Second Affiliated Hospital of Chongqing Medical University

OBJECTIVE: The aim of this study was to investigate the clinical and computed tomography (CT) features associated with severe and critical coronavirus disease 2019 (COVID-19) pneumonia. MATERIALS AND METHODS: Eighty-three patients with COVID-19 pneumonia including 25 severe/critical cases and 58 ordinary cases were enrolled. The chest CT images and clinical data of them were reviewed and compared. The risk factors associated with disease severity were analyzed. RESULTS: Compared with the ordinary patients, the severe/critical patients had older ages, higher incidence of comorbidities, cough, expectoration, chest pain, and dyspnea. The incidences of consolidation, linear opacities, crazy-paving pattern, and bronchial wall thickening in severe/critical patients were significantly higher than those of the ordinary patients. Besides, severe/critical patients showed higher incidences of lymph node enlargement, pericardial effusion, and pleural effusion than the ordinary patients. The CT scores of severe/critical patients were significantly higher than those of the ordinary patients (P < 0.001). Receiver operating characteristic curve showed that the sensitivity and specificity of CT score were 80.0% and 82.8%, respectively, for the discrimination of the 2 types. The clinical factors of age older than 50 years, comorbidities, dyspnea, chest pain, cough, expectoration, decreased lymphocytes, and increased inflammation indicators were risk factors for severe/critical COVID-19 pneumonia. Computed tomography findings of consolidation, linear opacities, crazy-paving pattern, bronchial wall thickening, high CT scores, and extrapulmonary lesions were features of severe/critical COVID-19 pneumonia. CONCLUSIONS: There are significant differences in clinical symptoms, laboratory examinations, and CT manifestations between the ordinary patients and the severe/critical patients. Many factors are related to the severity of the disease, which can help clinicians to judge the severity of the patient and evaluate the prognosis.

BACKGROUND: Fetal macrosomia, defined as a birth weight ≥ 4,000 g, may affect 12% of newborns of normal women and 15-45% of newborns of women with gestational diabetes mellitus (GDM). The increased risk of macrosomia in GDM is mainly due to the increased insulin resistance of the mother. In GDM, a higher amount of blood glucose passes through the placenta into the fetal circulation. As a result, extra glucose in the fetus is stored as body fat causing macrosomia, which is also called 'large for gestational age'. This paper reviews studies that explored the impact of GDM and fetal macrosomia as well as macrosomia-related complications on birth outcomes and offers an evaluation of maternal and fetal health. SUMMARY: Fetal macrosomia is a common adverse infant outcome of GDM if unrecognized and untreated in time. For the infant, macrosomia increases the risk of shoulder dystocia, clavicle fractures and brachial plexus injury and increases the rate of admissions to the neonatal intensive care unit. For the mother, the risks associated with macrosomia are cesarean delivery, postpartum hemorrhage and vaginal lacerations. Infants of women with GDM are at an increased risk of becoming overweight or obese at a young age (during adolescence) and are more likely to develop type II diabetes later in life. Besides, the findings of several studies that epigenetic alterations of different genes of the fetus of a GDM mother in utero could result in the transgenerational transmission of GDM and type II diabetes are of concern.

MicroRNAs (miRNAs) are a class of small noncoding RNAs that have gained status as important regulators of gene expression. Here, we investigated the function and molecular mechanisms of the miR-208 family of miRNAs in adult mouse heart physiology. We found that miR-208a, which is encoded within an intron of alpha-cardiac muscle myosin heavy chain gene (Myh6), was actually a member of a miRNA family that also included miR-208b, which was determined to be encoded within an intron of beta-cardiac muscle myosin heavy chain gene (Myh7). These miRNAs were differentially expressed in the mouse heart, paralleling the expression of their host genes. Transgenic overexpression of miR-208a in the heart was sufficient to induce hypertrophic growth in mice, which resulted in pronounced repression of the miR-208 regulatory targets thyroid hormone-associated protein 1 and myostatin, 2 negative regulators of muscle growth and hypertrophy. Studies of the miR-208a Tg mice indicated that miR-208a expression was sufficient to induce arrhythmias. Furthermore, analysis of mice lacking miR-208a indicated that miR-208a was required for proper cardiac conduction and expression of the cardiac transcription factors homeodomain-only protein and GATA4 and the gap junction protein connexin 40. Together, our studies uncover what we believe are novel miRNA-dependent mechanisms that modulate cardiac hypertrophy and electrical conduction.

