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Cytosolic DNA species derived from invading microbes or leaked from the nuclear or mitochondrial compartments of the cell can trigger the induction of host defense genes by activating the endoplasmic reticulum (ER)-associated protein STING. Using a mass spectrometry based approach, we show that after association with cyclic dinucleotides (CDN’s), delivery of Tank binding kinase 1 (TBK1) to interferon regulatory factors (IRF) such as IRF3 relies on K63-linked ubiquitination of K224 on STING. Blocking K224 ubiquitination specifically prevented IRF3 but not NF-κB activation, additionally indicating that STING trafficking is not required to stimulate the latter signaling pathway. By carrying out a limited siRNA screen we have identified mitochondrial E3 ubiquitin protein ligase 1 (MUL1) as an E3 ligase that catalyzes the ubiquitination of STING on K224. These data demonstrate the critical role of K224 ubiquitination in STING function and provide molecular insight into the mechanisms governing host defense responses.

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DNA viruses are linked to many infectious diseases and contribute significantly to human morbidity and mortality worldwide. Moreover, DNA viral infections are usually life long and hard to eradicate. Under certain circumstances, these viruses can cause fatal disease, especially in children and immunocompromised patients. An efficient innate immune response against these viruses is critical, not only as the first line of host defense against viral infection but also for mounting more specific and robust adaptive immunity against the virus. Recognition of the viral DNA genome is the very first step of this whole process and is crucial for understanding viral pathogenesis as well as for preventing and treating DNA virus–associated diseases. This review focuses on the current state of our knowledge on how human DNA viruses are sensed by the host innate immune system and how viral proteins counteract this immune response.

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STUDY DESIGN.: Prospective trial. OBJECTIVE.: To develop and validate a novel, patient-specific navigational template for cervical pedicle placement. SUMMARY OF BACKGROUND DATA.: Owing to the narrow bony anatomy and the proximity to the vertebral artery and the spinal cord, cervical instrumentation procedures demand the need for a precise technique for screw placement. PATIENT.: Specific drill template with preplanned trajectory has been thought as a promising solution for cervical pedicle screw placement. METHODS.: Patients with cervical spinal pathology (n = 25) requiring instrumentation were recruited. Volumetric CT scan was performed on each desired cervical vertebra and a 3-dimensional reconstruction model was generated from the scan data. Using reverse engineering technique, the optimal screw size and orientation were determined and a drill template was designed with a surface that is the inverse of the posterior vertebral surface. The drill template and its corresponding vertebra were manufactured using rapid prototyping technique and tested for violations. The navigational template was sterilized and used intraoperatively to assist with the placement of cervical screws. In total, 88 screws were inserted into levels C2-C7 with 2 to 6 screw in each patient. After surgery, the positions of the pedicle screws were evaluated using CT scan and graded for validation. RESULTS.: This method showed its ability to customize the placement and the size of each screw based on the unique morphology of the cervical vertebra. In all the cases, it was relatively very easy to manually place the drill template on the lamina of the vertebral body during the surgery. The required time between fixation of the template to the lamina and insertion of the pedicle screws was about 80 seconds. Of the 88 screws, 71 screws had no deviation and 14 screws had deviation <2 mm, 1 screw had a deviation between 2 to 4 mm and there were no misplacements. Fluoroscopy was used only once for every patient after the insertion of all the pedicle screws. CONCLUSION.: The authors have developed a novel patient-specific navigational template for cervical pedicle screw placement with good applicability and high accuracy. This method significantly reduces the operation time and radiation exposure for the members of the surgical team. The potential use of such a navigational template to insert cervical pedicle screws is promising. This technique has been clinically validated to provide an accurate trajectory for pedicle screw placement in the cervical spine.

Post-traumatic osteoarthritis (PTOA) develops after joint injury. Specifically, patients with anterior cruciate ligament (ACL) injury have a high risk of developing PTOA. In this review, we outline the incidence of ACL injury that progresses to PTOA, analyze the role of ACL reconstruction in preventing PTOA, suggest possible mechanisms thought to be responsible for PTOA, evaluate current diagnostic methods for detecting early OA, and discuss potential interventions to combat PTOA. We also identify important directions for future research. Although much work has been done, the incidence of PTOA among patients with a history of ACL injury remains high due to the complexity of ACL injury progression to PTOA, the lack of sensitive and easily accessible diagnostic methods to detect OA development, and the limitations of current treatments. A number of factors are thought to be involved in the underlying mechanism, including structural factors, biological factors, mechanical factors, and neuromuscular factor. Since there is a clear “start point” for PTOA, early detection and intervention is of great importance. Currently, imaging modalities and specific biomarkers allow early detection of PTOA. However, none of them is both sensitive and easily accessible. After ACL injury, many patients undergo surgical reconstruction of ACL to restore joint stability and prevent excessive loading. However, convincing evidence is still lacking for the superiority of ACL-R to conservative management in term of the incidence of PTOA. As for non-surgical treatment such as anti-cytokine and chemokine interventions, most of them are investigated in animal studies and have not been applied to humans. A complete understanding of mechanisms to stratify the patients into different subgroups on the basis of risk factors is critical. And the improvement of standardized and quantitative assessment techniques is necessary to guide intervention. Moreover, treatments targeted toward different pathogenic pathways may be crucial to the management of PTOA in the future.

This study suggests that TC provides a safe, feasible and useful exercise option for older Chinese female patients with knee OA.