Cartilage stem/progenitor cells-derived exosomes facilitate knee cartilage repair in a subacute osteoarthritis rat model.

Cartilage defects in the knee are often associated with the progression of degenerative osteoarthritis (OA), and cartilage repair is a useful strategy for managing this disease. However, cartilage repair is challenging because of the unique environment within the tissue. Recently, stem cell-based therapies have shed new light on this issue. In this study, we prepared exosomes (EXOs) from cartilage stem/progenitor cells (CSPCs) and found that treatment with EXOs increased the viability, migration, and proliferation of cultured primary chondrocytes. In a subacute OA rat model, the application of EXOs facilitated cartilage regeneration as evidenced by histological staining. Exosomal protein analysis together with bioinformatics suggested that cyclin-dependent kinase 9 (CDK9) is a key factor for chondrocyte growth and migration. Functional studies confirmed this prediction, that is, inhibiting CDK9 reduced the beneficial effects induced by EXOs in primary chondrocytes; while overexpression of CDK9 recapitulated the EXOs-induced phenotypes. RNA-Seq data showed that a set of genes involved in cell growth and migration were up-regulated by EXOs in chondrocytes. These changes could be partially reproduced by CDK9 overexpression. Overall, our data suggest that EXOs derived from primary CSPCs hold great therapeutic potential for treating cartilage defect-associated disorders such as degenerative OA, and that CDK9 is a key factor in this process.

Myeloid Trem2 ameliorates the progression of metabolic dysfunction-associated steatotic liver disease by regulating macrophage pyroptosis and inflammation resolution.

BACKGROUND: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing year by year and has become one of the leading causes of end-stage liver disease worldwide. Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) has been confirmed to play an essential role in the progression of MASLD, but its specific mechanism still needs to be clarified. This study aims to explore the role and mechanism of Trem2 in MASLD. METHODS: Human liver tissues were obtained from patients with MASLD and controls. Myeloid-specific knockout mice (Trem2mKO) and myeloid-specific overexpression mice (Trem2TdT) were fed a high-fat diet, either AMLN or CDAHFD, to establish the MASLD model. Relevant signaling molecules were assessed through lipidomics and RNA-seq analyses after that. RESULTS: Trem2 is upregulated in human MASLD/MASH-associated macrophages and is associated with hepatic steatosis and inflammation progression. Hepatic steatosis and inflammatory responses are exacerbated with the knockout of myeloid Trem2 in MASLD mice, while mice overexpressing Trem2 exhibit the opposite phenomenon. Mechanistically, Trem2mKO can aggravate macrophage pyroptosis through the PI3K/AKT signaling pathway and amplify the resulting inflammatory response. At the same time, Trem2 promotes the inflammation resolution phenotype transformation of macrophages through TGFß1, thereby promoting tissue repair. CONCLUSIONS: Myeloid Trem2 ameliorates the progression of Metabolic dysfunction-associated steatotic liver disease by regulating macrophage pyroptosis and inflammation resolution. We believe targeting myeloid Trem2 could represent a potential avenue for treating MASLD.

ALOX5 drives the pyroptosis of CD4+ T cells and tissue inflammation in rheumatoid arthritis.

Pyroptosis, an inflammatory form of programmed cell death, is linked to the pathology of rheumatoid arthritis (RA). Here, we investigated the molecular mechanism underlying pyroptosis in T cells isolated from patients with RA. Compared with healthy individuals, patients with RA had more pyroptotic CD4+ T cells in blood and synovia, which correlated with clinical measures of disease activity. Moreover, the mRNA expression and protein abundance of arachidonate 5-lipoxygenase (ALOX5), which converts arachidonic acid to leukotriene A4 (LTA4), were increased in CD4+ T cells from patients with RA and, among patients with RA, were lowest in those in clinical remission. Knockdown or pharmacological inhibition of ALOX5 suppressed CD4+ T cell pyroptosis and improved symptoms in two rodent models of RA. Mechanistically, the increase in ALOX5 activity in RA CD4+ T cells enhanced the production of the LTA4 derivative LTB4, which stimulated Ca2+ influx through ORAI3 channels, leading to the activation of NLRP3 inflammasomes and pyroptosis. Our findings reveal a role for ALOX5 in RA and provide a molecular basis for further exploring the clinical utility of ALOX5 inhibition in RA and for using ALOX5 as a biomarker to distinguish active disease and remission in RA.

