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Purpose Inflammatory and oxidative stress upregulates matrix metalloproteinase (MMP) activity, leading to intervertebral disc degeneration (IDD). Gene therapy using human tissue inhibitor of metalloproteinase 1 (hTIMP1) has effectively treated IDD in animal models. However, persistent unregulated transgene expression may have negative side effects. We developed a recombinant adeno-associated viral (AAV) gene vector, AAV-NFκB-hTIMP1, that only expresses the hTIMP1 transgene under conditions of stress. Methods Rabbit disc cells were transfected or transduced with AAV-CMV-hTIMP1, which constitutively expresses hTIMP1, or AAV-NFκB-hTIMP1. Disc cells were selectively treated with IL-1β. NFκB activation was verified by nuclear translocation. hTIMP1 mRNA and protein expression were measured by RT-PCR and ELISA, respectively. MMP activity was measured by following cleavage of a fluorogenic substrate. Results IL-1β stimulation activated NFκB demonstrating that IL-1β was a surrogate for inflammatory stress. Stimulating AAV-NFκB-hTIMP1 cells with IL-1β increased hTIMP1 expression compared to unstimulated cells. AAV-CMV-hTIMP1 cells demonstrated high levels of hTIMP1 expression regardless of IL-1β stimulation. hTIMP1 expression was comparable between IL-1β stimulated AAV-NFκB-hTIMP1 cells and AAV-CMV-hTIMP1 cells. MMP activity was decreased in AAV-NFκB-hTIMP1 cells compared to baseline levels or cells exposed to IL-1β. Conclusion AAV-NFκB-hTIMP1 is a novel inducible transgene delivery system. NFκB regulatory elements ensure that hTIMP1 expression occurs only with inflammation, which is central to IDD development. Unlike previous inducible systems, the AAV-NFκB-hTIMP1 construct is dependent on endogenous factors, which minimizes potential side effects caused by constitutive transgene overexpression. It also prevents the unnecessary production of transgene products in cells that do not require therapy.

In engineering, the method of charts can provide a convenient query for specific engineering problems. To provide the basis for the potential hazard evaluation and rational governance of the goaf, it is necessary to study the quantitative evaluation for the range of goaf roof caving. Undoubtedly, the charts used to visually query the caving range can simplify the workload of the quantitative evaluation. Therefore, the methods of dimensional analysis, numerical simulation, and linear interpolation are introduced to study the dimensionless charts for predicting the caving range. The dimensionless analysis is used to establish the fuzzy function relationship among the influence factors of the goaf roof caving, and the numerical simulation is used to calculate the dimensionless groups in the fuzzy function. Using the linear interpolation, the dimensionless charts in this work can predict the range of goaf roof caving under more working conditions. The results show that the characteristics of the goaf roof caving corresponding to the dimensionless curves are consistent with the actual situation. With the continuous increase of the goaf span l, the dimensionless curves of the caving range experience zero growth, rapid growth, and steady growth. The growth degree varies with the fracture spacing S. Especially in the zero growth phase, the duration of the relatively stable state in the overlying strata of the goaf increases with the increase of fracture spacing S. Moreover, based on the case study of Shirengou Iron Mine, the dimensionless charts obtained in this work can predict the range of goaf roof caving under different working conditions, which indicates the findings of this study have certain guiding significance to the treatment of the goaf.

Underground mining activities make the fractures in the natural rock mass develop randomly. The elastic modulus of the fractured rock mass Em is changed with the redistribution and development of the fractures. An equivalent model of fractured rock mass is structured to represent the hydraulic conductivity and the rock mass strain because of the continuum theory. Dimensional analysis is very useful to build relationship of the parameters in complex physical phenomena. Based on the engineering phenomenon of groundwater flowing into the goaf along the fracture in the rock mass, a fuzzy expression among parameters such as the parameter Em, the seepage flow Q, and the exposed area of the goaf A is obtained using dimensionless analysis. To calculate the parameter Em, the fuzzy relationship is then characterized by Darcy’s law and numerical simulation. Under the scripting environment of Python, an automated program to realize the numerical simulation of all scenarios is established, which also provides convenience for drawing the dimensionless flux charts. The results show that the parameter Em can be calculated by the dimensional analysis coupled with numerical simulation. In addition, the parameter Em decreases with the increase of the parameter Q, and the integrity of rock mass is also worse. Finally, a mine example is used to verify the feasibility of the method.

