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Background & Aims: Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) is a central player in triggering necroptotic cell death. However, whether macrophage RIPK3 may regulate NOD1-dependent inflammation and calcineurin/transient receptor potential cation channel subfamily M member 7 (TRPM7)-induced hepatocyte death in oxidative stress-induced liver inflammatory injury remains elusive. Methods: A mouse model of hepatic ischaemia–reperfusion (IR) injury, the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific RIPK3 knockout (RIPK3M-KO) and RIPK3-proficient (RIPK3FL/FL) mice. Results: RIPK3M-KO diminished IR stress-induced liver damage with reduced serum alanine aminotransferase/aspartate aminotransferase levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the RIPK3FL/FL controls. IR stress activated RIPK3, inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α), x-box binding protein 1 (XBP1), nucleotide-binding oligomerisation domain-containing protein 1 (NOD1), NF-κB, forkhead box O1 (Foxo1), calcineurin A, and TRPM7 in ischaemic livers. Conversely, RIPK3M-KO depressed IRE1α, XBP1, NOD1, calcineurin A, and TRPM7 activation with reduced serum tumour necrosis factor α (TNF-α) levels. Moreover, Foxo1M-KO alleviated IR-induced liver injury with reduced NOD1 and TRPM7 expression. Interestingly, chromatin immunoprecipitation coupled with massively parallel sequencing revealed that macrophage Foxo1 colocalised with XBP1 and activated its target gene Zc3h15 (zinc finger CCCH domain-containing protein 15). Activating macrophage XBP1 enhanced Zc3h15, NOD1, and NF-κB activity. However, disruption of macrophage Zc3h15 inhibited NOD1 and hepatocyte calcineurin/TRPM7 activation, with reduced reactive oxygen species production and lactate dehydrogenase release after macrophage/hepatocyte coculture. Furthermore, adoptive transfer of Zc3h15-expressing macrophages in RIPK3M-KO mice augmented IR-triggered liver inflammation and cell death. Conclusions: Macrophage RIPK3 activates the IRE1α–XBP1 pathway and Foxo1 signalling in IR-stress livers. The XBP1–Foxo1 interaction is essential for modulating target gene Zc3h15 function, which is crucial for the control of NOD1 and calcineurin-mediated TRPM7 activation. XBP1 functions as a transcriptional coactivator of Foxo1 in regulating NOD1-driven liver inflammation and calcineurin/TRPM7-induced cell death. Our findings underscore a novel role of macrophage RIPK3 in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases. Impact and implications: Macrophage RIPK3 promotes NOD1-dependent inflammation and calcineurin/TRPM7-induced cell death cascade by triggering the XBP1–Foxo1 axis and its target gene Zc3h15, which is crucial for activating NOD1 and calcineurin/TRPM7 function, implying the potential therapeutic targets in stress-induced liver inflammatory injury.

Over the past few decades, cellular senescence has been identified in cancer patients undergoing chemotherapy and radiotherapy. Senescent cells are generally characterized by permanent cell cycle arrest as a response to endogenous and exogenous stresses. In addition to exiting the cell cycle process, cellular senescence also triggers profound phenotypic changes such as senescence-associated secretory phenotype (SASP), autophagy modulation, or metabolic reprograming. Consequently, cellular senescence is often considered as a tumor-suppressive mechanism that permanently arrests cells at risk of malignant transformation. However, accumulating evidence shows that therapy-induced senescence can promote epithelial-mesenchymal transition and tumorigenesis in neighboring cells, as well as re-entry into the cell cycle and activation of cancer stem cells, thereby promoting cancer cell survival. Therefore, it is particularly important to rapidly eliminate therapy-induced senescent cells in patients with cancer. Here we review the hallmarks of cellular senescence and the relationship between cellular senescence and cancer. We also discuss several pathways to induce senescence in tumor therapy, as well as strategies to eliminate senescent cells after cancer treatment. We believe that exploiting the intersection between cellular senescence and tumor cells is an important means to defeat tumors.