Endoplasmic reticulum aminopeptidase 2 regulates CD4+ T cells pyroptosis in rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease with a complex pathogenesis that has not yet been fully elucidated, and T-cell pyroptosis is an important pathogenetic factor in RA. This study aimed to investigate the role of endoplasmic reticulum aminopeptidase 2 (ERAP2) in the pyroptosis of CD4+ T cells in RA and the specific molecular mechanism. METHODS: Peripheral venous blood was collected from human subjects, and CD4+ T cells were isolated and activated to measure the level of pyroptosis and ERAP2 expression. Pyroptosis levels were assessed using immunofluorescence, flow cytometry, qRT-PCR, and Western blotting. Changes in pyroptosis levels were observed upon knockdown or overexpression of ERAP2. To detect activated Caspase-1 in tissues, chimeric mice were engrafted with human synovial tissue and reconstituted with human CD4+ T cells. CD4 + T cells were treated with GLI1 antagonists and SMO receptor agonists to detect changes in pyroptosis levels. RESULTS: CD4+ T cell levels undergoing pyroptosis were found to be elevated in the blood and synovium of RA patients. The gene and protein expression of ERAP2 were significantly higher in CD4+ T cells from RA patients. Deletion of ERAP2 suppressed pyroptosis of these cells, attenuated the activation of Caspase-1 in tissue T cells, and reduced tissue inflammatory responses. Reciprocally, overexpression of ERAP2 triggered inflammasome assembly, activated Caspase-1, and induced pyroptosis in CD4+ T cells. Mechanistically, ERAP2 inhibits the Hedgehog signaling pathway and upregulates the expression of nucleotide-binding oligomerization segment-like receptor family 3(NLRP3), cleaved Caspase-1, and Gasdermin D to promote pyroptosis in CD4+ T cells. CONCLUSIONS: Taken together, our results identify a novel mechanism by which ERAP2 regulates RA development and document the effect of the ERAP2/Hedgehog signaling axis on pyroptosis of CD4+ T cells from RA patients.

Blockade of Hepatocyte PCSK9 Ameliorates Hepatic Ischemia-Reperfusion Injury by Promoting Pink1-Parkin-Mediated Mitophagy.

BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury is a significant complication of partial hepatic resection and liver transplantation, impacting the prognosis of patients undergoing liver surgery. The protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily synthesized by hepatocytes and has been implicated in myocardial ischemic diseases. However, the role of PCSK9 in hepatic ischemia-reperfusion injury remains unclear. This study aims to investigate the role and mechanism of PCSK9 in hepatic ischemia-reperfusion injury. METHODS: We first examined the expression of PCSK9 in mouse warm ischemia-reperfusion models and AML12 cells subjected to hypoxia/reoxygenation. Subsequently, we explored the impact of PCSK9 on liver ischemia-reperfusion injury by assessing mitochondrial damage and the resulting inflammatory response. RESULTS: Our findings reveal that PCSK9 is up-regulated in response to ischemia-reperfusion injury and exacerbates hepatic ischemia-reperfusion injury. Blocking PCSK9 can alleviate hepatocyte mitochondrial damage and the consequent inflammatory response mediated by ischemia-reperfusion. Mechanistically, this protective effect is dependent on mitophagy. CONCLUSIONS: Inhibiting PCSK9 in hepatocytes attenuates the inflammatory responses triggered by reactive oxygen species and mitochondrial DNA by promoting PINK1-Parkin-mediated mitophagy. This, in turn, ameliorates hepatic ischemia-reperfusion injury.

Macrophage migration inhibitory factor facilitates astrocytic production of the CCL2 chemokine following spinal cord injury.

Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation. Overproduced chemokines are responsible for the migratory process of the leukocytes, but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated. We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury. The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes. Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells, and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect. Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor. Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats. Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.

Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3.

