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Histones are intra-nuclear cationic proteins that are present in all eukaryotic cells and are highly conserved across species. Within the nucleus, they provide structural stability to chromatin and regulate gene expression. Histone may be released into the extracellular space in three forms: freely, as a DNA-bound nucleosome or as part of neutrophil extracellular traps, and all three can be detected in serum after significant cellular death such as sepsis, trauma, ischaemia/reperfusion injury and autoimmune disease. Once in the extracellular space, histones act as damage-associated molecular pattern proteins, activating the immune system and causing further cytotoxicity. They interact with Toll-like receptors (TLRs), complement and the phospholipids of cell membranes inducing endothelial and epithelial cytotoxicity, TLR2/TLR4/TLR9 activation and pro-inflammatory cytokine/chemokine release via MyD88, NFκB and NLRP3 inflammasome-dependent pathways. Drugs that block the release of histone, neutralise circulating histone or block histone signal transduction provide significant protection from mortality in animal models of acute organ injury but warrant further research to inform future clinical applications.

AbstractThe widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional “receptor” and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the “cytokine storm.” Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.

In urban road environments, global navigation satellite system (GNSS) signals may be interrupted due to occlusion by buildings and obstacles, resulting in reduced accuracy and discontinuity of combined GNSS/inertial navigation system (INS) positioning. Improving the accuracy and robustness of combined GNSS/INS positioning systems for land vehicles in the presence of GNSS interruptions is a challenging task. The main objective of this paper is to develop a method for predicting GNSS information during GNSS outages based on a long short-term memory (LSTM) neural network to assist in factor graph-based combined GNSS/INS localization, which can provide a reliable combined localization solution during GNSS signal outages. In an environment with good GNSS signals, a factor graph fusion algorithm is used for data fusion of the combined positioning system, and an LSTM neural network prediction model is trained, and model parameters are determined using the INS velocity, inertial measurement unit (IMU) output, and GNSS position incremental data. In an environment with interrupted GNSS signals, the LSTM model is used to predict the GNSS positional increments and generate the pseudo-GNSS information and the solved results of INS for combined localization. In order to verify the performance and effectiveness of the proposed method, we conducted real-world road test experiments on land vehicles installed with GNSS receivers and inertial sensors. The experimental results show that, compared with the traditional combined GNSS/INS factor graph localization method, the proposed method can provide more accurate and robust localization results even in environments with frequent GNSS signal loss.

Pinpointing the role of geometric phaseDuring chemical reactions, electrons usually rearrange more quickly than nuclei. Thus, theorists often adopt an adiabatic framework that considers vibrational and rotational dynamics within single electronic states. Near the regime where two electronic states intersect, the dynamics get more complicated, and a geometric phase factor is introduced to maintain the simplifying power of the adiabatic treatment. Yuan et al. conducted precise experimental measurements that validate this approach. They studied the elementary H + HD reaction at energies just above the intersection of electronic states and observed angular oscillations in the product-state cross sections that are well reproduced by simulations that include the geometric phase.Science, this issue p. 1289Theory has established the importance of geometric phase (GP) effects in the adiabatic dynamics of molecular systems with a conical intersection connecting the ground- and excited-state potential energy surfaces, but direct observation of their manifestation in chemical reactions remains a major challenge. Here, we report a high-resolution crossed molecular beams study of the H + HD → H2 + D reaction at a collision energy slightly above the conical intersection. Velocity map ion imaging revealed fast angular oscillations in product quantum state–resolved differential cross sections in the forward scattering direction for H2 products at specific rovibrational levels. The experimental results agree with adiabatic quantum dynamical calculations only when the GP effect is included.

AbstractNETosis is a type of regulated cell death dependent on the formation of neutrophil extracellular traps (NET), where net-like structures of decondensed chromatin and proteases are produced by polymorphonuclear (PMN) granulocytes. These structures immobilise pathogens and restrict them with antimicrobial molecules, thus preventing their spread. Whilst NETs possess a fundamental anti-microbial function within the innate immune system under physiological circumstances, increasing evidence also indicates that NETosis occurs in the pathogenic process of other disease type, including but not limited to atherosclerosis, airway inflammation, Alzheimer’s and stroke. Here, we reviewed the role of NETosis in the development of organ injury, including injury to the brain, lung, heart, kidney, musculoskeletal system, gut and reproductive system, whilst therapeutic agents in blocking injuries induced by NETosis in its primitive stages were also discussed. This review provides novel insights into the involvement of NETosis in different organ injuries, and whilst potential therapeutic measures targeting NETosis remain a largely unexplored area, these warrant further investigation.

Circular ribonucleic acids (circRNAs) are a class of long non-coding RNA that were once regarded as non-functional transcription byproducts. However, recent studies suggested that circRNAs may exhibit important regulatory roles in many critical biological pathways and disease pathologies. These studies have identified significantly differential expression profiles of circRNAs upon changes in physiological and pathological conditions of eukaryotic cells. Importantly, a substantial number of studies have suggested that circRNAs may play critical roles in organ injuries. This review aims to provide a summary of recent studies on circRNAs in organ injuries with respect to (1) changes in circRNAs expression patterns, (2) main mechanism axi(e)s, (3) therapeutic implications and (4) future study prospective. With the increasing attention to this research area and the advancement in high-throughput nucleic acid sequencing techniques, our knowledge of circRNAs may bring fruitful outcomes from basic and clinical research.