The prognosis of patients with cholangiocarcinoma (CCA) is closely related to both immune cell infiltration and mRNA expression. Therefore, we aimed at conducting multi-immune-related gene analyses to improve the prediction of CCA recurrence. Immune-related genes were selected from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and the Immunology Database and Analysis Portal (ImmPort). The least absolute shrinkage and selection operator (LASSO) regression model was used to establish the multi-gene model that was significantly correlated with the recurrence-free survival (RFS) in two test series. Furthermore, compared with single genes, clinical characteristics, tumor immune dysfunction and exclusion (TIDE), and tumor inflammation signature (TIS), the 8-immune-related differentially expressed genes (8-IRDEGs) signature had a better prediction value. Moreover, the high-risk subgroup had a lower density of B-cell, plasma, B-cell naïve, CD8+ T-cell, CD8+ T-cell naïve, and CD8+ T-cell memory infiltration, as well as more severe immunosuppression and higher mutation counts. In conclusion, the 8-IRDEGs signature was a promising biomarker for distinguishing the prognosis and the molecular and immune features of CCA, and could be beneficial to the individualized immunotherapy for CCA patients.

Abstract Background Increases in the levels of serum C-reactive protein (CRP) and creatinine (Cr) and decreases in those of albumin (Alb) are commonly observed in acute pancreatitis (AP). We aimed to evaluate the efficacy of the Cr/Alb and CRP/Alb ratios in the prediction of surgical treatment effect in AP patients. Methods This study retrospectively analyzed clinical data obtained from 140 AP patients who underwent debridement from January 2008 to November 2018 in Shanghai Ruijin Hospital. The Cr/Alb and CRP/Alb ratios at admission and before surgery were assessed in the analysis of clinical statistics, prediction of prognoses, and logistic regression analysis. Results The admission Cr/Alb had the best predictive value of the four ratios. This value was significantly higher in patients with re-operation and those who died (P

Abstract Background Acute liver failure (ALF) is a complicated condition that is characterized by global hepatocyte death and often requires immediate liver transplantation. However, this therapy is limited by shortage of donor organs. Mesenchymal stem cells (MSCs) and hepatocytes are two attractive sources of cell-based therapies to treat ALF. The combined transplantation of hepatocytes and MSCs is considered to be more effective for the treatment of ALF than single-cell transplantation. We have previously demonstrated that HNF4α-overexpressing human umbilical cord MSCs (HNF4α-UMSCs) promoted the expression of hepatic-specific genes. In addition, microencapsulation allows exchange of nutrients, forming a protective barrier to the transplanted cells. Moreover, encapsulation of hepatocytes improves the viability and synthetic ability of hepatocytes and circumvents immune rejection. This study aimed to investigate the therapeutic effect of microencapsulation of hepatocytes and HNF4α-UMSCs in ALF mice. Methods Human hepatocytes and UMSCs were obtained separately from liver and umbilical cord, followed by co-encapsulation and transplantation into mice by intraperitoneal injection. LPS/D-gal was used to induce ALF by intraperitoneal injection 24 h after transplantation. In addition, Raw 264.7 cells (a macrophage cell line) were used to elucidate the effect of HNF4α-UMSCs-hepatocyte microcapsules on polarization of macrophages. The protein chip was used to define the important paracrine factors in the conditioned mediums (CMs) of UMSCs and HNF4α-UMSCs and investigate the possible mechanism of HNF4α-UMSCs for the treatment of ALF in mice. Results HNF4α-UMSCs can enhance the function of primary hepatocytes in alginate–poly-L-lysine–alginate (APA) microcapsules. The co-encapsulation of both HNF4α-UMSCs and hepatocytes achieved better therapeutic effects in ALF mice by promoting M2 macrophage polarization and reducing inflammatory response mainly mediated by the paracrine factor HB-EGF secreted by HNF4α-UMSCs. Conclusions The present study confirms that the co-encapsulation of HNF4α-UMSC and hepatocytes could exert therapeutic effect on ALF mainly by HB-EGF secreted by HNF4α-UMSCs and provides a novel strategy for the treatment of ALF.

