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Background: The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents. Methods: We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant. Arterial ligation or wire injury was used to induce neointima in mice, whereas ApoE -/- and LDLR -/- (LDLR [low-density lipoprotein receptor]) mice fed a high-fat diet were applied to assess atherosclerosis. In addition, coronary stent implantation was performed on vaccine-immunized Bama miniature pigs, followed by optical coherence tomography to evaluate coronary intimal hyperplasia. Results: A vaccine, ATS7vac, was screened out from 3 candidates to effectively inhibit intimal thickening in murine carotid artery ligation models after vaccination. As well, immunization with ATS7vac alleviated neointima formation in murine wire injury models and mitigated atherosclerotic lesions in both hyperlipidemic ApoE -/- and LDLR -/- mice without lowering lipid levels. Preclinically, ATS7vac markedly impeded intimal hyperplasia in swine stented coronary arteries, but without significant immune-related organ injuries. Mechanistically, ATS7vac vaccination produced specific antibodies against ADAMTS-7, which markedly repressed ADAMTS-7–mediated COMP (cartilage oligomeric matrix protein) and TSP-1 (thrombospondin-1) degradation and subsequently inhibited vascular smooth muscle cell migration but promoted re-endothelialization. Conclusions: ATS7vac is a novel atherosclerosis vaccine that also alleviates in-stent restenosis. The application of ATS7vac would be a complementary therapeutic avenue to the current lipid-lowering strategy for atherosclerotic disease.

Rock burst has always been a major problem for deep underground engineering with high stress. In order to effectively predict and evaluate rock burst intensity grade of underground rock mass engineering. In this paper, a cloud model (CM) rock burst intensity evaluation method based on CRITIC method and order relation analysis method (G1) is established. Firstly, the rock's uniaxial compressive strength σc, tangential stress σθ, uniaxial tensile strength σt, ratio of uniaxial compressive strength to tensile strength σc/σt (brittleness coefficient), ratio of tangential stress to uniaxial compressive strength σθ/σc (stress coefficient), elastic deformation energy index Wet and buried depth H are selected as evaluation indexes of rock burst intensity. 95 groups of rock burst measured data at home and abroad are selected, and the objective weight and subjective weight of each index are calculated by using CRITIC method and G1 method respectively. The combined weighting method of game theory is used to calculate the final weight and analyze the sensitivity of each evaluation index. MATLAB software was used to calculate the membership degree of different rock burst grades, and compared with the evaluation results of CRITIC-CM method and G1-CM method and the actual grades. And the rock burst classification ability of the model is analyzed. Finally, the rock burst case of W39 line in Chengchao Iron Mine was analyzed by using this model. The research results show that the rock burst evaluation results based on CRITIC-G1-CM are basically consistent with the actual rock burst grade, and the rock burst intensity grade evaluation model has good practicability and reliability.

In an acidic environment, the mineral components in rock begin to break down. As a result, the microstructure will be damaged, and then the mechanical properties will deteriorate, which will eventually have a negative effect on engineering stability. In order to study acid damage’s effect on this kind of rock, limestone samples were acidified for 0 days, 5 days, 10 days, 15 days, and 20 days. The microstructure changes in the limestone after acidification were studied via the wave velocity test and electron microscope scanning, and the damage deterioration mechanism was revealed. The results show that the acoustic signal of acidified samples has an obvious absorption effect at high frequency, and the surface pore structure of acidified samples shows fractal characteristics. The P-wave velocity, main peak amplitude, and fractal dimension of the acidified samples did not gradually decrease with time; however, there was a short-term strengthening phenomenon during immersion, which was mainly caused by the formation of CaSO4 crystals.

Neurodegenerative diseases are debilitating impairments that affect millions of people worldwide and are characterized by progressive degeneration of structure and function of the central or peripheral nervous system. Effective biomarkers for neurodegenerative diseases can be used to improve the diagnostic workup in the clinic as well as facilitate the development of effective disease-modifying therapies. Progranulin (PGRN) has been reported to be involved in various neurodegenerative disorders. Hence, in the current study we systematically compared the inflammation and accumulation of typical neurodegenerative disease markers in the brain tissue between PGRN knockout (PGRN KO) and wildtype (WT) mice. We found that PGRN deficiency led to significant neuron loss as well as activation of microglia and astrocytes in aged mice. Several characteristic neurodegenerative markers, including α-synuclein, TAR DNA-binding protein 43 (TDP-43), Tau, and β-amyloid, were all accumulated in the brain of PGRN-deficient mice as compared to WT mice. Moreover, higher aggregation of lipofuscin was observed in the brain tissue of PGRN-deficient mice compared with WT mice. In addition, the autophagy was also defective in the brain of PGRN-deficient mice, indicated by the abnormal expression level of autophagy marker LC3-II. Collectively, comprehensive assays support the idea that PGRN plays an important role during the development of neurodegenerative disease, indicating that PGRN might be a useful biomarker for neurodegenerative diseases in clinical settings.