BACKGROUND: Liver metastasis is the leading cause of death in patients with colorectal cancer (CRC). Surgical resection of the liver metastases increases the incidence of long-term survival in patients with colorectal liver metastasis (CRLM). However, many patients experience CRLM recurrence after the initial liver resection. As an unavoidable pathophysiological process in liver surgery, liver ischemia-reperfusion (IR) injury increases the risk of tumor recurrence and metastasis. METHODS: Colorectal liver metastasis (CRLM) mouse models and mouse liver partial warm ischemia models were constructed. The levels of lipid peroxidation were detected in cells or tissues. Western Blot, qPCR, elisa, immunofluorescence, immunohistochemistry, scanning electron microscope, flow cytometry analysis were conducted to evaluate the changes of multiple signaling pathways during CRLM recurrence under liver ischemia-reperfusion (IR) background, including SGK1/IL-6/STAT3, neutrophil extracellular traps (NETs) formation, polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration. RESULTS: Hepatocyte serum/glucocorticoid regulated kinase 1 (SGK1) was activated in response to hepatic ischemia-reperfusion injury to pass hepatocyte STAT3 phosphorylation and serum amyloid A (SAA) hyperactivation signals in CRLM-IR mice, such regulation is dependent on SGK-activated IL-6 autocrine. Administration of the SGK1 inhibitor GSK-650394 further reduced ERK-related neutrophil extracellular traps (NETs) formation and polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) infiltration compared with targeting hepatocyte SGK1 alone, thereby alleviating CRLM in the context of IR. CONCLUSIONS: Our study demonstrates that hepatocyte and immune cell SGK1 synergistically promote postoperative CRLM recurrence in response to hepatic IR stress, and identifies SGK1 as a translational target that may improve postoperative CRLM recurrence.

4-Iodo-6-phenylpyrimidine (4-IPP) suppresses fibroblast-like synoviocyte- mediated inflammation and joint destruction associated with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic immune-mediated inflammatory disease that significantly impacts patients' quality of life. Fibroblast-like synovial cells (FLSs) within the synovial intima exhibit "tumor-like" properties such as increased proliferation, migration, and invasion. Activation of FLSs and secretion of pro-inflammation factors result in pannus formation and cartilage destruction. As an inhibitor of the cytokine, macrophage migration inhibitory factor (MIF), 4-Iodo-6-phenylpyrimidine (4-IPP) has been shown to reduce cell proliferation, migration, invasion, and the secretion of pro-inflammatory mediators in a variety of diseases. However, the usefulness of 4-IPP for RA treatment has not been assessed and was the purpose of this study. In vitro, 4-IPP was demonstrated to inhibit proliferation, migration, and invasion of RA FLSs, as well as the expression of pro-inflammatory cytokines. 4-IPP was also shown to inhibit MIF-induced phosphorylation of ERK, JNK, and p38, as well as reduce expression of COX2 and PGE2. In order to efficiently deliver 4-IPP to anatomical RA sites, we developed lactic-co-glycolic acid (PLGA) nanospheres, which not only protected 4-IPP from degradation but also controlled the release of 4-IPP. 4-IPP/PLGA nanospheres had potent anti-inflammatory activity and a high degree of biosafety. Results showed that local 4-IPP concentration was increased by nanosphere delivery, effectively reducing the inflammatory microenvironment as well as synovial inflammation, joint swelling, and cartilage destruction in a collagen-induced rheumatoid arthritis (CIA) rat model. Therefore, 4-IPP nanospheres are a sustained-release delivery system that may be an effective therapeutic strategy for RA treatment.

Targeting Senescent Tendon Stem/Progenitor Cells to Prevent or Treat Age-Related Tendon Disorders.

Age-related tendon disorder, a primary motor system disease, is characterized by biological changes in the tendon tissue due to senescence and seriously affects the quality of life of the elderly. The pathogenesis of this disease is not well-understood. Tendon stem/progenitor cells (TSPCs) exhibit multi-differentiation capacity. These cells are important cellular components of the tendon because of their roles in tendon tissue homeostasis, remodeling, and repair. Previous studies revealed alterations in the biological characteristics and tenogenic differentiation potential of TSPCs in senescent tendon tissue, in turn contributing to insufficient differentiation of TSPCs into tenocytes. Poor tendon repair can result in age-related tendinopathies. Therefore, targeting of senescent TSPCs may restore the tenogenic differentiation potential of these cells and achieve homeostasis of the tendon tissue to prevent or treat age-related tendinopathy. In this review, we summarize the biological characteristics of TSPCs and histopathological changes in age-related tendinopathy, as well as the potential mechanisms through which TSPCs contribute to senescence. This information may promote further exploration of innovative treatment strategies to rescue TSPCs from senescence.

[Effectiveness analysis of proximal humerus internal locking system plate combined with rotator cuff reinforcement suture in treatment of Neer type â £ proximal humerus fracture].