A three-dimensional numerical model was established with OpenFOAM-5.x to investigate plume characteristics under windless and rainless weather conditions. The large eddy simulation was applied, combined with a modified solver for solving governing equations with the Boussinesq approximation in a single rotating frame. The relationship between plume characteristics (e.g., gradient Richardson number and maximum plume width) and quantified parameters (e.g., rotation period, shelf slope, and reduced gravity) was analyzed progressively. The results show the model can reproduce the change in plume types and instability found in the laboratory experiments. With the increase in the rotation period, river plumes change from a surface-advected type to a bottom-attached type. The outline of the plume bulge accurately delineates the external region where the gradient Richardson number is less than 0.25, as well as the region near the wall. When the shelf slope approaches 0, the offshore movement becomes stronger while the alongshore coastal current comes into being with a delay associated with the slope and the rotation period. Compared with the extremely gentle slope case and the steep slope case, the maximum width in the gentle slope case changes significantly at about 1.5 rotation periods. Greater reduced gravity does promote offshore propagation, especially near the surface.

In nature, plumes usually enter the coastal ocean after they leave the estuary, and most of them interact with the continental shelf slope. To understand plume dynamics, laboratory experiments were carried out on a rotating table to simulate the evolution of plumes over a sloping bottom. We modified reduced gravity g’, Coriolis parameter f, and shelf slope α to study their impacts on plume characteristics and freshwater fate, and used the optical thickness method to obtain the depth field. We found that with the increasing g’ or decreasing f, plume maximum depth hmax decreases and plume maximum width Wmax increases. We proposed a method to determine plume types based on their attachment to the shelf slope: when PCN (plume classification number) > 1.6, the plume is bottom-attached; when PCN< 1.6, the plume is surface-advected. In addition, we found the bulge will become unstable when BIN (bulge instability number)< 0.8. Our analysis shows that the sloping bottom is the most significant factor determining the ratio of freshwater accumulated in the bulge over transported with coastal currents. Generally, bottom-attached plume trapped near the coast inhibits offshore freshwater transport and promotes coastal current transport, while baroclinic instability tends to produce a large cyclonic vortex over a gentle slope which strongly enhances the offshore transport.

This paper carried out laboratory experiments to study evolution of internal solitary waves (ISWs) over submarine canyons with a combination of PIV (particle image velocimetry) and PLIF (planar laser-induced fluorescence) techniques. Taking canyon angle θ and collapse height ∆H as variables, Froude number Fr, head position, energy loss, vorticity field and turbulence intensity when ISWs propagate to the canyon were analyzed. According to the Froude number Fr values, the study cases can be divided into three types: Fr > 1.7 means complete internal hydraulic jump (IHJ); 1 < Fr < 1.7 denotes wavy IHJ and Fr < 1 represents no IHJ. The greater canyon angle, collapse depth and amplitude of the incident wave more easily generate IHJs, which can lead to more energy loss, greater vorticity and turbulence intensity in the canyon area. Among all canyon cases, vorticity and turbulence intensity of the no IHJ case showing an obvious bimodal distribution are smaller than IHJ cases. For wavy IHJ, the energy dissipation is not obvious, and the average turbulent intensity performs a “sharp unimodal distribution”. Complete IHJ cases last for a long time and cause violent mixing, the average turbulent intensity is the largest and its distribution presents a “gentle single peak” pattern. For the 180° conditions (no canyon cases), less energy is delivered to the reflected wave and more energy is dissipated near the terrain, so the energy loss is the largest in comparison to other conditions. These findings will deepen our understanding of the evolution mechanisms of ISWs propagating over submarine canyons.

