Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing.

Background: Mechanical forces are indispensable for bone healing, disruption of which is recognized as a contributing cause to nonunion or delayed union. However, the underlying mechanism of mechanical regulation of fracture healing is elusive. Methods: We used the lineage-tracing mouse model, conditional knockout depletion mouse model, hindlimb unloading model and single-cell RNA sequencing to analyze the crucial roles of mechanosensitive protein polycystin-1 (PC1, Pkd1) promotes periosteal stem/progenitor cells (PSPCs) osteochondral differentiation in fracture healing. Results: Our results showed that cathepsin (Ctsk)-positive PSPCs are fracture-responsive and mechanosensitive and can differentiate into osteoblasts and chondrocytes during fracture repair. We found that polycystin-1 declines markedly in PSPCs with mechanical unloading while increasing in response to mechanical stimulus. Mice with conditional depletion of Pkd1 in Ctsk+ PSPCs show impaired osteochondrogenesis, reduced cortical bone formation, delayed fracture healing, and diminished responsiveness to mechanical unloading. Mechanistically, PC1 facilitates nuclear translocation of transcriptional coactivator TAZ via PC1 C-terminal tail cleavage, enhancing osteochondral differentiation potential of PSPCs. Pharmacological intervention of the PC1-TAZ axis and promotion of TAZ nuclear translocation using Zinc01442821 enhances fracture healing and alleviates delayed union or nonunion induced by mechanical unloading. Conclusion: Our study reveals that Ctsk+ PSPCs within the callus can sense mechanical forces through the PC1-TAZ axis, targeting which represents great therapeutic potential for delayed fracture union or nonunion.

Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma.

Soft tissue sarcoma is a broad family of mesenchymal malignancies exhibiting remarkable histological diversity. We portray the proteomic landscape of 272 soft tissue sarcomas representing 12 major subtypes. Hierarchical classification finds the similarity of proteomic features between angiosarcoma and epithelial sarcoma, and elevated expression of SHC1 in AS and ES is correlated with poor prognosis. Moreover, proteomic clustering classifies patients of soft tissue sarcoma into 3 proteomic clusters with diverse driven pathways and clinical outcomes. In the proteomic cluster featured with the high cell proliferation rate, APEX1 and NPM1 are found to promote cell proliferation and drive the progression of cancer cells. The classification based on immune signatures defines three immune subtypes with distinctive tumor microenvironments. Further analysis illustrates the potential association between immune evasion markers (PD-L1 and CD80) and tumor metastasis in soft tissue sarcoma. Overall, this analysis uncovers sarcoma-type-specific changes in proteins, providing insights about relationships of soft tissue sarcoma.

Energy homeostasis in the bone.

The bone serves as an energy reservoir and actively engages in whole-body energy metabolism. Numerous studies have determined fuel requirements and bioenergetic properties of bone under physiological conditions as well as the dysregulation of energy metabolism associated with bone metabolic diseases. Here, we review the main sources of energy in bone cells and their regulation, as well as the endocrine role of the bone in systemic energy homeostasis. Moreover, we discuss metabolic changes that occur as a result of osteoporosis. Exploration in this area will contribute to an enhanced comprehension of bone energy metabolism, presenting novel possibilities to address metabolic diseases.

Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing.

Skeletal stem/progenitor cell (SSPC) senescence is a major cause of decreased bone regenerative potential with aging, but the causes of SSPC senescence remain unclear. In this study, we revealed that macrophages in calluses secrete prosenescent factors, including grancalcin (GCA), during aging, which triggers SSPC senescence and impairs fracture healing. Local injection of human rGCA in young mice induced SSPC senescence and delayed fracture repair. Genetic deletion of Gca in monocytes/macrophages was sufficient to rejuvenate fracture repair in aged mice and alleviate SSPC senescence. Mechanistically, GCA binds to the plexin-B2 receptor and activates Arg2-mediated mitochondrial dysfunction, resulting in cellular senescence. Depletion of Plxnb2 in SSPCs impaired fracture healing. Administration of GCA-neutralizing antibody enhanced fracture healing in aged mice. Thus, our study revealed that senescent macrophages within calluses secrete GCA to trigger SSPC secondary senescence, and GCA neutralization represents a promising therapy for nonunion or delayed union in elderly individuals.

An Investigation of the Energy Harvesting Capabilities of a Novel Three-Dimensional Super-Cell Phononic Crystal with a Local Resonance Structure.