Objective: To investigate the effectiveness of proximal humerus internal locking system (PHILOS) plate combined with rotator cuff reinforcement suture in the treatment of Neer type Ⅳ proximal humerus fracture. Methods: The clinical data of 48 patients with proximal humeral fractures admitted between January 2016 and December 2020 were retrospectively analyzed, including 18 males and 30 females. The age ranged from 28 to 69 years (mean, 56.3 years). The causes of injury included falling in 39 cases and traffic accident in 9 cases. The time from injury to operation was 2-5 days (mean, 2.8 days). All of them were Neer type Ⅳ proximal humerus fractures, including 11 patients with dislocation. All patients underwent internal fixation with a PHILOS plate after anatomical reduction of the greater nodule, and the rotator cuff was sutured to the plate to reinforce fixation. The operation time was recorded, the wound healing, fracture healing, and complications were observed. The visual analogue scale (VAS) score, Constant-Murley shoulder score, University of California Los Angeles (UCLA) score, and American Shoulder and Elbow Surgeons (ASES) score were used to evaluate shoulder function before operation, at 3 months after operation, and at last follow-up. Results: The operation time ranged from 65 to 90 minutes (mean, 76.9 minutes). All incisions healed by first intention. All patients were followed up 9-16 months (mean, 12 months). Fracture reduction was good and all fractures healed, the healing time was 2-6 months (mean, 4.6 months). There was no complication such as subacromial impingement, fracture redisplacement, and screw removal during follow-up. One patient had humeral head necrosis, but the basic function of the shoulder joint was acceptable, the symptoms were mild, and no treatment was performed. At 3 months after operation, the upper limb function of the patients basically recovered. The VAS score, Constant-Murley score, UCLA score, and ASES score significantly improved at 3 months after operation and at last follow-up when compared with preoperative, and further improved at last follow-up than at 3 months after operation ( P<0.05). Conclusion: PHILOS plate combined with rotator cuff reinforcement suture in the treatment of Neer type Ⅳ proximal humerus fracture has the advantages of promoting early postoperative rehabilitation exercise, improving postoperative function of shoulder joint, and reducing complications.

Manipulation of pantothenate kinase in Anopheles stephensi suppresses pantothenate levels with minimal impacts on mosquito fitness.

Pantothenate (Pan) is an essential nutrient required by both the mosquito vector and malaria parasite. We previously demonstrated that increasing pantothenate kinase (PanK) activity and co-enzyme A (CoA) biosynthesis led to significantly decreased parasite infection prevalence and intensity in the malaria mosquito Anopheles stephensi. In this study, we demonstrate that Pan stores in A. stephensi are a limited resource and that manipulation of PanK levels or activity, via small molecule modulators of PanK or transgenic mosquitoes, leads to the conversion of Pan to CoA and an overall reduction in Pan levels with minimal to no effects on mosquito fitness. Transgenic A. stephensi lines with repressed insulin signaling due to PTEN overexpression or repressed c-Jun N-terminal kinase (JNK) signaling due to MAPK phosphatase 4 (MKP4) overexpression exhibited enhanced PanK levels and significant reductions in Pan relative to non-transgenic controls, with the PTEN line also exhibiting significantly increased CoA levels. Provisioning of the PTEN line with the small molecule PanK modulator PZ-2891 increased CoA levels while provisioning Compound 7 decreased CoA levels, affirming chemical manipulation of mosquito PanK. We assessed effects of these small molecules on A. stephensi lifespan, reproduction and metabolism under optimized laboratory conditions. PZ-2891 and Compound 7 had no impact on A. stephensi survival when delivered via bloodmeal throughout mosquito lifespan. Further, PZ-2891 provisioning had no impact on egg production over the first two reproductive cycles. Finally, PanK manipulation with small molecules was associated with minimal impacts on nutritional stores in A. stephensi mosquitoes under optimized rearing conditions. Together with our previous data demonstrating that PanK activation was associated with significantly increased A. stephensi resistance to Plasmodium falciparum infection, the studies herein demonstrate a lack of fitness costs of mosquito Pan depletion as a basis for a feasible, novel strategy to control parasite infection of anopheline mosquitoes.

JAK-STAT signaling mediates the senescence of cartilage-derived stem/progenitor cells.