OBJECTIVES: The aim of this study was to investigate the chest computed tomography (CT) findings in patients with confirmed coronavirus disease 2019 (COVID-19) and to evaluate its relationship with clinical features. MATERIALS AND METHODS: Study sample consisted of 80 patients diagnosed as COVID-19 from January to February 2020. The chest CT images and clinical data were reviewed, and the relationship between them was analyzed. RESULTS: Totally, 80 patients diagnosed with COVID-19 were included. With regards to the clinical manifestations, 58 (73%) of the 80 patients had cough, and 61 (76%) of the 80 patients had high temperature levels. The most frequent CT abnormalities observed were ground glass opacity (73/80 cases, 91%), consolidation (50/80 cases, 63%), and interlobular septal thickening (47/80, 59%). Most of the lesions were multiple, with an average of 12 ± 6 lung segments involved. The most common involved lung segments were the dorsal segment of the right lower lobe (69/80, 86%), the posterior basal segment of the right lower lobe (68/80, 85%), the lateral basal segment of the right lower lobe (64/80, 80%), the dorsal segment of the left lower lobe (61/80, 76%), and the posterior basal segment of the left lower lobe (65/80, 81%). The average pulmonary inflammation index value was (34% ± 20%) for all the patients. Correlation analysis showed that the pulmonary inflammation index value was significantly correlated with the values of lymphocyte count, monocyte count, C-reactive protein, procalcitonin, days from illness onset, and body temperature (P < 0.05). CONCLUSIONS: The common chest CT findings of COVID-19 are multiple ground glass opacity, consolidation, and interlobular septal thickening in both lungs, which are mostly distributed under the pleura. There are significant correlations between the degree of pulmonary inflammation and the main clinical symptoms and laboratory results. Computed tomography plays an important role in the diagnosis and evaluation of this emerging global health emergency.

Postpartum depression (PPD) is the most common psychological condition following childbirth, and may have a detrimental effect on the social and cognitive health of spouses, infants, and children. The aim of this study was to complete a comprehensive overview of the current literature on the global epidemiology of PPD. A total of 565 studies from 80 different countries or regions were included in the final analysis. Postpartum depression was found in 17.22% (95% CI 16.00-18.51) of the world's population. Meta-regression analysis showed that study size, country or region development, and country or region income were the causes of heterogeneity. Multivariable meta-regression analysis found that study size and country or area development were the most important predictors. Varied prevalence rates were noted in geographic regions with the highest rate found in Southern Africa (39.96%). Of interested was a significantly lower rate of PPD in developed countries or high-income countries or areas. Furthermore, the findings showed that there was a substantial difference in rates of PPD when marital status, educational level, social support, spouse care, violence, gestational age, breast feeding, child mortality, pregnancy plan, financial difficulties, partnership, life stress, smoking, alcohol intake, and living conditions were considered in the pooled estimates. Our results indicated that one out of every five women experiences PPD which is linked to income and geographic development. It is triggered by a variety of causes that necessitate the attention and committed intervention of primary care providers, clinicians, health authorities, and the general population.

Skeletal muscle satellite cells are adult stem cells responsible for postnatal skeletal muscle growth and regeneration. Paired-box transcription factor Pax7 plays a central role in satellite cell survival, self-renewal, and proliferation. However, how Pax7 is regulated during the transition from proliferating satellite cells to differentiating myogenic progenitor cells is largely unknown. In this study, we find that miR-1 and miR-206 are sharply up-regulated during satellite cell differentiation and down-regulated after muscle injury. We show that miR-1 and miR-206 facilitate satellite cell differentiation by restricting their proliferative potential. We identify Pax7 as one of the direct regulatory targets of miR-1 and miR-206. Inhibition of miR-1 and miR-206 substantially enhances satellite cell proliferation and increases Pax7 protein level in vivo. Conversely, sustained Pax7 expression as a result of the loss of miR-1 and miR-206 repression elements at its 3' untranslated region significantly inhibits myoblast differentiation. Therefore, our experiments suggest that microRNAs participate in a regulatory circuit that allows rapid gene program transitions from proliferation to differentiation.

