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Out-of-hospital cardiac arrest (OHCA) is a leading cause of global mortality. Regional variations in reporting frameworks and survival mean the exact burden of OHCA to public health is unknown. Nevertheless, overall prognosis and neurological outcome are relatively poor following OHCA and have remained almost static for the past three decades. In this Series paper, we explore the aetiology of OHCA. Coronary artery disease remains the predominant cause, but there is a diverse range of other potential cardiac and non-cardiac causes to be aware of. Additionally, we describe how investigators and key stakeholders in resuscitation science have formulated specific Utstein data element domains in an attempt to standardise the definitions and outcomes reported in OHCA research so that management pathways can be improved. Finally, we identify the predictors of survival after OHCA and what primary and secondary prevention strategies can be instigated to mitigate the devastating sequelae of this growing public health issue.

Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U 13 C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages. Redirection of the TCA cycle intermediate aconitate to itaconate production has anti-inflammatory effects. Here the authors show that the itaconate derivative 4-octyl-itaconate is anti-inflammatory partly as a result of inhibiting GAPDH enzymatic activity and thereby glycolysis in macrophages.

This review (with 145 refs.) summarizes the progress that has been made in the use of zeolitic imidazolate frameworks in chemical sensing and biosensing. Zeolitic imidazolate frameworks (ZIFs) are a type of porous material with zeolite topological structure that combine the advantages of zeolite and traditional metal–organic frameworks. Owing to the structural flexibility of ZIFs, their pore sizes and surface functionalization can be reasonably designed. Following an introduction into the field of metal–organic frameworks and the zeolitic imidazolate framework (ZIF) subclass, a first large section covers the various kinds and properties of ZIFs. The next large section covers electrochemical sensors and assays (with subsections on methods for gases, electrochemiluminescence, electrochemical biomolecules). This is followed by main sections on ZIF-based colorimetric and luminescent sensors, with subsections on sensors for metal ions and anions, for gases, and for organic biomolecules. The last section covers SERS-based assays. Several tables are presented that give an overview on the wealth of methods and materials. A concluding section summarizes the current status, addresses current challenges, and gives an outlook on potential future trends. Graphical abstract In recent years, ZIFs and their composites have been widely used as probes in chemical sensing, and these probes have shown great advantages over other materials. This review describes the current progress on ZIFs toward electrochemical, luminescence, colorimetric, and SERS-based sensing applications, highlighting the different strategies for designing ZIFs and their composites and potential challenges in this field.

New architectures of multilayer artificial neural networks and new methods for training them are rapidly revolutionizing the application of machine learning in diverse fields, including business, social science, physical sciences, and biology. Interpreting deep neural networks, however, currently remains elusive, and a critical challenge lies in understanding which meaningful features a network is actually learning. We present a general method for interpreting deep neural networks and extracting network-learned features from input data. We describe our algorithm in the context of biological sequence analysis. Our approach, based on ideas from statistical physics, samples from the maximum entropy distribution over possible sequences, anchored at an input sequence and subject to constraints implied by the empirical function learned by a network. Using our framework, we demonstrate that local transcription factor binding motifs can be identified from a network trained on ChIP-seq data and that nucleosome positioning signals are indeed learned by a network trained on chemical cleavage nucleosome maps. Imposing a further constraint on the maximum entropy distribution also allows us to probe whether a network is learning global sequence features, such as the high GC content in nucleosome-rich regions. This work thus provides valuable mathematical tools for interpreting and extracting learned features from feed-forward neural networks.

Increased crop yields are required to support rapid population growth worldwide. Grain weight is a key compo- nent of rice yield, but the underlying molecular mechanisms that control it remain elusive. Here, we report the clon- ing and characterization of a new quantitative trait locus （QTL） for the control of rice grain length, weight and yield. This locus, GL3.1, encodes a protein phosphatase kelch （PPKL） family -- Ser/Thr phosphatase. GL3.1 is a member of the large grain WY3 variety, which is associated with weaker dephosphorylation activity than the small grain FAZ1 variety. GL3.I-WY3 influences protein phosphorylation in the spikelet to accelerate cell division, thereby re- suiting in longer grains and higher yields. Further studies have shown that GL3.1 directly dephosphorylates its sub- strate, Cyclin-TI;3, which has only been rarely studied in plants. The downregulation of Cyclin-T1;3 in rice resulted in a shorter grain, which indicates a novel function for Cyclin-T in cell cycle regulation. Our findings suggest a new mechanism for the regulation of grain size and yield that is driven through a novel phosphatase-mediated process that affects the phosphorylation of Cyclin-T1;3 during cell cycle progression, and thus provide new insight into the mechanisms underlying crop seed development. We bred a new variety containing the natural GL3.1 allele that demonstrated increased grain yield, which indicates that GL3.1 is a powerful tool for breeding high-yield crops.