Aging is a major risk factor for degenerative joint diseases, such as osteoarthritis (OA). Previous studies have confirmed the link between senescent mesenchymal stem cells (MSCs) and OA. Cartilage-derived stem/progenitor cells (CSPCs) with MSCs properties have been extracted from a variety of species. We inferred that the senescence of CSPCs may promote the development of osteoarthritis. However, the cellular and molecular mechanisms of CSPCs senescence remains unknown. In this study, we investigated the role of JAK-STAT signaling pathway in a replicative senescence model of CSPCs. We showed that the late CSPCs (> 15th passage) exhibited distinct senescent phenotypes, including increased proportion of ß-gal positive senescent cells and F-actin content, as well as cell cycle arrest. In late CSPCs, the activity of JAK-STAT signaling pathway was significantly increased. Activation of JAK-STAT signaling pathway promoted cell senescence in early CSPCs (< 6th passage). Conversely, pharmacological inhibition or genetic knockdown of JAK-STAT signaling pathway attenuated cell senescence in late CSPCs. In conclusion, our results demonstrated the critical role of JAK-STAT signaling pathway in CSPCs senescence.

Assessing Near-Infrared Spectroscopy (NIRS) for Evaluation of Aedes aegypti Population Age Structure.

Given that older Aedes aegypti (L.) mosquitoes typically pose the greatest risk of pathogen transmission, the capacity to age grade wild Ae. aegypti mosquito populations would be a valuable tool in monitoring the potential risk of arboviral transmission. Here, we compared the effectiveness of near-infrared spectroscopy (NIRS) to age grade field-collected Ae. aegypti with two alternative techniques-parity analysis and transcript abundance of the age-associated gene SCP1. Using lab-reared mosquitoes of known ages from three distinct populations maintained as adults under laboratory or semi-field conditions, we developed and validated four NIRS models for predicting the age of field-collected Ae. aegypti. To assess the accuracy of these models, female Ae. aegypti mosquitoes were collected from Maricopa County, AZ, during the 2017 and 2018 monsoon season, and a subset were age graded using the three different age-grading techniques. For both years, each of the four NIRS models consistently graded parous mosquitoes as significantly older than nulliparous mosquitoes. Furthermore, a significant positive linear association occurred between SCP1 and NIRS age predictions in seven of the eight year/model combinations, although considerable variation in the predicted age of individual mosquitoes was observed. Our results suggest that although the NIRS models were not adequate in determining the age of individual field-collected mosquitoes, they have the potential to quickly and cost effectively track changes in the age structure of Ae. aegypti populations across locations and over time.

Pin1-mediated regulation of articular cartilage stem/progenitor cell aging.

Cartilage stem/progenitor cells (CSPCs) was recently isolated and identified from the cartilage tissue. CSPCs is essential for repair and regeneration of cartilage in osteoarthritis (OA). Aging is a primary risk factor for cartilage damage and joint OA. Although studies have confirmed the link between cell aging and OA, the underlying molecular mechanisms regulating CSPCs aging are not fully understood. In this study, we investigated the role of Pin1 in the aging of rat knee joint CSPCs. We isolated CSPCs from rat knee joints and demonstrated that, in long-term in vitro culture, Pin1 protein levels are significantly reduced. At the same time, expression of the senescence-related ß-galactosidase and the senescence marker p16INK4A were markedly elevated. In addition, Pin1 overexpression reversed the progression of cellular senescence, as evidenced by the down-regulation of senescence-related ß-galactosidase, increased EdU positive cells and diminished levels of p16INK4A. In contrast, Pin1 siRNA incorporation promoted CSPCs senescence. In addition, we also observed the distribution of cell cycles through flow cytometry and revealed that Pin1 deficiency results in cell cycle arrest in the G1 phase, suggesting severe lack of proliferation ability, a sign of cellular senescence. Collectively, these results validated that Pin1 is an essential regulator of CSPCs aging.

Identification of Conservation Priority Areas and a Protection Network for the Siberian Musk Deer (Moschus moschiferus L.) in Northeast China.