Background: Anterior cervical discectomy and fusion (ACDF) is the gold standard treatment for this cervical radiculopathy. Posterior endoscopic cervical foraminotomy (PECF), an effective alternative to ACDF, is becoming widely used by an increasing number of surgeons. However, comparisons of the clinical outcomes of ACDF and PECF remain poorly explored. The purpose of this study was to evaluate and compare visual analog scale (VAS)-arm scores, VAS-neck scores, neck disability index (NDI) scores, reoperation, and complications in PECF and ACDF. Materials and Methods: We comprehensively searched electronic databases or platforms, including PubMed, Web of Science, EMBASE, and the Cochrane Controlled Trial Center, using the PRISMA guidelines. The required information, including VAS-arm scores, VAS-neck scores, NDI scores, reoperation, and complications, was extracted from qualified studies and independently tested and compared by 2 researchers. The methodological index for nonrandomized studies was used to evaluate study quality. Results: Nine studies consisting of 230 males and 256 females were included. The mean age of the included patients was 49.6 years, and the mean follow-up time was 20.6 months. The VAS-arm scores were significantly higher, and VAS-neck scores and NDI scores of PECF showed greater improvement trends for PECF than ACDF. The complication proportion of patients with PECF was lower, while the proportion of reoperation was similar between PECF and ACDF. ACDF was the most common revision surgery. The most common complication of PECF was transient paresthesia. Conclusion: Compared with ACDF, PECF is safe and effective in patients with unilateral cervical radiculopathy without myelopathy, and PECF does not increase the probability of reoperation and complications.

The critical state of rock is an important index for measuring the changes in rock characteristics. However, this state is not unique because of the different researcher assumptions. Based on the theory of the partial differential equation proposed by Vutukuri, according to Mohr’s envelope, a piecewise yield failure criterion (referred to as the Mohr–Wedge criterion), including the critical state for brittle rock, is obtained by introducing the wedge model to solve this equation. The Mohr–Wedge (M–W) criterion consisting of nonlinear and linear components includes the critical state for brittle rock. When the minimum principal stress σ3 is lower than the confining pressure σk, the maximum principal stress σ1 varies nonlinearly with σ3; otherwise, σ1 varies linearly with σ3. This variation conforms to rock deformation features under triaxial compression. In this study, we investigate the rationality of this critical state by an analogy method and illustrate that the critical state mentioned in this criterion is related to the microcracks in the potential failure zone of the rock. Alternatively, the primary object of this study is to reveal the applicability of predicting the yield state for this criterion. The method used in our study is compared to the Mohr–Coulomb (M-C) criterion, the Hoek–Brown (H-B) criterion, and the Exponential (Exp.) criterion by the yield surfaces on the deviatoric plane. Notably, there is a vertex consistent region for the four criteria, but except for this region, the yield state of rock predicted by the four criteria is quite different, depending on the extent of the parameters for the criteria and the magnitude of the slopes of the yield surfaces. The results show that the M-W criterion has certain applicability for predicting the rock yield state by using the multiple data of rock triaxial compression tests in the published literature.