Inhibition and eradication of Staphylococcus aureus biofilms with conventional antibiotic is difficult, and the treatment is further complicated by the rise of antibiotic resistance among staphylococci. Consequently, there is a need for novel antimicrobials that can treat biofilm-related infections and decrease antibiotics burden. Natural compounds such as eugenol with anti-microbial properties are attractive agents that could reduce the use of conventional antibiotics. In this study we evaluated the effect of eugenol on MRSA and MSSA biofilms in vitro and bacterial colonization in vivo. Effect of eugenol on in vitro biofilm and in vivo colonization were studied using microtiter plate assay and otitis media-rat model respectively. The architecture of in vitro biofilms and in vivo colonization of bacteria was viewed with SEM. Real-time RT-PCR was used to study gene expression. Check board method was used to study the synergistic effects of eugenol and carvacrol on established biofilms. Eugenol significantly inhibited biofilms growth of MRSA and MSSA in vitro in a concentration-dependent manner. Eugenol at MIC or 2×MIC effectively eradicated the pre-established biofilms of MRSA and MSSA clinical strains. In vivo, sub-MIC of eugenol significantly decreased 88% S. aureus colonization in rat middle ear. Eugenol was observed to damage the cell-membrane and cause a leakage of the cell contents. At sub-inhibitory concentration, it decreases the expression of biofilm-and enterotoxin-related genes. Eugenol showed a synergistic effect with carvacrol on the eradication of pre-established biofilms. This study demonstrated that eugenol exhibits notable activity against MRSA and MSSA clinical strains biofilms. Eugenol inhibited biofilm formation, disrupted the cell-to-cell connections, detached the existing biofilms, and killed the bacteria in biofilms of both MRSA and MSSA with equal effectiveness. Therefore, eugenol may be used to control or eradicate S. aureus biofilm-related infections.

Luteolin is a flavonoid in a variety of fruits, vegetables, and herbs, which has shown anti-inflammatory, antioxidant, and anti-cancer neuroprotective activities. In this study, we investigated the potential beneficial effects of luteolin on memory deficits and neuroinflammation in a triple-transgenic mouse model of Alzheimer’s disease (AD) (3 × Tg-AD). The mice were treated with luteolin (20, 40 mg · kg −1  · d −1 , ip) for 3 weeks. We showed that luteolin treatment dose-dependently improved spatial learning, ameliorated memory deficits in 3 × Tg-AD mice, accompanied by inhibiting astrocyte overactivation (GFAP) and neuroinflammation (TNF-α, IL-1β, IL-6, NO, COX-2, and iNOS protein), and decreasing the expression of endoplasmic reticulum (ER) stress markers GRP78 and IRE1α in brain tissues. In rat C6 glioma cells, treatment with luteolin (1, 10 µM) dose-dependently inhibited LPS-induced cell proliferation, excessive release of inflammatory cytokines, and increase of ER stress marker GRP78. In conclusion, luteolin is an effective agent in the treatment of learning and memory deficits in 3 × Tg-AD mice, which may be attributable to the inhibition of ER stress in astrocytes and subsequent neuroinflammation. These results provide the experimental basis for further research and development of luteolin as a therapeutic agent for AD.

Formation of biofilm is a survival strategy for bacteria and fungi to adapt to their living environment, especially in the hostile environment. Under the protection of biofilm, microbial cells in biofilm become tolerant and resistant to antibiotics and the immune responses, which increases the difficulties for the clinical treatment of biofilm infections. Clinical and laboratory investigations demonstrated a perspicuous correlation between biofilm infection and medical foreign bodies or indwelling devices. Clinical observations and experimental studies indicated clearly that antibiotic treatment alone is in most cases insufficient to eradicate biofilm infections. Therefore, to effectively treat biofilm infections with currently available antibiotics and evaluate the outcomes become important and urgent for clinicians. The review summarizes the latest progress in treatment of clinical biofilm infections and scientific investigations, discusses the diagnosis and treatment of different biofilm infections and introduces the promising laboratory progress, which may contribute to prevention or cure of biofilm infections. We conclude that, an efficient treatment of biofilm infections needs a well-established multidisciplinary collaboration, which includes removal of the infected foreign bodies, selection of biofilm-active, sensitive and well-penetrating antibiotics, systemic or topical antibiotic administration in high dosage and combinations, and administration of anti-quorum sensing or biofilm dispersal agents.

Lattice oxygen redox offers an unexplored way to access superior electrochemical properties of transition metal oxides (TMOs) for rechargeable batteries. However, the reaction is often accompanied by unfavourable structural transformations and persistent electrochemical degradation, thereby precluding the practical application of this strategy. Here we explore the close interplay between the local structural change and oxygen electrochemistry during short- and long-term battery operation for layered TMOs. The substantially distinct evolution of the oxygen-redox activity and reversibility are demonstrated to stem from the different cation-migration mechanisms during the dynamic de/intercalation process. We show that the π stabilization on the oxygen oxidation initially aids in the reversibility of the oxygen redox and is predominant in the absence of cation migrations; however, the π-interacting oxygen is gradually replaced by σ-interacting oxygen that triggers the formation of O–O dimers and structural destabilization as cycling progresses. More importantly, it is revealed that the distinct cation-migration paths available in the layered TMOs govern the conversion kinetics from π to σ interactions. These findings constitute a step forward in unravelling the correlation between the local structural evolution and the reversibility of oxygen electrochemistry and provide guidance for further development of oxygen-redox layered electrode materials. Transition metal oxide electrodes are promising for rechargeable batteries but are subject to suffer from structural transformations and electrochemical degradation. The evolution of oxygen-redox activity and reversibility in layered electrodes are shown to arise from cation-migration mechanisms during de/intercalation.