Species conservation actions are guided by available information on the biogeography of the protected species. In this study, we integrated the occurrence data of Siberian musk deer (Moschus moschiferus L.) collected from 2019 to 2021 with species distribution models to estimate the species' potential distribution in Northeast China. We then identified conservation priority areas using a core-area zonation algorithm. In addition, we analyzed core patch fragmentation using FRAGSTATS. Lastly, we identified potential connectivity corridors and constructed a potential protection network based on the least-cost path and the circuit theory. The results showed concentrations of M. moschiferus in the northern Greater Khingan Mountains, the southeastern Lesser Khingan Mountains, and the eastern Changbai Mountains, with a potential distribution area of 127,442.14 km2. Conservation priority areas included 41 core patches with an area of 106,306.43 km2. Patch fragmentation mainly occurred in the Changbai Mountains and the Lesser Khingan Mountains. We constructed an ecological network composed of 41 core patches and 69 linkages for M. moschiferus in Northeast China. The results suggest that the Greater Khingan Mountains represent the most suitable area to maintain the stability of M. moschiferus populations in Northeast China. Considering the high habitat quality requirements of M. moschiferus and its endangered status, we propose that the Chinese government accelerates the construction of the Greater Khingan Mountains National Park and the Lesser Khingan Mountains National Park and enlarges the Northeast China Tiger and Leopard National Park to address the fragmentation of protected areas and the habitat of M. moschiferus.

A flagship species-based approach to efficient, cost-effective biodiversity conservation in the Qinling Mountains, China.

Prioritizing threatened species protection has been proposed as an efficient response to the global biodiversity crisis. We used in-situ conservation data to predict the potential habitat area of four flagship species: the giant panda (Ailuropoda melanoleuca), golden monkey (Rhinopithecus roxella quinlingensis), takin (Budorcas taxicolor bedfordi), and crested ibis (Nipponia nippon). We then designed systematic conservation planning schemes for various scenarios given species habitat preferences and anthropogenic activities and conducted a cost-effectiveness assessment. Broadly, the geographical distributions of suitable habitats for giant pandas, golden monkeys, and takins exhibited high spatial congruence (correlation coefficients of 0.59-0.90), and areas of high congruence were concentrated in the northern portion of the Qinling Mountains at high elevation (>1500 m). By contrast, the crested ibis was negatively correlated in space with its sympatric species (-0.47 to -0.29). Crested ibis habitats were clustered in the southern portion of the region at low elevation (<1500 m). A hypothetical conservation priority area (CPA) based on the giant panda, golden monkey, and takin included 39.64% of the Qinling Mountains and 100%, 99.99%, 99.59%, and 7.84% of the suitable habitats for giant pandas, golden monkeys, takins, and crested ibises, respectively. The same area included 99.07%, 70.87%, and 39.96% of the highly important areas for the ecosystem services of biodiversity conservation, water supply, and soil retention, respectively, and only 4.62%, 16.83%, and 13.4% of the area were associated with high-density residential area, impervious surfaces, and cropland, respectively. Therefore, we conclude that a CPA approach based on the specialist species could result in effective, low-cost biodiversity conservation in the Qinling Mountains. However, we note that existing protected areas account for only 26.52% of the CPA. We recommend that the main area of the proposed Qinling National Park should be based on the CPA developed here.

Noncanonical Wnt5a signaling regulates tendon stem/progenitor cells senescence.

BACKGROUND: The structural and functional properties of tendon decline with age, and these changes contribute to tendon disorder. Tendon stem/progenitor cells (TSPCs) play a vital role in tendon repair, regeneration and homeostasis maintaining. Although studies have demonstrated that tendon aging is closely associated with the altered TSPCs function on senescence, the cellular and molecular mechanisms of TSPCs senescence remain largely unknown. This study was designed to investigate the role of Wnt5a in TSPCs senescence. METHODS: TSPCs were isolated from 2-month-old and 20-month-old male C57BL/6 mice. The expression of Wnt5a was determined by RNA sequencing, qRT-PCR and western blotting. TSPCs were then treated with Wnt5a shRNA or recombinant Wnt5a or AG490 or IFN-γ or Ror2-siRNA. Western blotting, ß-gal staining, qRT-PCR, immunofluorescence staining and cell cycle analysis were used for confirming the role of Wnt5a in TSPCs senescence. RESULTS: We found a canonical to noncanonical Wnt signaling shift due to enhanced expression of Wnt5a in aged TSPCs. Functionally, we demonstrated that inhibition of Wnt5a attenuated TSPCs senescence, age-related cell polarity and the senescence-associated secretory phenotype (SASP) expression in aged TSPCs. Mechanistically, the JAK-STAT signaling pathway was activated in aged TSPCs, while Wnt5a knockdown inhibited the JAK-STAT signaling pathway, suggesting that Wnt5a modulates TSPCs senescence via JAK-STAT signaling pathway. Moreover, knockdown of Ror2 inhibited Wnt5a-induced activation of the JAK-STAT signaling pathway, which indicates that Wnt5a potentiates JAK-STAT signaling pathway through Ror2, and Ror2 acts as the functional receptor of Wnt5a in TSPCs senescence. CONCLUSION: Our results demonstrate a critical role of noncanonical Wnt5a signaling in TSPCs senescence, and Wnt5a could be an attractive therapeutic target for antagonizing tendon aging.

