Linear ubiquitination is a critical regulator of inflammatory signaling pathways. However, linearly ubiquitinated substrates and the biological significance of linear ubiquitination is incompletely understood. Here, we show that STAT1 has linear ubiquitination at Lys511 and Lys652 residues in intact cells, which inhibits STAT1 binding to the type-I interferon receptor IFNAR2, thereby restricting STAT1 activation and resulting in type-I interferon signaling homeostasis. Linear ubiquitination of STAT1 is removed rapidly by OTULIN upon type-I interferon stimulation, which facilitates activation of interferon-STAT1 signaling. Furthermore, viruses induce HOIP expression through the NF-κB pathway, which in turn increases linear ubiquitination of STAT1 and thereby inhibits interferon antiviral response. Consequently, HOIL-1L heterozygous mice have active STAT1 signaling and enhanced responses to type-I interferons. These findings demonstrate a linear ubiquitination-mediated switch between homeostasis and activation of type-I interferon signaling, and suggest potential strategies for clinical antiviral therapy.

PurposeTo compare the effects of dexmedetomidine (Dex) and fentanyl as adjuvants to local anesthetics in spinal anesthesia.MethodsTwo researchers independently searched the PUBMED, EMBASE, Cochrane library, and CBM for randomized controlled trials comparing the effects of Dex and fentanyl as adjuvants to local anesthetics for intrathecal injection.ResultsA total of 639 patients from nine studies were included in this meta-analysis. The results showed that Dex resulted in statistically significant longer duration of stable sensory block (mean difference [MD] =27.12; 95% confidence interval [CI] [9.89, 44.34], P<0.01, I2=97%), sensory block (standardized mean difference [SMD] =3.81; 95% CI [2.35, 5.27], P<0.01, I2=97%), motor block (SMD =3.64; 95% CI [2.19, 5.08], P<0.01, I2=97%), and pain free period (SMD =2.98; 95% CI [1.69, 4.27], P<0.01, I2=96%); reducing the incidence of pruritus (relative risk [RR] =0.15; 95% CI [0.06, 0.39], P<0.01, I2=0%) compared with fentanyl. However, the onset of sensory and motor block, the time to peak sensory level, and the incidence of hypotension and bradycardia, and the side effects (nausea, vomiting, shivering and respiratory depression) were not significantly different between Dex and fentanyl.ConclusionCompared to fentanyl, Dex as local anesthetics adjuvant in spinal anesthesia prolonged the duration of spinal anesthesia, improved postoperative analgesia, reduced the incidence of pruritus, and did not increase the incidence of hypotension and bradycardia.

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The learning curves for video-assisted thoracoscopic lobectomy were similar for both surgeons. Between 100 and 200 cases are required to achieve efficiency, and consistency requires even more cases.