Inflammatory and oxidative stress upregulates matrix metalloproteinase (MMP) activity, leading to intervertebral disc degeneration (IDD). Gene therapy using human tissue inhibitor of metalloproteinase 1 (hTIMP1) has effectively treated IDD in animal models. However, persistent unregulated transgene expression may have negative side effects. We developed a recombinant adeno-associated viral (AAV) gene vector, AAV-NFκB-hTIMP1, that only expresses the hTIMP1 transgene under conditions of stress.Rabbit disc cells were transfected or transduced with AAV-CMV-hTIMP1, which constitutively expresses hTIMP1, or AAV-NFκB-hTIMP1. Disc cells were selectively treated with IL-1β. NFκB activation was verified by nuclear translocation. hTIMP1 mRNA and protein expression were measured by RT-PCR and ELISA, respectively. MMP activity was measured by following cleavage of a fluorogenic substrate.IL-1β stimulation activated NFκB demonstrating that IL-1β was a surrogate for inflammatory stress. Stimulating AAV-NFκB-hTIMP1 cells with IL-1β increased hTIMP1 expression compared to unstimulated cells. AAV-CMV-hTIMP1 cells demonstrated high levels of hTIMP1 expression regardless of IL-1β stimulation. hTIMP1 expression was comparable between IL-1β stimulated AAV-NFκB-hTIMP1 cells and AAV-CMV-hTIMP1 cells. MMP activity was decreased in AAV-NFκB-hTIMP1 cells compared to baseline levels or cells exposed to IL-1β.AAV-NFκB-hTIMP1 is a novel inducible transgene delivery system. NFκB regulatory elements ensure that hTIMP1 expression occurs only with inflammation, which is central to IDD development. Unlike previous inducible systems, the AAV-NFκB-hTIMP1 construct is dependent on endogenous factors, which minimizes potential side effects caused by constitutive transgene overexpression. It also prevents the unnecessary production of transgene products in cells that do not require therapy.

Introduction: Gene therapy using the anti-catabolic factor Tissue Inhibitor of Metalloproteinase-1 (hTIMP1) has shown promising efficacy in treating disc degeneration. However, a major limitation of the current gene therapy technique is the use of a constitutive promoter to drive transgene expression that results in uncontrolled and excessive expression of therapeutic gene product which could result in undesirable side effects. To overcome this important limitation, we successfully developed a new gene therapy recombinant adeno-associated viral (rAAV)vector, rAAV-NFkB-hTIMP1, in which the therapeutic recombinant human TIMP1 gene is placed under the control of a promoter containing the NF-kB element. The rAAV-NFkB-hTIMP1 construct is designed to produce the therapeutic gene product TIMP1 only when the cells experience stress which activates the NF-kB pathway. Hence we expect using this strategy that hTIMP1 will be selectively expressed in cells under inflammatory conditions typically found in active degenerating discs and not under normal conditions, in which the therapeutic gene was not needed. In this study we tested our hypothesis that rabbit annulus fibrosus cells transfected with aserotype 2 of rAAV vector carrying a hTIMP1 gene will not express high level of hTIMP1 unless stimulated with the IL-1b.Methods: Cultured rabbit annulus fibrosus (rAF) cells were divided into six groups; “Control” (cell only); “rAAV-CMV-hTIMP1(cells transfected with AAV-CMV-hTIMP1 plasmid DNA)” and “rAAV-NFkB-hTIMP1(cells transfected with AAV-NFkB-hTIMP1 plasmid DNA)” treated with and without IL-1b (n=4 for each group). Production of hTIMP1 was determined by RT-PCR. To determine if MMP activity was inhibited by the produced TIMP1, MMP activity assay was measured by following cleavage of a fluorogenic substrate.Results: RT-PCR analysis demonstrated that the level of hTIMP1 transcription from cells and culture media transfected with rAAV-NFkB-hTIMP1 construct was greater than in the IL-1b stimulated condition compared to unstimulated control. The result shows that the level of MMP activity was decreased compared to baseline levels or cells exposed to IL-1.Discussion: The RT-PCR result showed cells transfected with AAV-NFkB-hTIMP1 plasmid DNA had significant increase in the hTIMP-1 mRNA expression after stimulation with IL-1b. These results demonstrate the novelty of this strategy in which the NF-kB element containing promoter ensures that the transgene hTIMP1 is expressed highly only under conditions of inflammation typically found in injured and degenerating discs which would act to block MMP-mediated matrix proteolytic destruction. Low levels of hTIMP1 were also observed under unstimulated conditions and the bioenergetic consequences of the cell are unclear.