Refereed/Peer-reviewed Introductions: Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive mechanical loading leads to a catabolic response as well as exaggerated cell death. Ferroptosis is a recently identified form of cell death during cell aging and degeneration. However, it's potential association with mechanical stress remains to be illustrated. Objectives: To identify whether excessive mechanical stress can cause ferroptosis. To explore the role of mechanical overloading in chondrocyte ferroptosis. Methods: Chondrocytes were collected from loading and unloading zones of cartilage in patients with osteoarthritis (OA), and the ferroptosis phenotype was analyzed through transmission electron microscope and microarray. Moreover, the relationship between ferroptosis and OA was analyzed by GPX4-conditional knockout (Col2a1-CreERT: GPX4flox/flox) mice OA model and chondrocytes cultured with high strain mechanical stress. Furthermore, the role of Piezo1 ion channel in chondrocyte ferroptosis and OA development was explored by using its inhibitor (GsMTx4) and agonist (Yoda1). Additionally, chondrocyte was cultured in calcium-free medium with mechanical stress, and ferroptosis phenotype was tested. Results: Human cartilage and mouse chondrocyte experiments revealed that mechanical overloading can induce GPX4-associated ferroptosis. Conditional knockout of GPX4 in cartilage aggravated experimental OA process, while additional treatment with ferroptosis suppressor protein (FSP-1) and coenzyme Q10 (CoQ10) abated OA development in GPX4-CKO mice. In mouse OA model and chondrocyte experiments, inhibition of Piezo1 channel activity increased GPX4 expression, attenuated ferroptosis phenotype and reduced the severity of osteoarthritis. Additionally, high strain mechanical stress induced ferroptosis damage in chondrocyte was largely abolished by blocking calcium influx through calcium-free medium. Conclusions: Our findings show that mechanical overloading induces ferroptosis through Piezo1 activation and subsequent calcium influx in chondrocytes, which might provide a potential target for OA treatment.

The mechanics of rock masses in cold regions have attracted the attention of researchers from all over the world, and the concern here is that the mechanical properties of rock masses are inevitably weakened under freeze–thaw cycles. In this paper, first, granite samples were subjected to different freeze–thaw cycles, and then treated in four different states, such as saturated and frozen states, saturated and normal temperature states, dry and frozen states, as well as dry and normal temperature states. The impact compression test was carried out using the Split Hopkinson Pressure Bar (SHPB) device. Results show that the impact strength of granite samples deteriorates with the increase of freeze–thaw cycles in the same state; for samples in different states, although the number of freeze–thaw cycles is equal, the degree of deterioration of the impact strength is different. For freeze–thawed granite samples in the same state, the dynamic elastic modulus decreases with the increase of freeze–thaw cycles, and its degree of decrease is different for different states. Under the same freeze–thaw cycles, the deterioration of mechanical properties of granite samples is different in four different weather states; for example, the dynamic elastic modulus from large to small is generally as follows: saturated and frozen states, saturated and normal temperature states, dry and frozen states, as well as dry and normal temperature states. Finally, the freeze–thaw influence factor is proposed to describe the damage of granite samples. All in all, it can be concluded that water and low temperature strengthen the influence of freeze–thaw cycles on the dynamic mechanical properties of granite.

Articular cartilage injury, as a hallmark of arthritic diseases, is difficult to repair and causes joint pain, stiffness, and loss of mobility. Over the years, the most significant problems for the drug-based treatment of arthritis have been related to drug administration and delivery. In recent years, much research has been devoted to developing new strategies for repairing or regenerating the damaged osteoarticular tissue. The RNA interference (RNAi) has been suggested to have the potential for implementation in targeted therapy in which the faulty gene can be edited by delivering its complementary Short Interfering RNA (siRNA) at the post-transcriptional stage. The successful editing of a specific gene by the delivered siRNA might slow or halt osteoarthritic diseases without side effects caused by chemical inhibitors. However, cartilage siRNA delivery remains a challenging objective because cartilage is an avascular and very dense tissue with very low permeability. Furthermore, RNA is prone to degradation by serum nucleases (such as RNase H and RNase A) due to an extra hydroxyl group in its phosphodiester backbone. Therefore, successful delivery is the first and most crucial requirement for efficient RNAi therapy. Nanomaterials have emerged as highly advantage tools for these studies, as they can be engineered to protect siRNA from degrading, address barriers in siRNA delivery to joints, and target specific cells. This review will discuss recent breakthroughs of different siRNA delivery technologies for cartilage diseases.

