A global survey conducted by arXiv in 2016 showed that 58% of arXiv users thought arXiv should have a peer review system. The current opinion is that arXiv should adopt the Community Peer Review model. This paper evaluates and identifies two weak points of Community Peer Review and proposes a new peer review model – Self‐Organizing Peer Review. We propose a model in which automated methods of matching reviewers to articles and ranking both users and articles can be implemented. In addition, we suggest a strategic plan to increase recognition of articles in preprint databases within academic circles so that second generation preprint databases can achieve faster and cheaper publication.

Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor‐interacting protein kinase 1/3 (RIP1/3) and phosphorylated‐MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage‐depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What’s more, HMGB1 neutralization further protects against intestinal I/R‐associated liver damage in microbiota‐depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec‐1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R‐induced acute remote organ dysfunction.

Influx of activated neutrophils into the lungs is the histopathologic hallmark of acute lung injury (ALI) after intestinal ischemia/reperfusion (I/R). Neutrophils can release DNA and granular proteins to form cytotoxic neutrophil extracellular traps (NETs), which promotes bystander tissue injury. However, whether NETs are responsible for the remote ALI after intestinal I/R and the mechanisms underlying the dissemination of harmful gut-derived mediators to the lungs are unknown. In the C57BL/6J mouse intestinal I/R model, DNase I–mediated degradation and protein arginine deiminase 4 (PAD4) inhibitor–mediated inhibition of NET treatments reduced NET formation, tissue inflammation, and pathological injury in the lung. High-mobility group protein B1 (HMGB1) blocking prevented NET formation and protected against tissue inflammation, as well as reduced cell apoptosis and improved survival rate. Moreover, recombinant human HMGB1 administration further drives NETs and concurrent tissue toxic injury, which in turn can be reversed by neutrophil deletion via anti-Ly6G Ab i.p. injection. Furthermore, global MyD88 deficiency regulated NET formation and alleviated the development of ALI induced by intestinal I/R. Thus, HMGB1 released from necroptotic enterocytes caused ALI after intestinal I/R by inducing NET formation. Targeting NETosis and the HMGB1 pathway might extend effective therapeutic strategies to minimize intestinal I/R-induced ALI.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) challenge often results in gut barrier dysfunction and induces distant organ injury. Dexmedetomidine has been shown to protect intestinal epithelial barrier against I/R attack. The present study aims to investigate the degree to which intestinal I/R attack will contribute to gut-vascular barrier (GVB) damage, and to examine the ability of dexmedetomidine to minimize GVB and liver injuries in mice. METHODS: In vivo, intestinal ischemic challenge was induced in mice by clamping the superior mesenteric artery for 45 minutes. After clamping, the mice were subjected to reperfusion for either 2, 4, 6, or 12 hours. Intraperitoneal injection of dexmedetomidine 15, 20, or 25 μg•kg -1 was performed intermittently at the phase of reperfusion. For the in vitro experiments, the challenge of oxygen-glucose deprivation/reoxygenation (OGD/R) was established in cultured vascular endothelial cells, and dexmedetomidine (1 nM) was used to treat the cells for 24 hours. Moreover, in vivo and in vitro, SKL2001 (a specific agonist of β-catenin) or XAV939 (a specific inhibitor of β-catenin) was applied to determine the role of β-catenin in the impacts provided by dexmedetomidine. RESULTS: The attack of intestinal I/R induced GVB damage. The greatest level of damage was observed at 4 hours after intestinal reperfusion. There was a significant increase in plasmalemma vesicle-associated protein-1 (PV1, a specific biomarker for endothelial permeability) expression (5.477 ± 0.718 vs 1.000 ± 0.149; P < .001), and increased translocation of intestinal macromolecules and bacteria to blood and liver tissues was detected (all P < .001). Liver damages were observed. There were significant increases in histopathological scores, serum parameters, and inflammatory factors (all P < .001). Dexmedetomidine 20 μg•kg -1 reduced PV1 expression (0.466 ± 0.072 vs 1.000 ± 0.098; P < .001) and subsequent liver damages (all P < .01). In vitro, dexmedetomidine significantly improved vascular endothelial cell survival (79.387 ± 6.447% vs 50.535 ± 1.766%; P < .001) and increased the productions of tight junction protein and adherent junction protein (all P < .01) following OGD/R. Importantly, in cultured cells and in mice, β-catenin expression significantly decreased (both P < .001) following challenge. Dexmedetomidine or SKL2001 upregulated β-catenin expression and produced protective effects (all P < .01). However, XAV939 completely eliminated the protective effects of dexmedetomidine on GVB (all P < .001).

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