Using the piezoelectric (PZT) effect, energy-harvesting has become possible for phononic crystal (PnC). Low-frequency vibration energy harvesting is more of a challenge, which can be solved by local resonance phononic crystals (LRPnCs). A novel three-dimensional (3D) energy harvesting LRPnC is proposed and further analyzed using the finite element method (FEM) software COMSOL. The 3D LRPnC with spiral unit-cell structures is constructed with a low initial frequency and wide band gaps (BGs). According to the large vibration deformation of the elastic beam near the scatterer, a PZT sheet is mounted in the surface of that beam, to harvest the energy of elastic waves using the PZT effect. To further improve the energy-harvesting performance, a 5 × 5 super-cell is numerically constructed. Numerical simulations show that the present 3D super-cell PnC structure can make full use of the advantages of the large vibration deformation and the PZT effect, i.e., the BGs with a frequency range from 28.47 Hz to 194.21 Hz with a bandwidth of 142.7 Hz, and the maximum voltage output is about 29.3 V under effective sound pressure with a peak power of 11.5 µW. The present super-cell phononic crystal structure provides better support for low-frequency vibration energy harvesting, when designing PnCs, than that of the traditional Prague type.

Bone marrow immune cells respond to fluctuating nutritional stress to constrain weight regain.

Weight regain after weight loss is a major challenge in the treatment of obesity. Immune cells adapt to fluctuating nutritional stress, but their roles in regulating weight regain remain unclear. Here, we identify a stem cell-like CD7+ monocyte subpopulation accumulating in the bone marrow (BM) of mice and humans that experienced dieting-induced weight loss. Adoptive transfer of CD7+ monocytes suppresses weight regain, whereas inducible depletion of CD7+ monocytes accelerates it. These cells, accumulating metabolic memories via epigenetic adaptations, preferentially migrate to the subcutaneous white adipose tissue (WAT), where they secrete fibrinogen-like protein 2 (FGL2) to activate the protein kinase A (PKA) signaling pathway and facilitate beige fat thermogenesis. Nevertheless, CD7+ monocytes gradually enter a quiescent state after weight loss, accompanied by increased susceptibility to weight regain. Notably, administration of FMS-like tyrosine kinase 3 ligand (FLT3L) remarkably rejuvenates CD7+ monocytes, thus ameliorating rapid weight regain. Together, our findings identify a unique bone marrow-derived metabolic-memory immune cell population that could be targeted to combat obesity.

SARS-CoV-2 Omicron BA.5.2-infection and COVID-19 in persons with chronic myeloid leukaemia.

OBJECTIVE: A SARS-CoV-2 Omicron (BA.5.2) epidemic began in China in December, 2022 following stopping the zero COVID policy. METHODS: We studied features of the epidemic in 1,121 persons with chronic myeloid leukaemia (CML). RESULTS: 1103 (98%) were in chronic, 10 in accelerated and 8 in acute phases. 834 (74%) became infected almost all of whom met criteria for COVID-19. The most common symptoms were fever (91%), cough (90%) and fatigue (82%). 42 infected persons were asymptomatic. Most people quarantined at home and self-medicated. 22 were hospitalized for COVID-19. At admission 5 had mild, 14, moderate and 3, severe/critical disease according to World Health Organization (WHO) criteria. 5 received respiratory assistance, 3 were admitted to the intensive care unit (ICU) and 1 in accelerated phase died from COVID-19. Co-variates associated with a risk of COVID-19 in SARS-CoV-2-infected subjects include age ≥ 65 years, higher education level and imatinib therapy. CONCLUSION: In conclusion, most SARS-CoV-2 Omicron BA.5.2 infections in persons with CML resulted in COVID-19 most of which cases are mild with only 1 death.

Metal oxide nanoparticles embedded in porous carbon for sulfur absorption under hydrothermal conditions.

MOx (M = Zn, Cu, Mn, Fe, Ce) nanoparticles (NPs) embedded in porous C with uniform diameter and dispersion were synthesized, with potential application as S-absorbents to protect catalysts from S-poisoning in catalytic hydrothermal gasification (cHTG) of biomass. S-absorption performance of MOx/C was evaluated by reacting the materials with diethyl disulfide at HTG conditions (450 °C, 30 MPa, 15 min). Their S-absorption capacity followed the order CuOx/C > CeOx/C ≈ ZnO/C > MnOx/C > FeOx/C. S was absorbed in the first four through the formation of Cu1.8S, Ce2S3, ZnS, and MnS, respectively, with a capacity of 0.17, 0.12, 0.11, and 0.09 molS molM-1. The structure of MOx/C (M = Zn, Cu, Mn) evolved significantly during S-absorption reaction, with the formation of larger agglomerates and separation of MOx particles from porous C. The formation of ZnS NPs and their aggregation in place of hexagonal ZnO crystals indicate a dissolution/precipitation mechanism. Note that aggregated ZnS NPs barely sinter under these conditions. Cu(0) showed a preferential sulfidation over Cu2O, the sulfidation of the latter seemingly following the same mechanism as for ZnO. In contrast, FeOx/C and CeOx/C showed remarkable structural stability with their NPs well-dispersed within the C matrix after reaction. MOx dissolution in water (from liquid to supercritical state) was modeled and a correlation between solubility and particle growth was found, comforting the hypothesis of the importance of an Ostwald ripening mechanism. CeOx/C with high structural stability and promising S-absorption capacity was suggested as a promising bulk absorbent for sulfides in cHTG of biomass.