Rocks in cold regions are often exposed to extreme temperature change, and different loading conditions, therefore, will be subjected to deterioration. In this study, the deterioration of sandstone after freeze-thaw (F-T) cycles under quasi-static and dynamic loading conditions is investigated. In doing so, physical and mechanical properties of sandstone samples were studied after 20, 60, 100 and 140 F-T cycles. An increase in porosity and decrease in P wave velocity demonstrated a degradation in physical properties after F-T cycles. In addition, peak strengths of specimens were observed to be higher in the dynamic loading conditions as compared with the quasi-static conditions; while Young's modulus almost remained constant. Furthermore, a decay model was used to predict the deterioration of sandstone under different loading conditions and F-T cycles. Finally, the effects of F-T cycles on a brittleness and strain energy development were investigated. It was observed that rock became more brittle in the pre-peak regime after F-T cycles. It also demonstrated strain energies including the pre-peak, the peak, the post-peak and the total strain energies decrease after F-T cycles while variations of elastic strain energy with F-T cycles doesn't show any conclusive trend. Correlations between porosity and strain energies implied that porosity is a key factor in strain energy development for this kind of sandstone except that of elastic strain energy.

Abdominal aortic aneurysm (AAA) is a lethal cardiovascular disease, and there is no proven drug treatment for this condition. In this study, by using the Connectivity Map (CMap) approach, we explored naringenin, a naturally occurring citrus flavonoid, as a putative agent for inhibiting AAA. We then validated the prediction with two independent mouse models of AAA, calcium phosphate (CaPO4)-induced C57BL/6J mice and angiotensin II-infused ApoE−/− mice. Naringenin effectively blocked the formation of AAAs and the progression of established AAAs. Transcription factor EB (TFEB) is the master regulator of lysosome biogenesis. Intriguingly, the protective role of naringenin on AAA was abolished by macrophage-specific TFEB depletion in mice. Unbiased interactomics, combined with isothermal titration calorimetry (ITC) and cellular thermal shift assays (CETSAs), further revealed that naringenin is directly bound to 14-3-3 epsilon blocked the TFEB-14-3-3 epsilon interaction, and therefore promoted TFEB nuclear translocation and activation. On one hand, naringenin activated lysosome-dependent inhibition of the NLRP3 inflammasome and repressed aneurysmal inflammation. On the other hand, naringenin induced TFEB-dependent transcriptional activation of GATA3, IRF4, and STAT6 and therefore promoted reparative M2 macrophage polarization. In summary, naturally derived naringenin or macrophage TFEB activation shows promising efficacy for the treatment of AAA.

The mechanics of rock masses in cold regions have attracted the attention of researchers from all over the world, and the concern here is that the mechanical properties of rock masses are inevitably weakened under freeze-thaw cycles. In this paper, firstly, granite samples were subjected to different freeze-thaw cycles, after that, we dealt with the freeze-thawed samples considering four different states, such as saturated and frozen states, saturated and normal temperature states, dry and frozen states as well as dry and normal temperature states. The impact compression test was carried out by using the Split Hopkinson Pressure Bar (SHPB) device. Results show that the impact strength of granite samples deteriorates with the increase of freeze-thaw cycles in the same state, for samples in different states, although the number of freeze-thaw cycles is equal, the degree of deterioration of the impact strength is different. For freeze-thawed granite samples in the same state, the dynamic elastic modulus decreases with the increase of freeze-thaw cycles, and its degree of decrease is different for different states. Under the same freeze-thaw cycles, the deterioration of mechanical properties of granite samples is different in four different weather states, for example, the dynamic elastic modulus from large to small is generally as follows: saturated and frozen states, saturated and normal temperature states, dry and frozen states as well as dry and normal temperature states. Finally, the freeze-thaw influence factor is proposed to describe the damage of granite samples. All in all, it can be concluded that water and low temperature strengthen the influence of freeze-thaw cycles on the dynamic mechanical properties of granite samples.

