Gene knockout or inhibition of macrophage migration inhibitory factor alleviates lipopolysaccharide-induced liver injury via inhibiting inflammatory response

Background:Liver injury is one of the most common complications during sepsis.Macrophage migration inhibitory factor(MIF)is an important proinflammatory cytokine.This study explored the role of MIF in the lipopolysaccharide(LPS)-induced liver injury through genetically manipulated mouse strains.Methods:The model of LPS-induced liver injury was established in wild-type and Mif-knockout C57/BL6 mice.Serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),and total bilirubin(TBil)were detected,and the expressions of MIF,tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β)were measured.Liver histopathology was conducted to assess liver injury.Moreover,the inhibitions of MIF with(S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester(ISO-1)and 4-iodo-6-phenylpyrimidine(4-IPP)were used to evaluate their therapeutic potential of liver injury.Results:Compared with wild-type mice,the liver function indices and inflammation factors presented no significant difference in the Mif-/-mice.After 72 h of the LPS-induced liver injury,serum levels of ALT,AST,and TBil as well as TNF-αand IL-1βwere significantly increased,but the knockout of Mif attenuated liver injury and inflammatory response.In liver tissue,m RNA levels of TNF-α,IL-1βand NF-κB p65 were remarkably elevated in LPS-induced liver injury,while the knockout of Mif reduced these levels.Moreover,in LPS-induced liver injury,the inhibitions of MIF with ISO-1 and 4-IPP alleviated liver injury and slightly attenuated inflammatory response.Importantly,compared to mice with LPS-induced liver injury,Mif knockout or MIF inhibitions significantly prolonged the survival of the mice.Conclusions:In LPS-induced liver injury,the knockout of Mif or MIF inhibitions alleviated liver injury and slightly attenuated inflammatory response,thereby prolonged the survival of the mice.Targeting MIF may be an important strategy to protect the liver from injury during sepsis.

A new surgical technique for post-myocardial infarction ventricular septal rupture with hemodynamic instability

Ventricular septal rupture(VSR)is a rare but lethal complication of acute myocardial infarction(AMI).[1]Emergent repair surgery provides the only chance for survival for patients with VSR;however,the perioperative mortality rate remains extremely high at the early phase.[2] Elective surgery is widely utilized in real-world clinical practice and is associated with improved prognosis.[3] Nevertheless,the results of elective surgery might be a manifestation of survival bias,as it is usually performed in relatively stable patients with VSR who are expected to survive the early stage and have a better prognosis than patients complicated with hemodynamic instability in the early stage.[4]In this study,we aimed to present a novel surgical repair technique that can be safely,feasibly,and effectively used in hemodynamically unstable patients with VSR in the acute phase and to report the preliminary results.

Trace Semantics and Algebraic Laws for Total Store Order Memory Model

Modern multiprocessors deploy a variety of weak memory models(WMMs).Total Store Order(TSO)is a widely-used weak memory model in SPARC implementations and x86 architecture.It omits the store-load constraint by allowing each core to employ a write buffer.In this paper,we apply Unifying Theories of Programming(abbreviated as UTP)in investigating the trace semantics for TSO,acting in the denotational semantics style.A trace is expressed as a sequence of snapshots,which records the changes in registers,write buffers and the shared memory.All the valid execution results containing reorderings can be described after kicking out those that do not satisfy program order and modification order.This paper also presents a set of algebraic laws for TSO.We study the concept of head normal form,and every program can be expressed in the head normal form of the guarded choice which is able to model the execution of a program with reorderings.Then the linearizability of the TSO model is supported.Furthermore,we consider the linking between trace semantics and algebraic semantics.The linking is achieved through deriving trace semantics from algebraic semantics,and the derivation strategy under the TSO model is provided.