Lactate aggravates inflammation through the upregulation of ICAM-1 via GPR81-HSPA12B-mediated signaling in acute lung injury

To the Editor:Acute respiratory distress syndrome(ARDS)ranks among the most prevalent conditions in the intensive care unit(ICU),with mortality rates soaring to 50%in cases progressing to moderate-to-severe ARDS.[1]A central pathogenic mechanism in lung injury involves pulmonary vascular endothelial damage,marked by heightened adhesion molecule expression,neutrophil infiltration,and increased endothelial permeability,culminating in pulmonary vascular endothelial dysfunction and compromised gas exchange.

Free form deformation and symmetry constraint‐based multimodal brain image registration using generative adversarial nets

Multi‐modal brain image registration has been widely applied to functional localisation,neurosurgery and computational anatomy.The existing registration methods based on the dense deformation fields involve too many parameters,which is not conducive to the exploration of correct spatial correspondence between the float and reference images.Meanwhile,the unidirectional registration may involve the deformation folding,which will result in the change of topology during registration.To address these issues,this work has presented an unsupervised image registration method using the free form deformation(FFD)and the symmetry constraint‐based generative adversarial networks(FSGAN).The FSGAN utilises the principle component analysis network‐based structural representations of the reference and float images as the inputs and uses the generator to learn the FFD model parameters,thereby producing two deformation fields.Meanwhile,the FSGAN uses two discriminators to decide whether the bilateral registration have been realised simultaneously.Besides,the symmetry constraint is utilised to construct the loss function,thereby avoiding the deformation folding.Experiments on BrainWeb,high grade gliomas,IXI and LPBA40 show that compared with state‐of‐the‐art methods,the FSGAN provides superior performance in terms of visual comparisons and such quantitative indexes as dice value,target registration error and computational efficiency.

CHANGES IN NEUROPEPTIDES AFTER MUSIC EXPOSURE 429Cardioprotective effect of ivabradine via the AMPK/SIRT1/PGC-1αsignaling pathway in myocardial ischemia/reperfusion injuryinduced in H9c2 cell

Post-resuscitation myocardial dysfunction(PRMD)is the most severe myocardial ischemia-reperfusion injury(MIRI)and is characterized by difficult treatment and poor prognosis.Research has shown the protective effects of the rational use of ivabradine(IVA)against PRMD,however,the molecular mechanisms of IVA remain unknown.In this study,an ischemia-reperfusion injury(IRI)model was established using hypoxic chambers.The results demonstrated that pretreatment with IVA reduced IRI-induced cytotoxicity and apoptosis.IVA attenuated mitochondrial damage,eliminated excess reactive oxygen species(ROS),suppressed IRI-induced ATP and NAD+,and increased the AMP/ATP ratio.We further found that IVA increased the mRNA levels of sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α)and upregulated the expression levels of phosphorylated AMP-activated protein kinase(p-AMPK)/AMPK,SIRT1,and PGC-1αproteins.Interestingly,no change in AMPK mRNA levels was observed.Cardiomyocyte energy metabolism significantly changed after IRI.The aim of this study was to demonstrate the cardioprotective effect of Ivabradine via the AMPK/SIRT1/PGC-1αsignaling pathway in myocardial ischemia/reperfusion injury-induced in H9c2 cell.

Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity

Interleukin-2(IL-2)is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells(Tregs)and effector cells,leading to paradoxical consequences.Here,we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine(FSY)into IL-2 for proximity-enabled covalent binding to IL-2Rαto selectively promote Treg activation.We found that FSY-bearing IL-2 variants,such as L72-FSY,covalently bound to IL-2Rαvia sulfur-fluoride exchange when in proximity,resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells.Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation,as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3(LAG-3)and enhanced expression of programmed cell death protein-1(PD-1).Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease(GvHD)resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment.The efficacy of L72-FSY was further improved by N-terminal PEGylation,which increased its circulatory retention for preferential and sustained effects.This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.

The effect of prone position for ventilatorassociated pneumonia in adult patients:a systematic review and meta-analysis

Background:The effect and safety of prone position(PP)in ventilator-associated pneumonia(VAP)patients was uncertain.We systematically reviewed the literature published to investigate whether PP benefits for patients with VAP compared with conventional supine position(SP).Methods:PubMed,EMbase,Cochrane Library,CNKI and WanFang Database were electronically searched to collect randomized controlled trials(RCTs)about the PP ventilation and SP ventilation in intensive care unit(ICU)patients from inception to May 2020.Meta-analysis was performed by Revan 5.3 software.Results:A total of 7 RCTs involving 1604 patients were included.Compared to regular SP ventilation,the PP ventilation group had no statistical significance in the four aspects.The results of subgroup analysis showed that the incidence of VAP and all-cause mortality were not affected by the patient’s initial oxygenation index.However,the incidence of VAP tended to decrease when the duration of PP ventilation was less than 16 hours per day.Meanwhile,the all-cause mortality was significantly decreased while the daily time was more than 16 hours.Conclusions:Current evidence showed that the PP ventilation could not decrease the incidence of VAP,all-cause mortality,length of mechanical ventilation,and ICU stay.However,the daily duration of PP ventilation may have an impact on the incidence of VAP and all-cause mortality in critical patients.