The deterioration mechanism and dynamic tensile properties of rock subjected to the effects of freeze-thaw cycles are investigated in this study. Brazilian disc granite specimens are treated by 0, 30, 60, 90 and 120 freeze-thaw cycles. Freezing and thawing temperatures are −20 °C and 20 °C respectively. The microscopic damage in the rock samples induced by freeze-thaw treatment is detected by the nuclear magnetic resonance (NMR) technique. T2 spectrum and magnetic resonance imaging (MRI) are used to analyze the effect of freeze-thaw cycles on the pore structure of rock samples. Brazilian splitting tests are performed by a split Hopkinson pressure bar (SHPB) system to measure the dynamic tensile strength of granite and to investigate the effect of freeze-thaw cycles on the dynamic tensile strength and the dynamic mechanical behavior. A formula for dynamic tensile strength prediction considering loading rates and freeze-thaw cycles is presented to quantify the results. The dynamic failure process of specimen is observed by a high-speed camera, it was found that the rock materials were more susceptible to damage and deteriorate after freeze-thaw treatment compared with the untreated rock.

Rocks are often exposed to chemical erosion and extreme temperature changes in cold regions. In this study, the deterioration of sandstone is investigated under rapid freeze-thaw (F-T) cycles. To do so, physical and mechanical properties of sandstone specimens immersed in different chemical solutions were studied after 10, 20 and 30 freeze-thaw cycles. It was found that after applying freeze-thaw cycle specimens' mass, tensile strength and point load strength decrease at different extent while porosity increases. Coupled effects of chemical erosion and freeze-thaw cycles were observed to have a destructive damage on physical and mechanical properties. In this regard, the samples experienced deterioration at different extend when immersed in different chemical solutions. The maximum deterioration was observed for samples being immersed in NaOH solution, followed by that of NaCl solution, H2SO4 solution and pure water. Finally, a decay function model is used to further investigate the variations of splitting tensile strength and point load index with freeze-thaw cycles and predict deterioration of rock integrity.

To study the influence of freeze-thaw weathering on dynamic tensile properties and damage mechanism of rock material, the porosity and T2 spectrum distribution of rock samples underwent different freeze-thaw cycles were obtained by nuclear magnetic resonance (NMR), and the variation of micropores and macropore that caused by freeze-thaw cycles were calculated by T2 spectrum and then analyzed. In addition, the dynamic splitting tensile test was carried out on rock samples by using split Hopkins pressure bar (SHPB), and dynamic tensile peak strength, Young's modulus and peak strain were gained and analyzed. Dynamic tensile strength degradation prediction model was established to predict the damage of rock caused by freeze-thaw weathering. Results show that the porosity of the rock sample increases with freeze-thaw cycles increase, the freeze-thaw damage on rock microstructure is mainly caused by the expansion of micropores into macropores, while the initiation of micropores is the secondary reason. With freeze-thaw cycles increasing, the peak strain increases, the dynamic Young's modulus decreases. In addition, the effect of freeze-thaw weathering deteriorates the rock's anti-deformation ability and durability.

The peridynamic (PD) theory has achieved good and wide application in analysing the fracture and crack propagation of rock-like materials. However, the results of the calculation may not be reliable due to rock heterogeneity. In this paper, the critical stretch that obeys a distribution function is proposed to describe the heterogeneity of the non-homogeneous materials. In addition, the relationship between the eigenvalue of the distribution function of the critical stretch and the macroscopic mechanical parameters of the non-homogeneous material is established. Based on the Weibull distribution function, the peridynamic model reflecting the heterogeneity of rock-like materials is established, and the relationship between the average critical stretch of rock-like materials bond and the shape parameter of Weibull distribution function is analysed. On this basis, we compared and analysed the simulation results obtained by the homogeneous analysis method (HAM) and the non-homogeneous analysis method (NHAM) by analysing three typical numerical calculation cases. Results show that NHAM not only reflects the inhomogeneity of rock-like materials, but numerical results of the crack propagation path and speed are more accurate than the traditional HAM numerical results.

