Seasonal origin of the thermal maxima at the Holocene and the last interglacial.

Proxy reconstructions from marine sediment cores indicate peak temperatures in the first half of the last and current interglacial periods (the thermal maxima of the Holocene epoch, 10,000 to 6,000 years ago, and the last interglacial period, 128,000 to 123,000 years ago) that arguably exceed modern warmth1-3. By contrast, climate models simulate monotonic warming throughout both periods4-7. This substantial model-data discrepancy undermines confidence in both proxy reconstructions and climate models, and inhibits a mechanistic understanding of recent climate change. Here we show that previous global reconstructions of temperature in the Holocene1-3 and the last interglacial period8 reflect the evolution of seasonal, rather than annual, temperatures and we develop a method of transforming them to mean annual temperatures. We further demonstrate that global mean annual sea surface temperatures have been steadily increasing since the start of the Holocene (about 12,000 years ago), first in response to retreating ice sheets (12 to 6.5 thousand years ago), and then as a result of rising greenhouse gas concentrations (0.25 ± 0.21 degrees Celsius over the past 6,500 years or so). However, mean annual temperatures during the last interglacial period were stable and warmer than estimates of temperatures during the Holocene, and we attribute this to the near-constant greenhouse gas levels and the reduced extent of ice sheets. We therefore argue that the climate of the Holocene differed from that of the last interglacial period in two ways: first, larger remnant glacial ice sheets acted to cool the early Holocene, and second, rising greenhouse gas levels in the late Holocene warmed the planet. Furthermore, our reconstructions demonstrate that the modern global temperature has exceeded annual levels over the past 12,000 years and probably approaches the warmth of the last interglacial period (128,000 to 115,000 years ago).

Galectin-7 Induction by EHMT2 Inhibition Enhances Immunity in Microsatellite Stability Colorectal Cancer.

BACKGROUND & AIMS: Although immunotherapy shows substantial advancement in colorectal cancer (CRC) with microsatellite instability high, it has limited efficacy for CRC with microsatellite stability (MSS). Identifying combinations that reverse immune suppression and prime MSS tumors for current immunotherapy approaches remains an urgent need. METHODS: An in vitro CRISPR screen was performed using coculture models of primary tumor cells and autologous immune cells from MSS CRC patients to identify epigenetic targets that could enhance immunotherapy efficacy in MSS tumors. RESULTS: We revealed EHMT2, a histone methyltransferase, as a potential target for MSS CRC. EHMT2 inhibition transformed the immunosuppressive microenvironment of MSS tumors into an immunomodulatory one by altering cytokine expression, leading to T-cell-mediated cytotoxicity activation and improved responsiveness to anti-PD1 treatment. We observed galectin-7 up-regulation upon EHMT2 inhibition, which converted a "cold" MSS tumor environment into a T-cell-inflamed one. Mechanistically, CHD4 repressed galectin-7 expression by recruiting EHMT2 to form a cotranscriptional silencing complex. Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, serving as a potent adjunct cytokine therapy. CONCLUSIONS: Our findings suggest that targeting the EHMT2/galectin-7 axis could provide a novel combination strategy for immunotherapy in MSS CRC.

miRNome targeting NF-κB signaling orchestrates macrophage-triggered cancer metastasis and recurrence.

Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8% ± 2.6%/27.9% ± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma in vivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.

A water mediated multicomponent reaction for the synthesis of novel spirooxindole derivatives and their antifungal activity.

A water mediated three-component reaction of isatin, 4-aminocoumarin, and 1,3-cyclodicarbonyl compounds is reported for the synthesis of spiro[chromeno[4,3-b]cyclopenta[e]pyridine-7,3'-indoline]trione and the spiro[chromeno[4,3-b]quinoline 7,3'-indoline]trione. Up to 27 different spirooxindole derivatives were synthesized by this method. The bioactivity of these spirooxindole derivatives was evaluated and they were found to show antifungal activity against Cercospora arachidicola, Physalospora piricola, Rhizoctonia cerealis, and Fusarium moniliforme.

Alpha cells beget beta cells.