Inhibition of JAK-STAT Signaling Pathway Alleviates Age-Related Phenotypes in Tendon Stem/Progenitor Cells.

Diminished regeneration or healing capacity of tendon occurs during aging. It has been well demonstrated that tendon stem/progenitor cells (TSPCs) play a vital role in tendon maintenance and repair. Here, we identified an accumulation of senescent TSPCs in tendon tissue with aging. In aged TSPCs, the activity of JAK-STAT signaling pathway was increased. Besides, genetic knockdown of JAK2 or STAT3 significantly attenuated TSPC senescence in aged TSPCs. Pharmacological inhibition of JAK-STAT signaling pathway with AG490 similarly attenuated cellular senescence and senescence-associated secretory phenotype (SASP) of aged TSPCs. In addition, inhibition of JAK-STAT signaling pathway also restored the age-related dysfunctions of TSPCs, including self-renewal, migration, actin dynamics, and stemness. Together, our findings reveal the critical role of JAK-STAT signaling pathway in the regulation of TSPC aging and suggest an ideal therapeutic target for the age-related tendon disorders.

Prevalence, Characteristics, and Associated Risk Factors of the Elderly with Hip Fractures: A Cross-Sectional Analysis of NHANES 2005-2010.

OBJECTIVE: This cross-sectional study was aimed to update the assessment of prevalence, characteristics, and risk factors of the elderly with hip fractures in a non-institutionalized American population. METHODS: This current study included a total of 31,034 participants from the existing National Health and Nutritional Examination Survey (NHANES) database from 2005 to 2010, and 4,265 participants aged 65 years and older were ultimately identified. Their condition of hip fractures was determined by method of questionnaires according to the orthopedic surgeons' diagnosis, and related epidemiological and demographic data were further collected. The univariate analysis was used to screen the risk factors of hip fractures in the elderly, and the logistic regression model was established to conduct the multivariate analysis. RESULTS: Of the total 4,265 participants with clear information of hip fractures in elderly, 127 individuals with hip fractures were identified according to results of questionnaires, exhibiting a prevalence of 28.49 per 1,000 (95% confidence interval [CI]=21.38-35.60) for males and 31.03 per 1,000 (95% CI=23.72-38.35) for females. The mean age of the elderly with hip fractures was 77.12±5.88 years and tumble (48.0%) was the primary factor. In univariate analysis, age, race, smoking, drinking alcohol, and combined with osteoporosis were regarded as risk factors. Multivariate analysis showed that age (80 years and older), living alone, smoking, combined with diabetes and osteoporosis were the independent risk factors. CONCLUSION: Our nationwide data indicate the prevalence of hip fractures in the elderly is generally on the rise, and the female occupies a higher proportion. Age (especially aged 80 years and older), race (mainly Non-Hispanic white), smoking, drinking alcohol, living alone, combined with diabetes and osteoporosis may be closely linked to the occurrence of hip fractures in the elderly, although these variables still need to be verified in further prospective investigations.

Understanding cellular and molecular mechanisms of pathogenesis of diabetic tendinopathy.

There is accumulating evidence of an increased incidence of tendon disorders in people with diabetes mellitus. Diabetic tendinopathy is an important cause of chronic pain, restricted activity, and even tendon rupture in individuals. Tenocytes and tendon stem/progenitor cells (TSPCs) are the dominant cellular components associated with tendon homeostasis, maintenance, remodeling, and repair. Some previous studies have shown alterations in tenocytes and TSPCs in high glucose or diabetic conditions that might cause structural and functional variations in diabetic tendons and even accelerate the development and progression of diabetic tendinopathy. In this review, the biomechanical properties and histopathological changes in diabetic tendons are described. Then, the cellular and molecular alterations in both tenocytes and TSPCs are summarized, and the underlying mechanisms involved are also analyzed. A better understanding of the underlying cellular and molecular pathogenesis of diabetic tendinopathy would provide new insight for the exploration and development of effective therapeutics.