Cardiovascular disease is the leading cause of human morbidity and mortality. Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy associated with heart failure. Here, we report that cardiac-specific knockout of Dicer, a gene encoding a RNase III endonuclease essential for microRNA (miRNA) processing, leads to rapidly progressive DCM, heart failure, and postnatal lethality. Dicer mutant mice show misexpression of cardiac contractile proteins and profound sarcomere disarray. Functional analyses indicate significantly reduced heart rates and decreased fractional shortening of Dicer mutant hearts. Consistent with the role of Dicer in animal hearts, Dicer expression was decreased in end-stage human DCM and failing hearts and, most importantly, a significant increase of Dicer expression was observed in those hearts after left ventricle assist devices were inserted to improve cardiac function. Together, our studies demonstrate essential roles for Dicer in cardiac contraction and indicate that miRNAs play critical roles in normal cardiac function and under pathological conditions.

MXenes, an emerging family of graphene-analogues two-dimensional (2D) materials, have attracted continuous and tremendous attention in many application fields because of their intrinsic physiochemical properties and high performance in versatile applications. In this work, we report on the construction of tantalum carbide (Ta4C3) MXene-based composite nanosheets for multiple imaging-guided photothermal tumor ablation, which has been achieved by rational choice of the composition of MXenes and their surface functionalization. A redox reaction was activated on the surface of tantalum carbide (Ta4C3) MXene for in situ growth of manganese oxide nanoparticles (MnOx/Ta4C3) based on the reducing surface of the nanosheets. The tantalum components of MnOx/Ta4C3 acted as the high-performance contrast agents for contrast-enhanced computed tomography, and the integrated MnOx component functionalized as the tumor microenvironment-responsive contrast agents for T1-weighted magnetic resonance imaging. The photothermal-conversion performance of MnOx/Ta4C3 composite nanosheets not only has achieved contrast-enhanced photoacoustic imaging, but also realized the significant tumor-growth suppression by photothermal hyperthermia. This work broadens the biomedical applications of MXenes, not only by the fabrication of family members of biocompatible MXenes, but also by the development of functionalization strategies of MXenes for cancer-theranostic applications.

Abstract Two‐dimensional (2D) MXenes, as a new 2D functional material nanosystem, have been extensively explored for broad applications. However, their specific performance and applications in theranostic nanomedicine have still rarely been explored. This work reports on the drug‐delivery performance and synergistic therapeutic efficiency of Ti 3 C 2 MXenes for highly efficient tumor eradication. These Ti 3 C 2 MXenes not only possess high drug‐loading capability of as high as 211.8%, but also exhibit both pH‐responsive and near infrared laser‐triggered on‐demand drug release. Especially, based on the high photothermal‐conversion capability of Ti 3 C 2 MXenes, they have been further explored for efficient tumor eradication by synergistic photothermal ablation and chemotherapy, which has been systematically demonstrated both in vitro and in vivo. These Ti 3 C 2 MXenes have also been demonstrated as the desirable contrast agents for photoacoustic imaging, showing the potential for diagnostic‐imaging guidance and monitoring during therapy. The high in vivo histocompatibility of Ti 3 C 2 and their easy excretion out of the body have been evaluated and demonstrated, showing the potential high biosafety for further clinical translation. This work paves a new way for broadening biomedical applications of MXenes in nanomedicine where they can exert the high performance and functionality for synergistic therapy, especially on combating cancer.

A systematic review and meta-analysis was conducted in an attempt to systematically collect and evaluate the associations of epidemiological, comorbidity factors with the severity and prognosis of coronavirus disease 2019 (COVID-19). The systematic review and meta-analysis was conducted according to the guidelines proposed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Sixty nine publications met our study criteria, and 61 studies with more than 10,000 COVID-19 cases were eligible for the quantitative synthesis. We found that the males had significantly higher disease severity (RR: 1.20, 95% CI: 1.13-1.27, P <0.001) and more prognostic endpoints. Older age was found to be significantly associated with the disease severity and six prognostic endpoints. Chronic kidney disease contributed mostly for death (RR: 7.10, 95% CI: 3.14-16.02), chronic obstructive pulmonary disease (COPD) for disease severity (RR: 4.20, 95% CI: 2.82-6.25), admission to intensive care unit (ICU) (RR: 5.61, 95% CI: 2.68-11.76), the composite endpoint (RR: 8.52, 95% CI: 4.36-16.65,), invasive ventilation (RR: 6.53, 95% CI: 2.70-15.84), and disease progression (RR: 7.48, 95% CI: 1.60-35.05), cerebrovascular disease for acute respiratory distress syndrome (ARDS) (RR: 3.15, 95% CI: 1.23-8.04), coronary heart disease for cardiac abnormality (RR: 5.37, 95% CI: 1.74-16.54). Our study highlighted that the male gender, older age and comorbidities owned strong epidemiological evidence of associations with the severity and prognosis of COVID-19.