Understanding the origins of insulin-producing beta cells of the pancreas could lead to new treatments for diabetes. Collombat et al. (2009) now show that in response to injury, a population of pancreatic progenitor cells can give rise to glucagon-expressing alpha cells that then transdifferentiate into beta cells.

Investigation on Gold Dissolution Performance and Mechanism in Imidazolium Cyanate Ionic Liquids.

To explore green gold leaching reagents, a series of imidazolium cyanate ionic liquids (ILs), 1-ethyl-3-methyl-imidazolium cyanate ([C2MIM][OCN]), 1-propyl-3-methyl-imidazolium cyanate ([C3MIM][OCN]) and 1-butyl-3-methyl-imidazolcyanate ([C4MIM][OCN]) were synthesized and characterized by Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared Spectroscopy (FTIR) and thermogravimetric (TG) analysis. In this research, the imidazolium cyanates were utilized as a solute, which not only decreased the usage of ILs but also increased their gold dissolution capability. The gold dissolution performances of three imidazolium cyanates were characterized by dynamic leaching test and Scanning Electron Microscopy (SEM). The results show that the all three imidazolium cyanates had a gold dissolution ability, and the shorter the carbon chain on the imidazole ring in imidazolium cyanate, the faster the gold dissolution rate. The gold dissolution performance of [C2MIM][OCN] was the best, and the weight loss of gold leaf was 2.9 mg/cm2 at 40 °C after 120 h dissolution in [C2MIM][OCN] mixed with 10 wt. % water. Besides this, the gold dissolution rate increased with the increase in the concentration of imidazolium cyanates as well as the reaction temperature. The gold dissolution performances of imidazolium cyanates in different solvents including water, acetonitrile, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) were also investigated, and the weaker the polarity of the solvent, the more conducive it was to the gold dissolution reaction. The mechanism of gold dissolution by imidazolium cyanates was investigated through NMR spectroscopy and Electrospray Ionization Mass Spectrometry (ESI-MS). It was inferred that during the process of gold dissolution, Au was oxidized to Au+ and the imidazolium cations were deprotonated to form N-heterocyclic carbenes, which coordinated with gold to form gold complexes and achieve gold dissolution.

Increasing 1,4-Diaminobutane Production in Escherichia coli by Optimization of Cofactor PLP and NADPH Synthesis.

1,4-diaminobutane is widely used in the industrial production of polymers, pharmaceuticals, agrochemicals and surfactants. Owing to economic and environmental concerns, there has been a growing interest in using microbes to produce 1,4-diaminobutane. However, there is lack of research on the influence of cofactors pyridoxal phosphate (PLP) and NADPH on the synthesis of 1,4-diaminobutane. PLP serves as a cofactor of ornithine decarboxylase in the synthesis of 1,4-diaminobutane. Additionally, the synthesis of 1 mol 1,4-diaminobutane requires 2 mol NADPH, thus necessitating consideration of NADPH balance in the efficient synthesis of 1,4-diaminobutane by Escherichia coli. The aim of this study was to enhance the synthesis efficiency of 1,4-diaminobutane through increasing production of PLP and NADPH. By optimizing the expression of the genes associated with synthesis of PLP and NADPH in E. coli, cellular PLP and NADPH levels increased, and the yield of 1,4-diaminobutane also increased accordingly. Ultimately, using glucose as the primary carbon source, the yield of 1,4-diaminobutane in the recombinant strain NAP19 reached 272 mg/L·DCW, by increased 79% compared with its chassis strain.

Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.

OBJECTIVE: Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A+ TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer. DESIGN: The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation. RESULTS: MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8+ T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway. CONCLUSION: Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.

Evolution of Atlantic Meridional Overturning Circulation since the last glaciation: model simulations and relevance to present and future.

The Atlantic Meridional Overturning Circulation (AMOC) and the associated water masses have changed dramatically during the glacial-interglacial cycle. Here, I review some recent progress in the modelling of the AMOC and water masses since the Last Glacial Maximum and discuss the relevance of these past AMOC studies to the present and future AMOC study. Recent studies suggested that Atlantic water masses were constrained by carbon isotopes (δ13C) and neodymium isotopes (εNd), while the strength of the AMOC better was constrained by protactinium/thorium ratio (231Pa/230Th) and the spatial gradient of calcite oxygen isotopes (δ18Oc). In spite of the shallower AMOC at the glacial period, its intensity did not differ substantially from the present because of the cancellation of opposite responses to the rising CO2 and the retreating ice sheet. This article is part of a discussion meeting issue 'Atlantic overturning: new observations and challenges'.

