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BackgroundItch, chronic itch in particular, can have a significant negative impact on an individual’s quality of life. However, the molecular mechanisms underlying itch processing in the central nervous system remain largely unknown.ResultsWe report here that activation of ERK signaling in the spinal cord is required for itch sensation. ERK activation, as revealed by anti-phosphorylated ERK1/2 immunostaining, is observed in the spinal dorsal horn of mice treated with intradermal injections of histamine and compound 48/80 but not chloroquine or SLIGRL-NH2, indicating that ERK activation only occurs in histamine-dependent acute itch. In addition, ERK activation is also observed in 2, 4-dinitrofluorobenzene (DNFB)-induced itch. Consistently, intrathecal administration of the ERK phosphorylation inhibitor U0126 dramatically reduces the scratching behaviors induced by histamine and DNFB, but not by chloroquine. Furthermore, administration of the histamine receptor H1 antagonist chlorpheniramine decreases the scratching behaviors and ERK activation induced by histamine, but has no effect on DNFB-induced itch responses. Finally, the patch-clamp recording shows that in histamine-, chloroquine- and DNFB-treated mice the spontaneous excitatory postsynaptic current (sEPSC) of dorsal horn neurons is increased, and the decrease of action potential threshold is largely prevented by bathing of U0126 in histamine- and DNFB-treated mice but not those treated with chloroquine.ConclusionOur results demonstrate a critical role for ERK activation in itch sensation at the spinal level.

Metabolic reprogramming is one of the most important hallmarks of malignant tumors. Specifically, lipid metabolic reprogramming has marked impacts on cancer progression and therapeutic response by remodeling the tumor microenvironment (TME). In the past few decades, immunotherapy has revolutionized the treatment landscape for advanced cancers. Lipid metabolic reprogramming plays pivotal role in regulating the immune microenvironment and response to cancer immunotherapy. Here, we systematically reviewed the characteristics, mechanism, and role of lipid metabolic reprogramming in tumor and immune cells in the TME, appraised the effects of various cell death modes (specifically ferroptosis) on lipid metabolism, and summarized the antitumor therapies targeting lipid metabolism. Overall, lipid metabolic reprogramming has profound effects on cancer immunotherapy by regulating the immune microenvironment; therefore, targeting lipid metabolic reprogramming may lead to the development of innovative clinical applications including sensitizing immunotherapy.

IntroductionEarly detection of pneumothorax in multiple trauma patients is critically important. It can be argued that the efficacy of ultrasonography (US) for detection of pneumothorax is enhanced if it is performed and interpreted directly by the clinician in charge of the patients. The aim of this study was to assess the ability of emergency department clinicians to perform bedside US to detect and assess the size of the pneumothorax in patients with multiple trauma.MethodsOver a 14 month period, patients with multiple trauma treated in the emergency department were enrolled in this prospective study. Bedside US was performed by emergency department clinicians in charge of the patients. Portable supine chest radiography (CXR) and computed tomography (CT) were obtained within an interval of three hours. Using CT and chest drain as the gold standard, the diagnostic efficacy of US and CXR for the detection of pneumothorax, defined as rapidity and accuracy (sensitivity, specificity, positive predictive value, negative predictive value), were compared. The size of the pneumothorax (small, medium and large) determined by US was also compared to that determined by CT.ResultsOf 135 patients (injury severity score = 29.1 ± 12.4) included in the study, 83 received mechanical ventilation. The time needed for diagnosis of pneumothorax was significantly shorter with US compared to CXR (2.3 ± 2.9 versus 19.9 ± 10.3 minutes, p < 0.001). CT and chest drain confirmed 29 cases of pneumothorax (21.5%). The diagnostic sensitivity, specificity, positive and negative predictive values and accuracy for US and radiography were 86.2% versus 27.6% (p < 0.001), 97.2% versus 100% (not significant), 89.3% versus 100% (not significant), 96.3% versus 83.5% (p = 0.002), and 94.8% versus 84.4% (p = 0.005), respectively. US was highly consistent with CT in determining the size of pneumothorax (Kappa = 0.669, p < 0.001).ConclusionBedside clinician-performed US provides a reliable tool and has the advantages of being simple and rapid and having higher sensitivity and accuracy compared to chest radiography for the detection of pneumothorax in patients with multiple trauma.

Schizophrenia is a debilitating familial neuropsychiatric disorder which affects 1% of people worldwide. Although the heritability for schizophrenia approaches 80% only a small proportion of the overall genetic risk has been accounted for, and to date only a limited number of genetic loci have been definitively implicated. We have identified recently through genetic and in vitro functional studies, a novel serine/threonine kinase gene, unc-51-like kinase 4 (ULK4), as a rare risk factor for major mental disorders including schizophrenia. Now using the approach of in utero gene transfer we have discovered that Ulk4 plays a key modulatory role in corticogenesis. Knockdown of Ulk4 leads to significantly decreased cell proliferation in germinal zones and profound deficits in radial migration and neurite ramification. These abnormalities can be reversed successfully by Ulk4 gene supplementation. Ulk4 also regulated acetylation of α-tubulin, an important post-translational modification of microtubules. We conclude that Ulk4 plays an essential role in normal brain development and when defective, the risk of neurodevelopmental disorders such as schizophrenia is increased.