ABSTRACT Carbapenem-resistant Enterobacteriaceae (CRE) infection is highly endemic in China, but estimates of the infection burden are lacking. We established the incidence of CRE infection from a multicenter study that covered 25 tertiary hospitals in 14 provinces. CRE cases defined as carbapenem-nonsusceptible Citrobacter freundii , Escherichia coli , Enterobacter cloacae , or Klebsiella pneumoniae infections during January to December 2015 were collected and reviewed from medical records. Antimicrobial susceptibility testing and carbapenemase gene identification were performed. Among 664 CRE cases, most were caused by K. pneumoniae (73.9%), followed by E. coli (16.6%) and E. cloacae (7.1%). The overall CRE infection incidence per 10,000 discharges was 4.0 and differed significantly by region, with the highest in Jiangsu (14.97) and the lowest in Qinghai (0.34). Underlying comorbidities were found in 83.8% of patients; the median patient age was 62 years (range, 45 to 74 years), and 450 (67.8%) patients were male. Lower respiratory tract infections (65.4%) were the most common, followed by urinary tract infection (16.6%), intra-abdominal infection (7.7%), and bacteremia (7.7%). The overall hospital mortality rate was 33.5%. All isolates showed nonsusceptibility to carbapenems and cephalosporins. The susceptibility rate of polymyxin B was &gt;90%. Tigecycline demonstrated a higher susceptibility rate against E. coli than against K. pneumoniae (90.9% versus 40.2%). Of 155 clinical isolates analyzed, 89% produced carbapenemases, with a majority of isolates producing KPC (50%) or NDM (33.5%)-type beta-lactamases among K. pneumoniae and E. coli . The incidence of CRE infection in China was 4.0 per 10,000 discharges. The patient-based disease burden in tertiary hospitals in China is severe, suggesting an urgent need to enhance infection control.

BACKGROUND: Physical therapy can prevent functional impairments and improve the quality of life of patients after hospital discharge. However, the effect of early mobilization on patients with a critical illness remains unclear. This study was performed to assess the evidence available regarding the effect of early mobilization on critically ill patients in the intensive care unit (ICU). METHODS: Electronic databases were searched from their inception to March 21, 2019. Randomized controlled trials (RCTs) comprising critically ill patients who received early mobilization were included. The methodological quality and risk of bias of each eligible trial were assessed using the Cochrane Collaboration tool. Data were extracted using a standard collection form each included study, and processed using the Mantel-Haenszel (M-H) or inverse-variance (I-V) test in the STATA v12.0 statistical software. RESULTS: A total of 1,898 records were screened. Twenty-three RCTs comprising 2,308 critically ill patients were ultimately included. Early mobilization decreased the incidence of ICU-acquired weakness (ICU-AW) at hospital discharge (three studies, 190 patients, relative risk (RR): 0.60, 95% confidence interval (CI) [0.40, 0.90]; p = 0.013, I2 = 0.0%), increased the number of patients who were able to stand (one study, 50 patients, 90% vs. 62%, p = 0.02), increased the number of ventilator-free days (six studies, 745 patients, standardized mean difference (SMD): 0.17, 95% CI [0.02, 0.31]; p = 0.023, I2 = 35.5%) during hospitalization, increased the distance the patient was able to walk unassisted (one study, 104 patients, 33.4 (0-91.4) meters vs. 0 (0-30.4) meters, p = 0.004) at hospital discharge, and increased the discharged-to-home rate (seven studies, 793 patients, RR: 1.16, 95% CI [1.00, 1.34]; p = 0.046). The mortality (28-day, ICU and hospital) and adverse event rates were moderately increased by early mobilization, but the differences were statistically non-significant. However, due to the substantial heterogeneity among the included studies, and the low quality of the evidence, the results of this study should be interpreted with caution. Publication bias was not identified. CONCLUSIONS: Early mobilization appears to decrease the incidence of ICU-AW, improve the functional capacity, and increase the number of ventilator-free days and the discharged-to-home rate for patients with a critical illness in the ICU setting.

2D PEG-ylated MoS2/Bi2S3 composite nanosheets are successfully constructed by introducing bismuth ions to react with the two extra S atoms in a (NH4)2MoS4 molecule precursor for solvo­thermal synthesis of MoS2. The MBP nanosheets can serve as a promising platform for computed tomography and photoacoustic-imaging-guided tumor diagnosis, as well as combined tumor photothermal therapy and sensitized radiotherapy. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

CRC patients even in high doses, and some efficacy was observed in most of the treated patients.