The mesoscale eddies off the coast of Chile significantly impact the distribution of local chlorophyll and the development of marine ecosystem. Multiple processes, including eddy trapping, pumping, advection, Ekman-pumping, and submesoscale dynamics, exert their impacts simultaneously on transport of water masses at different distances with respect to the eddy center. The cyclonic (anticyclonic) eddies are generally characterized by upwelling (downwelling) within the eddy, which elevates (depresses) chlorophyll inside the eddy. Outside the eddy periphery, multiple processes are involved simultaneously, but their corresponding influences on chlorophyll are not well identified. In this study, the amplitudes of cyclonic and anticyclonic eddies are distinguished as positive and negative values, respectively. A linear regression method is applied to seek the connection between eddy's amplitude and chlorophyll distribution at different locations w.r.t. the eddy center. The regression slope between eddy amplitude and chlorophyll anomaly is found to be negative in the eddy interior and along the periphery, which gradually changes to positive away from the periphery. The location where the response of chlorophyll to an eddy switches its sign is defined as the transition zone. The location of the transition zone varies with offshore distance and is impacted by topography, such as the presence of islands, which can change the dynamics of eddies. Thus, the distance from eddy center and offshore distance from coast should be taken into consideration when investigating their influences on nutrient transport and chlorophyll distribution.

Accurate and reliable estimates of sediment yields from a watershed and identification of unstable stream reaches due to sediment-related disaster are crucial for watershed management, disaster prevention, and hazard mitigation purposes. In this study, we added hydrodynamic and sediment transport modules in a recently developed model to estimate sediment yields and identify the unstable stream reaches in a large-scale watershed (> 100km2). The calibrated and verified models can well reproduce the flow discharge and sediment discharge at the study site, the Shihmen Reservoir Watershed in Taiwan, during several typhoon events. For the scenario applications, the results revealed that the contribution (> 96%) of landslides on sediment supply is much more significant than compared to soil erosion (< 4%). The sediment contribution from the upstream of the hydrological station-Yufeng is approximately 36⁻55% of the total sediment supply for the rainfall events of 25, 50, 100, and 200 years return period. It also indicates that 22⁻52% of sediment still remain at foot of the slope and the streams, which become a potential source for sediment hazards in the future. Combining with the bed erosion and deposition depths, flow-induced shear stress from the SRH-2D model, and probability of slope failure within 250 m of stream reaches, the relatively stability of stream reaches can be identified. The results could provide the water resource authorities for reference to take precautionary measures in advance on the stream reaches with high-degree instability.

Seasonal cycle and interannual variability in coastal circulations in the northern South China Sea (NSCS) are investigated using satellite altimeter data from March 1993 to September 2016. Altimeter-derived velocity anomalies are in good agreement with acoustic Doppler current profilers (ADCP) observations at an adjacent location. Along-shelf volume transport anomalies in the NSCS indicate northeastward transports from mid-spring to summer and southwestward transports from mid-autumn to winter, which are consistent with previous studies in this region. According to convergence and divergence in the target control volumes, cross-shelf volume transports are estimated as the differences between two neighboring along-shelf volume transport anomalies, with the assumption that long-term mean along-shelf volume transports at each cross-sections are identical. The results show onshore transports in mid-autumn and offshore transports in early summer. The comparison between altimeter-derived and ADCP-estimated cross-shelf volume transports is encouraging, especially when the region has relatively low mesoscale activities and a low freshwater input. Reconstructed cross-shelf volume transports through multiple linear regression reveal that seasonal harmonics is the primary force in driving cross-shelf volume transports in the NSCS, while wind and El Niño have secondary effects on controlling cross-shelf volume transports in different regions. The present study helps to quantify the long-term coastal circulations, especially cross-shelf volume transports, based on altimeter data, which has important implications on the dynamics in coastal regions where observational data is limited.