Half-precessional cycle of thermocline temperature in the western equatorial Pacific and its bihemispheric dynamics.

The El Niño-Southern Oscillation (ENSO), which is tightly coupled to the equatorial thermocline in the Pacific, is the dominant source of interannual climate variability, but its long-term evolution in response to climate change remains highly uncertain. This study uses Mg/Ca in planktonic foraminiferal shells to reconstruct sea surface and thermocline water temperatures (SST and TWT) for the past 142 ky in a western equatorial Pacific (WEP) core MD01-2386. Unlike the dominant 100-ky glacial-interglacial cycle recorded by SST and δ18O, which echoes the pattern seen in other WEP sites, the upper ocean thermal gradient shows a clear half-precessional (9.4 ky or 12.7 ky) cycle as indicated by the reconstructed and simulated temperature (ΔT) and δ18O differences between the surface and thermocline waters. This phenomenon is attributed to the interplay of subtropical-to-tropical thermocline anomalies forced by the antiphased meridional insolation gradients in the two hemispheres at the precessional band. In particular, the TWT shows greater variability than SST, and dominates the ΔT changes which couple with the west-east SST difference in the equatorial Pacific at the half-precessional band, implying a decisive role of the tropical thermocline in orbital-scale climate change.

Identification of immune-related key genes in the peripheral blood of ischaemic stroke patients using a weighted gene coexpression network analysis and machine learning.

BACKGROUND: The immune system plays a vital role in the pathological process of ischaemic stroke. However, the exact immune-related mechanism remains unclear. The current research aimed to identify immune-related key genes associated with ischaemic stroke. METHODS: CIBERSORT was utilized to reveal the immune cell infiltration pattern in ischaemic stroke patients. Meanwhile, a weighted gene coexpression network analysis (WGCNA) was utilized to identify meaningful modules significantly correlated with ischaemic stroke. The characteristic genes correlated with ischaemic stroke were identified by the following two machine learning methods: the support vector machine-recursive feature elimination (SVM-RFE) algorithm and least absolute shrinkage and selection operator (LASSO) logistic regression. RESULTS: The CIBERSORT results suggested that there was a decreased infiltration of naive CD4 T cells, CD8 T cells, resting mast cells and eosinophils and an increased infiltration of neutrophils, M0 macrophages and activated memory CD4 T cells in ischaemic stroke patients. Then, three significant modules (pink, brown and cyan) were identified to be significantly associated with ischaemic stroke. The gene enrichment analysis indicated that 519 genes in the above three modules were mainly involved in several inflammatory or immune-related signalling pathways and biological processes. Eight hub genes (ADM, ANXA3, CARD6, CPQ, SLC22A4, UBE2S, VIM and ZFP36) were revealed to be significantly correlated with ischaemic stroke by the LASSO logistic regression and SVM-RFE algorithm. The external validation combined with a RT‒qPCR analysis revealed that the expression levels of ADM, ANXA3, SLC22A4 and VIM were significantly increased in ischaemic stroke patients and that these key genes were positively associated with neutrophils and M0 macrophages and negatively correlated with CD8 T cells. The mean AUC value of ADM, ANXA3, SLC22A4 and VIM was 0.80, 0.87, 0.91 and 0.88 in the training set, 0.85, 0.77, 0.86 and 0.72 in the testing set and 0.87, 0.83, 0.88 and 0.91 in the validation samples, respectively. CONCLUSIONS: These results suggest that the ADM, ANXA3, SLC22A4 and VIM genes are reliable serum markers for the diagnosis of ischaemic stroke and that immune cell infiltration plays a crucial role in the occurrence and development of ischaemic stroke.

Identifying patterns of immune related cells and genes in the peripheral blood of acute myocardial infarction patients using a small cohort.