The conventional inorganic semiconductors are not suitable for in vivo therapeutic nanomedicine because of the lack of an adequate and safe irradiation source to activate them. This work reports on the rational design of titania (TiO2)-based semiconductors for enhanced and synergistic sono-/photoinduced tumor eradication by creating an oxygen-deficient TiO2–x layer onto the surface of TiO2 nanocrystals, which can create a crystalline-disordered core/shell structure (TiO2@TiO2–x) with black color. As found in the lessons from traditional photocatalysis, such an oxygen-deficient TiO2–x layer with abundant oxygen defects facilitates and enhances the separation of electrons (e–) and holes (h+) from the energy-band structure upon external ultrasound irradiation, which can significantly improve the efficacy of sono-triggered sonocatalytic tumor therapy. Such an oxygen-deficient TiO2–x layer can also endow black titania nanoparticles with high photothermal-conversion efficiency (39.8%) at the NIR-II biowindow (1064 nm) for enhanced photothermal hyperthermia. Both in vitro cell level and systematic in vivo tumor-bearing mice xenograft evaluations have demonstrated the high synergistic efficacy of combined and enhanced sonodynamic therapy and photothermal ablation as assisted by oxygen-deficient black titania, which has achieved complete tumor eradication with high therapeutic biosafety and without obvious reoccurrence. This work not only provides the paradigm of high therapeutic efficacy of a combined sono-/photoinduced tumor-treatment protocol but also significantly broadens the nanomedical applications of semiconductor-based nanoplatforms by rational design of their nanostructures and control of their physiochemical properties.

Tumor hypoxia is one of the major challenges for the treatment of tumors, as it may negatively affect the efficacy of various anticancer modalities. In this study, a tumor-targeted redox-responsive composite biocatalyst is designed and fabricated, which may combine tumor starvation therapy and low-temperature photothermal therapy for the treatment of oxygen-deprived tumors. The nanosystem was prepared by loading porous hollow Prussian Blue nanoparticles (PHPBNs) with glucose oxidase (GOx) and then coating their surface with hyaluronic acid (HA) via redox-cleavable linkage, therefore allowing the nanocarrier to bind specifically with CD44-overexpressing tumor cells while also exerting control over the cargo release profile. The nanocarriers are designed to enhance the efficacy of the hypoxia-suppressed GOx-mediated starvation therapy by catalyzing the decomposition of intratumoral hydroperoxide into oxygen with PHPBNs, and the enhanced glucose depletion by the two complementary biocatalysts may consequently suppress the expression of heat shock proteins (HSPs) after photothermal treatment to reduce their resistance to the PHPBN-mediated low-temperature photothermal therapies.

Patient-derived xenograft (PDX) models, in which tumor tissues from patients are implanted into immunocompromised or humanized mice, have shown superiority in recapitulating the characteristics of cancer, such as the spatial structure of cancer and the intratumor heterogeneity of cancer. Moreover, PDX models retain the genomic features of patients across different stages, subtypes, and diversified treatment backgrounds. Optimized PDX engraftment procedures and modern technologies such as multi-omics and deep learning have enabled a more comprehensive depiction of the PDX molecular landscape and boosted the utilization of PDX models. These irreplaceable advantages make PDX models an ideal choice in cancer treatment studies, such as preclinical trials of novel drugs, validating novel drug combinations, screening drug-sensitive patients, and exploring drug resistance mechanisms. In this review, we gave an overview of the history of PDX models and the process of PDX model establishment. Subsequently, the review presents the strengths and weaknesses of PDX models and highlights the integration of novel technologies in PDX model research. Finally, we delineated the broad application of PDX models in chemotherapy, targeted therapy, immunotherapy, and other novel therapies.

