a conserved pro-fibrotic signal cascade might underlie β-catenin-mediated bone marrow fibrosis, involving TGFβ1-enhanced fibrocyte activation and immunoregulatory responses. This study might shed new light on the understanding and development of a therapeutic strategy for bone fibrous dysplasia.

The positioning accuracy and positioning time of CNC systems have recently been the main performance criteria for industrial applications. The acceleration/deceleration modes, especially the deceleration modes, have an important effect on them. In this paper, firstly, some problems of the conventional linear deceleration algorithm are analyzed. Then an improved linear acceleration/deceleration algorithm is introduced. In this algorithm, the deceleration point is predicted exactly, and then the deceleration point error is compensated for at higher feedrates. Furthermore, a higher resultant maximum acceleration than that in the conventional scheme is selected to shorten the acceleration/deceleration time. Compared with the conventional linear acceleration and deceleration algorithm, the system performance has been significantly improved. Finally, the performance is confirmed by several simulations and experiments.

Hair follicle stem cells (HFSCs) in the bugle circularly generate outer root sheath (ORS) through linear proliferation within limited cycles during anagen phases. However, the mechanisms controlling the pace of HFSC proliferation remain unclear. Here we revealed that Foxp1, a transcriptional factor, was dynamically relocated from the nucleus to the cytoplasm of HFSCs in phase transitions from anagen to catagen, coupled with the rise of oxidative stress. Mass spectrum analyses revealed that the S468 phosphorylation of Foxp1 protein was responsive to oxidative stress and affected its nucleocytoplasmic translocation. Foxp1 deficiency in hair follicles led to compromised ROS accrual and increased HFSC proliferation. And more, NAC treatment profoundly elongated the anagen duration and HFSC proliferation in Foxp1-deficient background. Molecularly, Foxp1 augmented ROS levels through suppression of Trx1-mediated reductive function, thereafter imposing the cell cycle arrest by modulating the activity of p19/p53 pathway. Our findings identify a novel role for Foxp1 in controlling HFSC proliferation with cellular dynamic location in response to oxidative stress during hair cycling.