BACKGROUND: The immune system plays a vital role in the pathophysiology of acute myocardial infarction (AMI). However, the exact immune related mechanism is still unclear. This research study aimed to identify key immune-related genes involved in AMI. METHODS: CIBERSORT, a deconvolution algorithm, was used to determine the proportions of 22 subsets of immune cells in blood samples. The weighted gene co-expression network analysis (WGCNA) was used to identify key modules that are significantly associated with AMI. Then, CIBERSORT combined with WGCNA were used to identify key immune-modules. The protein-protein interaction (PPI) network was constructed and Molecular Complex Detection (MCODE) combined with cytoHubba plugins were used to identify key immune-related genes that may play an important role in the occurrence and progression of AMI. RESULTS: The CIBERSORT results suggested that there was a decrease in the infiltration of CD8 + T cells, gamma delta (γδ) T cells, and resting mast cells, along with an increase in the infiltration of neutrophils and M0 macrophages in AMI patients. Then, two modules (midnightblue and lightyellow) that were significantly correlated with AMI were identified, and the salmon module was found to be significantly associated with memory B cells. Gene enrichment analysis indicated that the 1,171 genes included in the salmon module are mainly involved in immune-related biological processes. MCODE analysis was used to identify four different MCODE complexes in the salmon module, while four hub genes (EEF1B2, RAC2, SPI1, and ITGAM) were found to be significantly correlated with AMI. The correlation analysis between the key genes and infiltrating immune cells showed that SPI1 and ITGAM were positively associated with neutrophils and M0 macrophages, while they were negatively associated with CD8 + T cells, γδ T cells, regulatory T cells (Tregs), and resting mast cells. The RT-qPCR validation results found that the expression of the ITGAM and SPI1 genes were significantly elevated in the AMI samples compared with the samples from healthy individuals, and the ROC curve analysis showed that ITGAM and SPI1 had a high diagnostic efficiency for the recognition of AMI. CONCLUSIONS: Immune cell infiltration plays a crucial role in the occurrence and development of AMI. ITGAM and SPI1 are key immune-related genes that are potential novel targets for the prevention and treatment of AMI.

Ginsenoside-Rg1 attenuates sepsis-induced cardiac dysfunction by modulating mitochondrial damage via the P2X7 receptor-mediated Akt/GSK-3ß signaling pathway.

Ginsenoside-Rg1 (G-Rg1), a saponin that is a primary component of ginseng, is effective against inflammatory diseases. The P2X purinoceptor 7 (P2X7) receptor is an ATP-gated ion channel that is predominantly expressed in immune cells and plays a key role in inflammatory processes. We investigated the role of G-Rg1 in sepsis-related cardiac dysfunction and the underlying mechanism involving the regulation of the P2X7 receptor. We detected cell viability, cytotoxicity, cellular reactive oxygen species (ROS) levels, and mitochondrial membrane potential (MMP) with or without G-Rg1 in lipopolysaccharide (LPS)- or hypoxia/reoxygenation (H/R)-induced H9c2 cell models of ischemia/reperfusion injury. We applied cecal ligation and puncture (CLP) to induce a mouse model of sepsis and measured the survival duration and cardiac function of CLP mice. Next, we quantified the ROS level, MMP, respiratory chain complex I-IV enzymatic activity, and mitochondrial fusion in CLP mouse heart tissues. We then investigated the role of G-Rg1 in repairing LPS-induced cell mitochondrial damage, including mitochondrial superoxidation products. The results showed that G-Rg1 inhibited LPS- or H/R-induced cardiomyocyte apoptosis, cytotoxicity, ROS levels, and mitochondrial damage. In addition, G-Rg1 prolonged the survival time of CLP mice. G-Rg1 attenuated LPS-induced superoxide production in the mitochondria of cardiomyocytes and the excessive release of cytochrome c from mitochondria into the cytoplasm. Most importantly, G-Rg1 suppressed LPS-mediated induction of proapoptotic Bax, activated Akt, induced GSK-3ß phosphorylation, and balanced mitochondrial calcium levels. Overall, G-Rg1 activates the Akt/GSK-3ß pathway through P2X7 receptors to inhibit sepsis-induced cardiac dysfunction and mitochondrial dysfunction.