Importance: Overweight and obesity in childhood and adolescence is a global health issue associated with adverse outcomes throughout the life course. Objective: To estimate worldwide prevalence of overweight and obesity in children and adolescents from 2000 to 2023 and to assess potential risk factors for and comorbidities of obesity. Data Sources: MEDLINE, Web of Science, Embase, and Cochrane. Study Selection: The inclusion criteria were: (1) studies provided adequate information, (2) diagnosis based on body mass index cutoffs proposed by accepted references, (3) studies performed on general population between January 2000 and March 2023, (4) participants were younger than 18 years. Data Extraction and Synthesis: The current study was performed in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines. DerSimonian-Laird random-effects model with Free-Tukey double arcsine transformation was used for data analysis. Sensitivity analysis, meta-regression, and subgroup analysis of obesity among children and adolescents were conducted. Main Outcomes and Measures: Prevalence of overweight and obesity among children and adolescents assessed by World Health Organization, International Obesity Task Force, the US Centers for Disease Control and Prevention, or other national references. Results: A total of 2033 studies from 154 different countries or regions involving 45 890 555 individuals were included. The overall prevalence of obesity in children and adolescents was 8.5% (95% CI 8.2-8.8). We found that the prevalence varied across countries, ranging from 0.4% (Vanuatu) to 28.4% (Puerto Rico). Higher prevalence of obesity among children and adolescents was reported in countries with Human Development Index scores of 0.8 or greater and high-income countries or regions. Compared to 2000 to 2011, a 1.5-fold increase in the prevalence of obesity was observed in 2012 to 2023. Substantial differences in rates of obesity were noted when stratified by 11 risk factors. Children and adolescents with obesity had a high risk of depression and hypertension. The pooled estimates of overweight and excess weight in children and adolescents were 14.8% (95% CI 14.5-15.1) and 22.2% (95% CI 21.6-22.8), respectively. Conclusions and Relevance: This study's findings indicated 1 of 5 children or adolescents experienced excess weight and that rates of excess weight varied by regional income and Human Development Index. Excess weight among children and adolescents was associated with a mix of inherent, behavioral, environmental, and sociocultural influences that need the attention and committed intervention of primary care professionals, clinicians, health authorities, and the general public.

In the era of ubiquitous high-throughput sequencing studies, there is a growing need for analysis tools that are not just performant but also comprehensive and user-friendly enough to cater to both novice and advanced users. This article introduces SeqKit2, the next iteration of the widely used sequence analysis tool SeqKit, featuring expanded functionality, performance optimizations, and support for additional compression methods. Retaining a pragmatic subcommand architecture, SeqKit2 represents substantial enhancement through the inclusion of 19 additional subcommands, expanding its overall repertoire to a total of 38 in eight categories. The new subcommands add functionality such as amplicon processing and robust, error-tolerant parsing of sequence records. In addition, three subcommands designed for real-time analysis are added for periodic monitoring of properties of FASTQ and Binary Alignment/Map alignment records and real-time streaming from multiple sequence files. The performance of SeqKit2 is benchmarked against the old version of SeqKit, Bioawk, Seqtk, and SeqFu tools. SeqKit2 consistently outperforms its predecessor, albeit with marginally higher memory usage, while maintaining competitive runtimes against other tools. With its broad functionality, proven usability, and ongoing development driven by user feedback, we hope that bioinformaticians will find SeqKit2 useful as a "Swiss army knife" of sequence and alignment processing-equally adept at facilitating ad hoc analyses and seamlessly integrating into larger pipelines.

Pluripotent mesenchymal stem cells (MSCs) are bone marrow stromal progenitor cells that can differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. Several signaling pathways have been shown to regulate the lineage commitment and terminal differentiation of MSCs. Here, we conducted a comprehensive analysis of the 14 types of bone morphogenetic protein (BMPs) for their abilities to regulate multilineage specific differentiation of MSCs. We found that most BMPs exhibited distinct abilities to regulate the expression of Runx2, Sox9, MyoD, and PPARgamma2. Further analysis indicated that BMP-2, BMP-4, BMP-6, BMP-7, and BMP-9 effectively induced both adipogenic and osteogenic differentiation in vitro and in vivo. BMP-induced commitment to osteogenic or adipogenic lineage was shown to be mutually exclusive. Overexpression of Runx2 enhanced BMP-induced osteogenic differentiation, whereas knockdown of Runx2 expression diminished BMP-induced bone formation with a decrease in adipocyte accumulation in vivo. Interestingly, overexpression of PPARgamma2 not only promoted adipogenic differentiation, but also enhanced osteogenic differentiation upon BMP-2, BMP-6, and BMP-9 stimulation. Conversely, MSCs with PPARgamma2 knockdown or mouse embryonic fibroblasts derived from PPARgamma2(-/-) mice exhibited a marked decrease in adipogenic differentiation, coupled with reduced osteogenic differentiation and diminished mineralization upon BMP-9 stimulation, suggesting that PPARgamma2 may play a role in BMP-induced osteogenic and adipogenic differentiation. Thus, it is important to understand the molecular mechanism behind BMP-regulated lineage divergence during MSC differentiation, as this knowledge could help us to understand the pathogenesis of skeletal diseases and may lead to the development of strategies for regenerative medicine.