A Domain Adaption ResNet Model to Detect Faults in Roller Bearings Using Vibro-Acoustic Data.

Intelligent fault diagnosis of roller bearings is facing two important problems, one is that train and test datasets have the same distribution, and the other is the installation positions of accelerometer sensors are limited in industrial environments, and the collected signals are often polluted by background noise. In the recent years, the discrepancy between train and test datasets is decreased by introducing the idea of transfer learning to solve the first issue. In addition, the non-contact sensors will replace the contact sensors. In this paper, a domain adaption residual neural network (DA-ResNet) model using maximum mean discrepancy (MMD) and a residual connection is constructed for cross-domain diagnosis of roller bearings based on acoustic and vibration data. MMD is used to minimize the distribution discrepancy between the source and target domains, thereby improving the transferability of the learned features. Acoustic and vibration signals from three directions are simultaneously sampled to provide more complete bearing information. Two experimental cases are conducted to test the ideas presented. The first is to verify the necessity of multi-source data, and the second is to demonstrate that transfer operation can improve recognition accuracy in fault diagnosis.

Refining the time-frequency characteristic of non-stationary signal for improving time-frequency representation under variable speeds.

Time-frequency ridge not only exhibits the variable process of non-stationary signal with time changing but also provides the information of signal synchronous or non-synchronous components for subsequent detection research. Consequently, the key is to decrease the error between real and estimated ridge in the time-frequency domain for accurate detection. In this article, an adaptive weighted smooth model is presented as a post-processing tool to refine the time-frequency ridge which is based on the coarse estimated time-frequency ridge using newly emerging time-frequency methods. Firstly, the coarse ridge is estimated by using multi-synchrosqueezing transform for vibration signal under variable speed conditions. Secondly, an adaptive weighted method is applied to enhance the large time-frequency energy value location of the estimated ridge. Then, the reasonable smooth regularization parameter associated with the vibration signal is constructed. Thirdly, the majorization-minimization method is developed for solving the adaptive weighted smooth model. Finally, the refined time-frequency characteristic is obtained by utilizing the stop criterion of the optimization model. Simulation and experimental signals are given to validate the performance of the proposed method by average absolute errors. Compared with other methods, the proposed method has the highest performance in refinement accuracy.

Splicing factor YBX1 regulates bone marrow stromal cell fate during aging.

Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age-related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y-box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis-splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age-related osteoporosis.

Region-resolved multi-omics of the mouse eye.

The eye is a complex organ consisting of multiple compartments with unique and specialized properties, and small disturbances in one eye region can result in impaired vision and blindness. Although there have been advancements in ocular research, the hierarchical molecular network in region-wide resolution, indicating the division of labor and crosstalk among different eye regions, is not yet comprehensively illuminated. Here, we present an atlas of region-resolved proteome and lipidome of mouse eye. Multiphoton microscopy-guided laser microdissection combined with in-depth label-free proteomics identifies 13,536 proteins across various mouse eye regions. Further integrative analysis of spectral imaging, label-free proteome, and imaging mass spectrometry of the lipidome and phosphoproteome reveals distinctive molecular features, including proteins and lipids of various anatomical mouse eye regions. These deposited datasets and our open proteome server integrating all information provide a valuable resource for future functional and mechanistic studies of mouse eye and ocular disease.

Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms.

Diffuse gliomas are devastating brain tumors. Here, we perform a proteogenomic profiling of 213 retrospectively collected glioma tumors. Proteogenomic analysis reveals the downstream biological events leading by EGFR-, IDH1-, TP53-mutations. The comparative analysis illustrates the distinctive features of GBMs and LGGs, indicating CDK2 inhibitor might serve as a promising drug target for GBMs. Further proteogenomic integrative analysis combined with functional experiments highlight the cis-effect of EGFR alterations might lead to glioma tumor cell proliferation through ERK5 medicates nucleotide synthesis process. Proteome-based stratification of gliomas defines 3 proteomic subgroups (S-Ne, S-Pf, S-Im), which could serve as a complement to WHO subtypes, and would provide the essential framework for the utilization of specific targeted therapies for particular glioma subtypes. Immune clustering identifies three immune subtypes with distinctive immune cell types. Further analysis reveals higher EGFR alteration frequencies accounts for elevation of immune check point protein: PD-L1 and CD70 in T-cell infiltrated tumors.