The split Hopkinson pressure bar (SHPB) system with a spindle-shaped striker is widely used to test the characteristics of rock-like materials subjected to dynamic loading, and the crack propagation of ring-shaped specimens under dynamic loading is a research focus in rock mechanics. In this paper, a model of the SHPB system, including the striker, incident bar, specimen, and transmitted bar, is established based on peridynamics theory and is validated by comparing two kinds of stress waves obtained by a peridynamics simulation and experiment. Based on these results, the crack propagation of a ring-shaped specimen with an aperture is simulated, and the influences of the apertures of the specimen on the failure patterns are discussed. The results show that there are four cracks distributed on the specimen with an aperture of 24 mm: crack-1 first initiates at the end of the inner diameter near the incident bar, crack-2 then occurs at the end of the inner diameter near the transmitted bar, and then crack-3, also called a secondary crack, initiates on the upper and lower outer boundaries of the specimen; these secondary cracks are perpendicular to the other cracks. The sequence of starting velocities and average propagation velocities of cracks from high to low is crack-3, crack-2, and crack-1, and the failure of the ring-shaped specimen occurs due to tension. Controlled by the structure effect of the ring-shaped specimen, the loading rate and the peak stress decrease gradually, and the failure patterns of the specimens transform from splatted by one initial crack to broken by two cracks that are perpendicular to each other and then to asymmetrical failure with an increase in the apertures of the specimen. The comparison results of peak stresses and failure patterns between the peridynamics simulation and the experimental results verify the accuracy of peridynamics theory.

Progranulin (PGRN) is a growth factor with a unique beads-on-a-string structure that is involved in multiple pathophysiological processes, including anti-inflammation, tissue repair, wound healing, neurodegenerative diseases, and tumorigenesis. This review presents up-to-date information concerning recent studies on the role of PGRN in inflammatory arthritis and osteoarthritis, with a special focus on the involvement of the interactions and interplay between PGRN and tumor necrosis factor receptor (TNFR) family members in regulating such musculoskeletal diseases. In addition, this paper highlights the applications of atsttrin, an engineered protein comprising three TNFR-binding fragments of PGRN, as a promising intervention in treating arthritis.

Deformation and failure of freeze-thawed rocks under dynamic loads are of practical meaning in studying the stability of slopes and tunnels in cold regions. The rock failure process is essentially actuated by the transfer and transformation of energy. In this paper, the energy dissipation characteristics and failure patterns of freeze-thawed granite under dynamic loads were investigated. A split Hopkinson pressure bar (SHPB) system was used to conduct the experiments on semicircular bend (SCB) specimens subjected to 30, 60, 90, and 120 freeze-thaw (F-T) cycles. The results found that the incident energy, reflected energy, and dissipation energy were loading rate-dependent, while the transmitted energy was not correlated with the loading rate. The reflected energy accounted for the largest proportion (greater than 60%) of the incident energy. In addition, the energy reflection rate (ERR) decreased when the loading rate or porosity increased, whereas the energy dissipation rate increased when the loading rate or porosity increased. A model was established to predict the ERR and EDR evolution. Finally, the failure patterns of freeze-thawed granite under dynamic loads demonstrated that a higher loading rate caused a change in failure patterns, whereas a larger porosity led to greater fragmentation in the specimens.

Hepatic progenitor/oval cell (OC) activation occurs when hepatocyte proliferation is inhibited and is tightly associated with the fibrogenic response during severe liver damage. Connective tissue growth factor (CTGF) is important for OC activation and contributes to the pathogenesis of liver fibrosis. By using the Yeast Two-Hybrid approach, we identified a disintegrin and metalloproteinase with thrombospondin repeat 7 (ADAMTS7) as a CTGF binding protein. In vitro characterization demonstrated CTGF binding and processing by ADAMTS7. Moreover, Adamts7 mRNA was induced during OC activation, after the implantation of 2-acetylaminofluorene with partial hepatectomy in rats or on feeding a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet in mice. X-Gal staining showed Adamts7 expression in hepatocyte nuclear factor 4α(+) hepatocytes and desmin(+) myofibroblasts surrounding reactive ducts in DDC-treated Adamts7(-/-) mice carrying a knocked-in LacZ gene. Adamts7 deficiency was associated with higher transcriptional levels of Ctgf and OC markers and enhanced OC proliferation compared to Adamts7(+/+) controls during DDC-induced liver injury. We also observed increased α-smooth muscle actin and procollagen type I mRNAs, large fibrotic areas in α-smooth muscle actin and Sirius red staining, and increased production of hepatic collagen by hydroxyproline measurement. These results suggest that ADAMTS7 is a new protease for CTGF protein and a novel regulator in the OC compartment, where its absence causes CTGF accumulation, leading to increased OC activation and biliary fibrosis.