Post-ecological effect and risk assessment of using modified clay in harmful algal bloom mitigation: An attempt based on the responses of zooplankton Brachionus plicatilis and bivalve Mytilus edulis.

The modified clay is the only worldwide-accepted practical method for mitigating algal bloom. Is it ecologically safe? To evidence it, a simulative bloom-occurring system of Karenia mikimotoi was set up, and the sentinel organisms of rotifer Brachionus plicatilis in sea surface and blue mussel Mytilus edulis on the benthos were respectively included. The organisms' physiological responses were determined as the indicators to reflect the ecological impacts when clay settled from surface to the bottom during the mimic bloom-mitigating process. Modified clay at a concentration of 0.1 g/L effectively removed the K. mikimotoi at an 81% removal rate, and its addition would not significantly strengthen the negative impacts on population dynamics and reproductive activities of B. plicatilis induced by sole K. mikimotoi within the first 2 h. Even an alleviation was observed at 2 d indicated by the increase of survival rate, egg and larva production after clay addition compared with those of 2 h. When the clay particles settled to benthos, the physical damage to the gills and digestive glands of M. edulis were found via the tissue and SEM observation, especially in higher treatment groups of 0.5 and 1.0 g/L, and filtering rate, digestive enzymes, condition index, water content and mortality were also influenced. However, little impact was found in group of 0.1 g/L. Risk assessment based on the adverse outcome pathway (AOP) model further revealed that the complete key event-key event relationship-adverse outcome pathway was only clearly observed in 0.5 g/L and 1 g/L groups but not in 0.1 g/L group, inferring the small ecological risk of 0.1 g/L. The integrated biomarker response (IBR) based on the mussel's physiological responses further backed up the AOP outcoming. The combined results from rotifer to bivalve emphasized on one conclusion that modified clay at 0.1 g/L was effective and ecologically safe in coastal bloom mitigation.

Zero contrast optical coherence tomography-guided percutaneous coronary intervention in patients with non-ST segment elevation myocardial infarction and chronic kidney disease.

OBJECTIVES: To investigate a strategy for ultra-low volume contrast percutaneous coronary intervention (PCI) with the aims of preserving renal function and observing the 90-day clinical endpoint in patients with non-ST-elevated myocardial infarction (non-STEMI) and chronic kidney disease (CKD). BACKGROUND: The feasibility, safety, and clinical utility of PCI with ultra-low radio-contrast medium in patients with non-STEMI and CKD are unknown. METHODS: A total of 29 patients with non-STEMI and CKD (estimated glomerular filtration rate [eGFR] of ≤60 ml/min/1.73 m2 ) were included. Ultra-low volume contrast PCI was performed after minimal contrast coronary angiography using zero contrast optical coherence tomography (OCT) guidance. Pre- and post-PCI angiographic measurements were performed using quantitative flow ratio (QFR) for pre-perfusion assessment and verifying improvement. RESULTS: The median creatinine level was 2.1 (inter-quartile range 1.8-3.3), and mean eGFR was 48 ± 8 ml/min/1.73 m2 pre-PCI. During the PCI procedure, OCT revealed 15 (52%) cases of abnormalities post-dilation. There was no significant change in the creatinine level and eGFR in the short- or long-term, and no major adverse events were observed. CONCLUSION: In non-STEMI patients with high-risk CKD who require revascularization, QFR and no contrast OCT-guided ultra-low contrast PCI may be performed safely without major adverse events.

Melt Crystallization of Indomethacin Polymorphs in the Presence of Poly(ethylene oxide): Selective Enrichment of the Polymer at the Crystal-Liquid Interface.

