TNF␣ is an important cytokine in antimicrobial immunity and inflammation. The receptor-interacting protein RIP1 is an essential component of the TNF receptor 1 signaling pathway that mediates the activation of NF-B, MAPKs, and programmed cell death. It also transduces signals derived from Toll-like receptors and intracellular sensors of DNA damage and double-stranded RNA. Here, we show that the murine CMV M45 protein binds to RIP1 and inhibits TNF␣-induced activation of NF-B, p38 MAPK, and caspase-independent cell death. M45 also inhibited NF-B activation upon stimulation of Toll-like receptor 3 and ubiquitination of RIP1, which is required for NF-B activation. Hence, M45 functions as a viral inhibitor of RIP1-mediated signaling. The results presented here reveal a mechanism of viral immune subversion and demonstrate how a viral protein can simultaneously block proinflammatory and innate immune signaling pathways by interacting with a central mediator molecule.apoptosis ͉ necrosis ͉ herpesvirus ͉ ribonucleotide reductase A ntiviral innate immune responses are triggered by receptors and sensors that recognize pathogen-, damage-, or stressassociated molecular patterns (1). These receptors can be located at endosomal or cell surface membranes, as is the case for the Toll-like receptors (TLRs). Other receptors, such as the double-stranded RNA (dsRNA)-activated helicases RIG-I and Mda5, sense the presence of potentially dangerous molecular patterns inside of the cell. The receptors initiate specific signaling cascades that lead to the activation of transcription factors, (such as NF-B and IFN regulatory factors) and MAPKs, or the initiation of programmed cell death (PCD). Very similar responses are triggered by proinflammatory cytokines such as TNF␣, which also play important roles in controlling viral infections.The receptor-interacting protein RIP1 (also called RIP) is located at the intersection of several signaling pathways [supporting information (SI) Fig. 7]. It integrates signals from membrane-bound receptors and intracellular stress sensors (reviewed in refs. 2 and 3). RIP1 has been investigated extensively because of its crucial role in the TNF receptor (TNFR)1 signaling pathway (4). Stimulation with TNF␣ initially induces the recruitment of RIP1, the TNFR-associated factor (TRAF)2, and the TNFR-associated death domain to the plasma membrane (5, 6). The subsequent ubiquitination of RIP1 by TRAF2 (7, 8) is required for activation of IB kinase and NF-B (9). RIP1 also activates the MAPKs p38 and ERK and participates in the activation of JNK (10, 11). In addition, RIP1 mediates NF-B activation upon stimulation of TLR3 and TLR4 via the TIR domain-containing adaptor-inducing INF-␤ (TRIF) (12, 13). RIP1 also transmits signals derived from DNA-damage sensors (14) and from intracellular sensors of dsRNA (15, 16).TNFR1 and other death receptors can trigger apoptosis by inducing the formation of a complex containing the Fasassociated death domain and procaspase-8, in which the latter is activated autocatalytically (5)....

Interspinous implants are used to treat lumbar spinal stenosis or facet joint arthritis. The aims of implanting interspinous devices are to unload the facet joints, restore foraminal height and provide stability especially in extension but still allow motion. The aim of this in vitro study was to compare four different interspinous implants--Colfex, Wallis, Diam and X-Stop--in terms of their three-dimensional flexibility and the intradiscal pressure. Twenty-four human lumbar spine specimens were divided into four equal groups and tested with pure moments in flexion/extension, lateral bending and axial rotation: (1) intact, (2) defect, (3) after implantation. Range of motion and the intradiscal pressure were determined.In each implant-group the defect caused an increase in range of motion by about 8% in lateral bending to 18% in axial rotation. Implantation had similar effects with all four implants. In extension, Coflex, Wallis, Diam, and X-Stop all overcompensated the instability caused by the defect and allowed about 50% of the range of motion of the intact state. In contrast, in flexion, lateral bending and axial rotation the values of the range of motion stayed about the values of the defect state. Similarly the intradiscal pressure after implantation was similar to that of the intact specimens in flexion, lateral bending and axial rotation but much smaller during extension. All tested interspinous implants had a similar effect on the flexibility: they strongly stabilized and reduced the intradiscal pressure in extension, but had almost no effect in flexion, lateral bending and axial rotation.

The early host response to viral infections involves transient activation of pattern recognition receptors leading to an induction of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα). Subsequent activation of cytokine receptors in an autocrine and paracrine manner results in an inflammatory cascade. The precise mechanisms by which viruses avert an inflammatory cascade are incompletely understood. Nuclear factor (NF)-κB is a central regulator of the inflammatory signaling cascade that is controlled by inhibitor of NF-κB (IκB) proteins and the IκB kinase (IKK) complex. In this study we show that murine cytomegalovirus inhibits the inflammatory cascade by blocking Toll-like receptor (TLR) and IL-1 receptor-dependent NF-κB activation. Inhibition occurs through an interaction of the viral M45 protein with the NF-κB essential modulator (NEMO), the regulatory subunit of the IKK complex. M45 induces proteasome-independent degradation of NEMO by targeting NEMO to autophagosomes for subsequent degradation in lysosomes. We propose that the selective and irreversible degradation of a central regulatory protein by autophagy represents a new viral strategy to dampen the inflammatory response.

Early stages of intervertebral disc degeneration are postulated to cause instability. In the literature, however, some authors report the opposite. These contradictory positions are probably supported by the mostly small number of segments which are investigated. The aim of this project therefore was to investigate the influence of intervertebral disc degeneration on lumbar spine rotational stability using a large data set. The flexibility data from all spine specimens tested in our institute so far were collected in a large in vitro database. From this database, all lumbar spine specimens were selected, which had been tested for flexibility under pure moment loads of ±7.5 N m and for which radiographs were accessible. 203 segments met these criteria. Their radiographic degree of disc degeneration was determined on a scale from 0 (no degeneration) to 3 (severe degeneration) and their influence on the respective range of motion and neutral zone was examined. The different lumbar levels differ in flexibility, which increases the variability of the data if pooled together. To minimise this effect a statistical model was fitted. The model-based mean estimates showed a decrease of the range of motion from grade 0 to 3 in flexion/extension (by 3.1°, p \ 0.05) and lateral bending (by 3.4°, p \ 0.05). In contrast, in axial rotation the range of motion tended to increase; however, not only from grade 0 to 1 but also towards grade 3 (by 0.2°) (p [ 0.05). The neutral zone was affected in a similar way but to a smaller degree (p [ 0.05). In conclusion, the results indicated that early stages of intervertebral disc degeneration do not necessarily cause rotational instability. In contrast, stability increased in flexion/extension and lateral bending. Only in axial rotation stability tended to decrease.

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