multimedia: Multimodal Mediation Analysis of Microbiome Data.

Mediation analysis has emerged as a versatile tool for answering mechanistic questions in microbiome research because it provides a statistical framework for attributing treatment effects to alternative causal pathways. Using a series of linked regression models, this analysis quantifies how complementary data modalities relate to one another and respond to treatments. Despite these advances, the rigid modeling assumptions of existing software often results in users viewing mediation analysis as a black box, not something that can be inspected, critiqued, and refined. We designed the multimedia R package to make advanced mediation analysis techniques accessible to a wide audience, ensuring that all statistical components are easily interpretable and adaptable to specific problem contexts. The package provides a uniform interface to direct and indirect effect estimation, synthetic null hypothesis testing, and bootstrap confidence interval construction. We illustrate the package through two case studies. The first re-analyzes a study of the microbiome and metabolome of Inflammatory Bowel Disease patients, uncovering potential mechanistic interactions between the microbiome and disease-associated metabolites, not found in the original study. The second analyzes new data about the influence of mindfulness practice on the microbiome. The mediation analysis identifies a direct effect between a randomized mindfulness intervention and microbiome composition, highlighting shifts in taxa previously associated with depression that cannot be explained by diet or sleep behaviors alone. A gallery of examples and further documentation can be found at https://go.wisc.edu/830110.

China's energy-water-land system co-evolution under carbon neutrality goal and climate impacts.

China's 2060 carbon neutrality goal has significant implications for energy, water, and land systems. However, the multi-sector dynamics among China's energy-water-land system have rarely been examined explicitly. This study adopts an integrated assessment framework to simulate China's energy-water-land system co-evolution under alternative carbon neutrality scenarios and climate impacts. Results show that although the net zero emission target provides the incentive for the energy system to move away from fossil fuels, total water withdrawal will increase due to the deployment of nuclear, bioenergy, and coal power plants with carbon capture and storage. Diversifying the negative emission technologies, by leveraging direct air capture technology, can alleviate the potential water stress and land use conflicts, which would otherwise be exacerbated by large-scale deployment of afforestation and bioenergy with carbon capture and storage. Northwest and northeast regions of China are the hotspots experiencing water withdrawal increases, while Bohai Rim and coastal regions are identified to experience fierce land competition. This study demonstrates the potential for general applicability to carry out resource planning and policy evaluation from the multi-sector coordination perspective.

A systematic assessment of city-level climate change mitigation and air quality improvement in China.

China is facing dual challenges of air pollution and climate change. By using city-level data, we comprehensively assessed air quality and CO2 emission changes from 2015 to 2019 for 335 Chinese cities. We selected important regions for air pollution control and categorized all cities into different classes according to their development levels. Our novel approach revealed new insights on different patterns of changes of PM2.5, O3, and CO2 by region and city class. We found that PM2.5 concentrations decreased remarkably due to mandatory city-level reduction targets, especially in the Beijing-Tianjin-Hebei (-27%) region. Nonetheless, O3 concentrations and CO2 emissions increased in 91% and 69% of Chinese cities, respectively. Observed CO2 emission reductions in more developed cities were mainly due to prominent energy intensity reduction and energy structure improvement. Our study indicates a lack of synergy in air pollution control and CO2 mitigation under current policies in China. To address both challenges holistically, we suggest setting mandatory city-level CO2 emission reduction targets and reinforcing clean energy and energy efficiency measures.

Correction to: A novel organ preservation solution with efficient clearance of red blood cells improves kidney transplantation in a canine model.

[This corrects the article DOI: 10.1186/s13578-018-0226-2.].

A novel organ preservation solution with efficient clearance of red blood cells improves kidney transplantation in a canine model.

Organ preservation solutions are designed to minimize organ damage during transplantation. A novel preservation solution, WMO-II, was developed to have a low viscosity and to improve microvasculature perfusion for kidneys. In an autologous canine transplantation model, kidney function and recovery were evaluated after organs were flushed and cold-stored with WMO-II or HTK solution, a perfusate currently approved for clinical use. The average number of red blood cells remaining in a single glomerulus after flushing with WMO-II was significantly reduced when compared with HTK solution. Additionally, WMO-II reduced the number of apoptotic bodies in stored kidneys compared to HTK treated tissue after 48 h of cold storage by reducing expression of Caspase-9, BiP, Chop, and Caspase-12. WMO-II solution reduced serum creatinine levels and serum potassium in kidneys stored for 48 h when compared to HTK perfusion. WMO-II preserves kidney function as evidenced by the reduction in serum creatinine and potassium during graft transplantation.