Sepsis is life-threatening and often leads to acute brain damage. Dexmedetomidine, an α 2 -adrenoceptor agonist, has been reported to possess neuroprotective effects against various brain injury but underlying mechanisms remain elusive. In this study, in vitro and in vivo models of sepsis were used to explore the effects of dexmedetomidine on the inflammasome activity and its associated glia pyroptosis and neuronal death. In vitro, inflammasome activation and pyroptosis were found in astrocytes following lipopolysaccharide (LPS) exposure. Dexmedetomidine significantly alleviated astrocyte pyroptosis and inhibited histone release induced by LPS. In vivo, LPS treatment in rats promoted caspase-1 immunoreactivity in astrocytes and caused an increase in the release of pro-inflammatory cytokines of IL-1β and IL-18, resulting in neuronal injury, which was attenuated by dexmedetomidine; this neuroprotective effect was abolished by α 2 -adrenoceptor antagonist atipamezole. Dexmedetomidine significantly reduced the high mortality rate caused by LPS challenge. Our data demonstrated that dexmedetomidine may protect glia cells via reducing pyroptosis and subsequently protect neurons, all of which may preserve brain function and ultimately improve the outcome in sepsis.

In recent years, inert gases such as helium, argon, and xenon have gained considerable attention for their medical value. Noble gases present an intriguing scientific paradox: although extremely chemically inert, they display a remarkable spectrum of clinically useful biological properties. Despite a relative paucity of knowledge about their mechanisms of action, some noble gases have been used successfully in clinical practice. The neuroprotection elicited by these noble gases has been investigated in experimental animal models of various types of brain injuries, such as traumatic brain injury, stroke, subarachnoid hemorrhage, cerebral ischemic/reperfusion injury, and neurodegenerative diseases. Collectively, these central nervous system injuries are a leading cause of morbidity and mortality every year worldwide. Treatment options are presently limited to thrombolytic drugs and clot removal for ischemic stroke, or therapeutic cooling for other brain injuries before the application of noble gas. Currently, there is increasing interest in noble gases as novel treatments for various brain injuries. In recent years, neuroprotection elicited by particular noble gases, xenon, for example, has been reported under different conditions. In this article, we have reviewed the latest in vitro and in vivo experimental and clinical studies of the actions of xenon, argon, and helium, and discuss their potential use as neuroprotective agents.

Povidone-iodine (PVI) is principally used as an antimicrobial agent. It has been found that 0.5% PVI can attenuate congestion, edema and pain induced by pressure sores. Thus this study aimed to assess the effects of 0.5% PVI on acute skin wounds. Four full-thickness excisional wounds were generated on the dorsal skin of male Sprague-Dawley rats with a 10-mm sterile punch. Two wounds were left untreated and the other two were dressed with gauze with 0.5% PVI for 1 hour per day for the first 5 days after injury. 10-mm full-thickness excisional wounds were also generated on the dorsal skin of rats treated with 10 mg/kg SB431542 and all wounds were treated with 0.5% PVI for 5 days. PVI treatment enhanced wound healing via promotion of expression of α SMA and TGF β, neovascularization and re-epithelialization. Interleukin 6 was reduced following PVI treatment. Inhibition of TGF β abolished the effect of PVI treatment on wound closure. These data show that topical application of 0.5% PVI could promote acute skin wound healing though increased expression of TGF β leading to enhanced formation of granulation tissue, even in the absence of obvious infection.

Glioblastoma (GBM) is a highly aggressive, infiltrative malignancy that cannot be completely cured by current treatment modalities, and therefore requires more precise molecular subtype signatures to predict treatment response for personalized precision therapy. Expression subtypes of GBM samples from the Cancer Genome Atlas (TCGA) were identified using BayesNM and compared with existing molecular subtypes of GBM. Biological features of the subtypes were determined by single-sample gene set enrichment analysis. Genomic and proteomic data from GBM samples were combined and Genomic Identification of Significant Targets in Cancer analysis was used to screen genes with recurrent somatic copy-number alterations phenomenon. The immune environment among subtypes was compared by assessing the expression of immune molecules and the infiltration of immune cells. Molecular subtypes adapted to immunotherapy were identified based on Tumor Immune Dysfunction and Exclusion (TIDE) score. Finally, least absolute shrinkage and selection operator (LASSO) logistic regression was performed on the expression profiles of S2, S3 and S4 in TCGA-GBM and RPPA to determine the respective corresponding best predictive model. Four novel molecular subtypes were classified. Specifically, S1 exhibited a low proliferative profile; S2 exhibited the profile of high proliferation, IDH1 mutation, TP53 mutation and deletion; S3 was characterized by high immune scores, innate immunity and adaptive immune infiltration scores, with the lowest TIDE score and was most likely to benefit from immunotherapy; S4 was characterized by high proliferation, EGFR amplification, and high protein abundance, and was the most suitable subtype for bevacizumab. LASSO analysis constructed the best prediction model composed of 13 genes in S2 with an accuracy of 96.7%, and the prediction model consisting of 17 genes in S3 with an accuracy of 86.7%, and screened 14 genes as components of the best prediction model in S4 with an accuracy of 93%. To conclude, our study classified reproducible and robust molecular subtypes of GBM, and these findings might contribute to the identification of patients responding to immunotherapy, thereby improving GBM prognosis.