Additives have been known to influence the crystallization behavior of amorphous pharmaceuticals. In this study, the semicrystalline polymer, poly(ethylene oxide) (PEO), exhibited a different impact on the crystal growth kinetics of indomethacin (IMC) polymorphs grown from the melt. Polarized light microscopy and Raman microscopy were employed to reveal the differences in phase separation occurring at the crystal-liquid interface of IMC polymorphs in the presence of PEO. It was found that at the same condition of melt crystallization PEO could be significantly enriched at the crystal growth front of IMC γ and α forms but not at that of the δ form. The local content of PEO at the growth front was proposed to correlate with the solubility of IMC polymorphs in the molten PEO. The distinct drug-polymer distribution at the crystal-liquid interface of IMC polymorphs could have different impacts on the thermodynamic and kinetic factors in the process of crystallization, resulting in different enhancements of crystal growth rates for the polymorphs. This study is beneficial to understanding the crystallization behavior of polymorphic drugs in the presence of polymeric additives, and more attention needs to be focused on the interfacial phenomena during crystal growth.

Emerging protective roles of shengmai injection in septic cardiomyopathy in mice by inducing myocardial mitochondrial autophagy via caspase-3/Beclin-1 axis.

BACKGROUND: Sepsis, a life-threatening systemic syndrome related to inflammatory response, usually accompanied by major organ dysfunctions. The aim of the present study was to elucidate the role by which Shengmai injection (SMI) acts to septic cardiomyopathy. METHODS: Initially, the induced mice with septic cardiomyopathy were treated with SMI or normal saline (NS) with oe-caspase-3, and HL-1 cells were treated with oe-Beclin-1 and oe-caspase-3 and then cultured with lipopolysaccharide (LPS). Subsequently, we measured the cardiac troponin I (cTnI) level, and expression of mitochondrial autophagy protein (parkin and pink1) and myocardial cell autophagy-related proteins (LC3-II and LC3-I). Additionally, we identified the cleavage of Beclin-1 by caspase-3 and detected the changes of mitochondrial membrane potential, level of reactive oxygen species (ROS), and apoptosis of myocardial cells in myocardial tissues of mice. RESULTS: It has been demonstrated that SMI contributed to the increase of myocardial mitochondrial autophagy, reduction of cTnI level, and elevation of mitochondrial membrane potential in septic cardiomyopathy mice. Both in vitro and in vivo experiments showed that caspase-3 promoted cleavage of Beclin-1 and release of ROS, whereas repressed lipopolysaccharide (LPS)-induced mitochondrial autophagy. Furthermore, the facilitation of myocardial mitochondrial autophagy and protection of myocardial mitochondria by SMI through inhibition of cleavage Beclin-1 by caspase-3 in septic cardiomyopathy mice were also proved by in vivo experiments. CONCLUSION: Taken together, SMI could protect myocardial mitochondria by promoting myocardial mitochondrial autophagy in septic cardiomyopathy via inhibition of cleavage of Beclin-1 by caspase-3. Our study demonstrates that SMI could represent a novel target for treatment of septic cardiomyopathy.

Evolution and forcing mechanisms of El Niño over the past 21,000 years.

The El Niño Southern Oscillation (ENSO) is Earth's dominant source of interannual climate variability, but its response to global warming remains highly uncertain. To improve our understanding of ENSO's sensitivity to external climate forcing, it is paramount to determine its past behaviour by using palaeoclimate data and model simulations. Palaeoclimate records show that ENSO has varied considerably since the Last Glacial Maximum (21,000 years ago), and some data sets suggest a gradual intensification of ENSO over the past ∼6,000 years. Previous attempts to simulate the transient evolution of ENSO have relied on simplified models or snapshot experiments. Here we analyse a series of transient Coupled General Circulation Model simulations forced by changes in greenhouse gasses, orbital forcing, the meltwater discharge and the ice-sheet history throughout the past 21,000 years. Consistent with most palaeo-ENSO reconstructions, our model simulates an orbitally induced strengthening of ENSO during the Holocene epoch, which is caused by increasing positive ocean-atmosphere feedbacks. During the early deglaciation, ENSO characteristics change drastically in response to meltwater discharges and the resulting changes in the Atlantic Meridional Overturning Circulation and equatorial annual cycle. Increasing deglacial atmospheric CO2 concentrations tend to weaken ENSO, whereas retreating glacial ice sheets intensify ENSO. The complex evolution of forcings and ENSO feedbacks and the uncertainties in the reconstruction further highlight the challenge and opportunity for constraining future ENSO responses.