Short-term Pharmacological Inhibition of MyD88 Homodimerization by a Novel Inhibitor Promotes Robust Allograft Tolerance in Mouse Cardiac and Skin Transplantation.

BACKGROUND: Most strategies for antirejection and tolerance induction in clinical transplantation have focused on modifying adaptive immunity, it is unclear whether pharmacological suppressing the innate immune system can promote transplant tolerance. METHODS: We inhibited innate immunity by using our self-generated inhibitor of myeloid differentiation factor 88 (MyD88), TJ-M2010-5, and investigated its therapeutic effects and mechanisms in cardiac and skin transplant models. RESULTS: TJ-M2010-5 directly and indirectly interacted with the Toll/IL-1R domain of MyD88, inhibiting MyD88 homodimerization. In vitro, TJ-M2010-5 inhibited maturation of dendritic cells, which suppressed nuclear translocation of NF-κB and T cell activation. In vivo, short-term (10 days) monotherapy of TJ-M2010-5 resulted in long time survival of 50% of the cardiac allografts, and longer-term (14 days) combination treatment of TJ-M2010-5 with CD154 mAb resulted in survival of 29% of skin allografts, which outperformed far more than CsA did and stimulated the proliferation of CD4CD25FoxP3 Regulatory T cells in recipient mice. CONCLUSIONS: Pharmacological inhibition of MyD88 signaling by this novel inhibitor TJ-M2010-5 shows a powerful anti-rejection effect, which may have therapeutic potential in clinical transplantation. The inhibition of both innate and adaptive immunity may be necessary for tolerance induction in nonsolid organs.

[Influence of p16 gene on the biological behavior of human hepatocellular carcinoma].

BACKGROUND & OBJECTIVE: Inactivation of the tumor suppressor gene p16INK4a is one of the most common genetic alterations in human hepatocellular carcinomas (HCC), making it an ideal target gene for treatment of HCC. The objective of this study was to investigate the influence of wild p16 gene on the biological behavior of HCC. METHODS: HCC cell strains SNU-449 (loss of p16 protein expression) and HepG2.2. 15 (positive p16 protein expression) were respectively infected by a retrovirus expression vector of p16 gene (pcLXSN-p16). The stable p16 protein expression cell strains were selected. The biological behaviors of the p16 gene transfected HCC cells were observed. RESULTS: SNU-449 with negative p16 protein expression demonstrated that pcLXSN-p16 treatment significantly inhibited cell growth (the amount of cells at G0-G1 phase increased). However, there was no treatment effect when pcLXSN-p16 was transfected in HepG2.2. 15 which has positive p16 protein expression. Subsequent study in a nude mouse model demonstrated that the p16 gene transfected SNU-449 had a lower succeeding rate of first time establishment of tumors and grew more slowly in the nude mice as compared with non-transfected SNU-449. Moreover, the nude mice inoculated with transfected SNU-449 had a longer survival time than those inoculated with non-transfected SNU-449. CONCLUSION: The transfer of wild p16 gene can inhibit the proliferation and reduce the invasion ability of HCC cells with p16 negative expression, but can not affect the HCC cells with p16 positive expression.

Effects of p16 gene on biological behaviours in hepatocellular carcinoma cells.

AIM: To investigate the effects of p16 gene on biological behaviours in hepatocellular carcinoma cells. METHODS: HCC cell lines SNU-449 and HepG2.2.15 were infected respectively by a replication defective, recombinant retrovirus capable of producing a high level of p16 protein expression (pCLXSN-p16). G418 resistant stable P16 protein expression cell lines were selected. And the biological behaviours of the p16 gene transfected HCC cells were observed. RESULTS: Initial in vitro experiments in HCC cell line SNU-449 with loss of p16 protein expression demonstrated the pCLXSN-p16 treatment significantly inhibited cell growth. But there was no treatment effect when the pCLXSN-p16 was used in another HCC cell line HepG2.2.15 which has positive p16 protein expression. Subsequent study in a nude mouse model demonstrated that the p16 gene transfected SNU-449 had a lower succeeding rate in the first time establishment of tumors and grew more slowly in the nude mice when compared with non-transfected SNU-449. Moreover, the nude mice inoculated with transfected SNU-449 had a longer surviving time than those inoculated with non-transfected SNU-449. CONCLUSION: Our results show that the p16INK4a gene transfer can inhibit the proliferation and reduce the invasion ability of hepatocellular carcinoma.