Mutated lncRNA increase the risk of type 2 diabetes by promoting ß cell dysfunction and insulin resistance.

Islet ß cell dysfunction and insulin resistance are the main pathogenesis of type 2 diabetes (T2D), but the mechanism remains unclear. Here we identify a rs3819316 C > T mutation in lncRNA Reg1cp mainly expressed in islets associated with an increased risk of T2D. Analyses in 16,113 Chinese adults reveal that Mut-Reg1cp individuals had higher incidence of T2D and presented impaired insulin secretion as well as increased insulin resistance. Mice with islet ß cell specific Mut-Reg1cp knock-in have more severe ß cell dysfunction and insulin resistance. Mass spectrometry assay of proteins after RNA pulldown demonstrate that Mut-Reg1cp directly binds to polypyrimidine tract binding protein 1 (PTBP1), further immunofluorescence staining, western blot analysis, qPCR analysis and glucose stimulated insulin secretion test reveal that Mut-Reg1cp disrupts the stabilization of insulin mRNA by inhibiting the phosphorylation of PTBP1 in ß cells. Furthermore, islet derived exosomes transfer Mut-Reg1cp into peripheral tissue, which then promote insulin resistance by inhibiting AdipoR1 translation and adiponectin signaling. Our findings identify a novel mutation in lncRNA involved in the pathogenesis of T2D, and reveal a new mechanism for the development of T2D.

A mechanosensitive lipolytic factor in the bone marrow promotes osteogenesis and lymphopoiesis.

Exercise can prevent osteoporosis and improve immune function, but the mechanism remains unclear. Here, we show that exercise promotes reticulocalbin-2 secretion from the bone marrow macrophages to initiate bone marrow fat lipolysis. Given the crucial role of lipolysis in exercise-stimulated osteogenesis and lymphopoiesis, these findings suggest that reticulocalbin-2 is a pivotal regulator of a local adipose-osteogenic/immune axis. Mechanistically, reticulocalbin-2 binds to a functional receptor complex, which is composed of neuronilin-2 and integrin beta-1, to activate a cAMP-PKA signaling pathway that mobilizes bone marrow fat via lipolysis to fuel the differentiation and function of mesenchymal and hematopoietic stem cells. Notably, the administration of recombinant reticulocalbin-2 in tail-suspended and old mice remarkably decreases bone marrow fat accumulation and promotes osteogenesis and lymphopoiesis. These findings identify reticulocalbin-2 as a novel mechanosensitive lipolytic factor in maintaining energy homeostasis in bone resident cells, and it provides a promising target for skeletal and immune health.

miR-188-3p targets skeletal endothelium coupling of angiogenesis and osteogenesis during ageing.

A specific bone capillary subtype, namely type H vessels, with high expression of CD31 and endomucin, was shown to couple angiogenesis and osteogenesis recently. The number of type H vessels in bone tissue declines with age, and the underlying mechanism for this reduction is unclear. Here, we report that microRNA-188-3p (miR-188-3p) involves this process. miRNA-188-3p expression is upregulated in skeletal endothelium and negatively regulates the formation of type H vessels during ageing. Mice with depletion of miR-188 showed an alleviated age-related decline in type H vessels. In contrast, endothelial-specific overexpression of miR-188-3p reduced the number of type H vessels, leading to decreased bone mass and delayed bone regeneration. Mechanistically, we found that miR-188 inhibits type H vessel formation by directly targeting integrin ß3 in endothelial cells. Our findings indicate that miR-188-3p is a key regulator of type H vessel formation and may be a potential therapeutic target for preventing bone loss and accelerating bone regeneration.

A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population.

Clear cell renal cell carcinoma (ccRCC) is a common and aggressive subtype of renal cancer. Here we conduct a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. By comparing with tumor adjacent tissues, we find that ccRCC shows extensive metabolic dysregulation and an enhanced immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1-3), among which the most aggressive GP1 exhibits the strongest immune phenotype, increased metastasis, and metabolic imbalance, linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT), a one-carbon metabolic enzyme, is identified as a potential marker of ccRCC and a drug target for GP1. We demonstrate that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes ccRCC tumor growth. This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.

Signatures of TOP1 transcription-associated mutagenesis in cancer and germline.

The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4-a cancer insertion-deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions -is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome.