Disentangling direct from indirect relationships in association networks.

Networks are vital tools for understanding and modeling interactions in complex systems in science and engineering, and direct and indirect interactions are pervasive in all types of networks. However, quantitatively disentangling direct and indirect relationships in networks remains a formidable task. Here, we present a framework, called iDIRECT (Inference of Direct and Indirect Relationships with Effective Copula-based Transitivity), for quantitatively inferring direct dependencies in association networks. Using copula-based transitivity, iDIRECT eliminates/ameliorates several challenging mathematical problems, including ill-conditioning, self-looping, and interaction strength overflow. With simulation data as benchmark examples, iDIRECT showed high prediction accuracies. Application of iDIRECT to reconstruct gene regulatory networks in Escherichia coli also revealed considerably higher prediction power than the best-performing approaches in the DREAM5 (Dialogue on Reverse Engineering Assessment and Methods project, #5) Network Inference Challenge. In addition, applying iDIRECT to highly diverse grassland soil microbial communities in response to climate warming showed that the iDIRECT-processed networks were significantly different from the original networks, with considerably fewer nodes, links, and connectivity, but higher relative modularity. Further analysis revealed that the iDIRECT-processed network was more complex under warming than the control and more robust to both random and target species removal (P < 0.001). As a general approach, iDIRECT has great advantages for network inference, and it should be widely applicable to infer direct relationships in association networks across diverse disciplines in science and engineering.

A randomized-controlled trial of ischemia-free liver transplantation for end-stage liver disease.

BACKGROUND & AIMS: Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes. METHODS: In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI. RESULTS: Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025). CONCLUSIONS: Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach. CLINICAL TRIAL REGISTRATION: chictr.org. ChiCTR1900021158. IMPACT AND IMPLICATIONS: Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.

Permafrost thaw with warming reduces microbial metabolic capacities in subsurface soils.

Microorganisms are major constituents of the total biomass in permafrost regions, whose underlain soils are frozen for at least two consecutive years. To understand potential microbial responses to climate change, here we examined microbial community compositions and functional capacities across four soil depths in an Alaska tundra site. We showed that a 5-year warming treatment increased soil thaw depth by 25.7% (p = .011) within the deep organic layer (15-25 cm). Concurrently, warming reduced 37% of bacterial abundance and 64% of fungal abundances in the deep organic layer, while it did not affect microbial abundance in other soil layers (i.e., 0-5, 5-15, and 45-55 cm). Warming treatment altered fungal community composition and microbial functional structure (p < .050), but not bacterial community composition. Using a functional gene array, we found that the relative abundances of a variety of carbon (C)-decomposing, iron-reducing, and sulphate-reducing genes in the deep organic layer were decreased, which was not observed by the shotgun sequencing-based metagenomics analysis of those samples. To explain the reduced metabolic capacities, we found that warming treatment elicited higher deterministic environmental filtering, which could be linked to water-saturated time, soil moisture, and soil thaw duration. In contrast, plant factors showed little influence on microbial communities in subsurface soils below 15 cm, despite a 25.2% higher (p < .05) aboveground plant biomass by warming treatment. Collectively, we demonstrate that microbial metabolic capacities in subsurface soils are reduced, probably arising from enhanced thaw by warming.

Association of Perfusion Characteristics and Posttransplant Liver Function in Ischemia-Free Liver Transplantation.

It has been shown that normothermic machine perfusion (NMP), a novel preservation method, is able to assess and resuscitate liver grafts with risk factors. However, there is no consistent criteria for the assessment of liver grafts with NMP. Ischemia-free liver transplantation (IFLT) includes innovative surgical techniques and NMP, which can protect liver grafts from ischemia throughout organ procurement, preservation, and implantation. In our center, 28 human livers from donation after brain death donors were subjected to IFLT between July 2017 and October 2018. The correlation between posttransplant liver function tests with the perfusion parameters, blood gas analysis of perfusate, and bile biochemistry were analyzed. During the preservation phase, the vascular flow was stable, and the lactate level decreased rapidly. The transaminase release in the perfusate was low but stable, whereas the glucose level remained high. The perfusate lactate and aspartate aminotransferase (AST) levels at 1 hour of perfusion were correlated with the posttransplant peak AST level. There were negative correlations between the portal vein and hepatic artery flows at the end of perfusion and the peak transaminase levels within 7 days after transplantation. In conclusion, during IFLT, NMP is able to bridge the liver grafts from donors to recipients and can allow the assessment of liver function by perfusion characteristics.

Arid1a Loss Drives Nonalcoholic Steatohepatitis in Mice Through Epigenetic Dysregulation of Hepatic Lipogenesis and Fatty Acid Oxidation.

Nonalcoholic steatohepatitis (NASH) is a rapidly growing cause of chronic liver damage, cirrhosis, and hepatocellular carcinoma. How fatty liver pathogenesis is subject to epigenetic regulation is unknown. We hypothesized that chromatin remodeling is important for the pathogenesis of fatty liver disease. AT-rich interactive domain-containing protein 1A (ARID1A), a DNA-binding component of the SWItch/sucrose nonfermentable adenosine triphosphate-dependent chromatin-remodeling complex, contributes to nucleosome repositioning and access by transcriptional regulators. Liver-specific deletion of Arid1a (Arid1a liver knockout [LKO]) caused the development of age-dependent fatty liver disease in mice. Transcriptome analysis revealed up-regulation of lipogenesis and down-regulation of fatty acid oxidation genes. As evidence of direct regulation, ARID1A demonstrated direct binding to the promoters of many of these differentially regulated genes. Additionally, Arid1a LKO mice were more susceptible to high-fat diet-induced liver steatosis and fibrosis. We deleted Pten in combination with Arid1a to synergistically drive fatty liver progression. Inhibition of lipogenesis using CAT-2003, a potent sterol regulatory element-binding protein inhibitor, mediated improvements in markers of fatty liver disease progression in this Arid1a/Pten double knockout model. Conclusion: ARID1A plays a role in the epigenetic regulation of hepatic lipid homeostasis, and its suppression contributes to fatty liver pathogenesis. Combined Arid1a and Pten deletion shows accelerated fatty liver disease progression and is a useful mouse model for studying therapeutic strategies for NASH.

Exportin-T promotes tumor proliferation and invasion in hepatocellular carcinoma.

Exportin-T (XPOT) belongs to the RAN-GTPase exportin family that mediates export of tRNA from the nucleus to the cytoplasm. Up-regulation of XPOT indicates poor prognosis in breast cancer patients. However, the correlation between XPOT and hepatocellular carcinoma (HCC) remains unclear. Here, we found that high expression of XPOT in HCC indicated worse prognosis via bioinformatics analysis. Consistently, immunohistochemical staining of 95 pairs of tumors and adjacent normal liver tissues (ANLT) also showed up-regulation of XPOT. Small interfering (si) RNA transfection was used to down-regulate XPOT in HepG2 and 7721 cell lines. Cell Counting Kit-8 (CCK8) assays were performed to analyze cell proliferation. Cell migration and invasion were measured by scratch wound healing assays and migration assays. Subcutaneous xenograft models were using to explore the role of XPOT in tumor formation in vivo. Down-regulation of XPOT significantly inhibited tumor proliferation and invasion in vitro and vivo. Gene set enrichment analysis (GSEA) results indicated that XPOT may affect tumor progression through cell cycle and ubiquitin-mediated proteolysis. Furthermore, knockdown of XPOT caused a block in G0/G1 phase as evidenced by down-regulation of cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), CyclinA1 (CCNA1), CyclinB1 (CCNB1), CyclinB2 (CCNB2), and CyclinE2 (CCNE2) in HCC cells. In conclusion, our findings indicate that XPOT could serve as a novel biomarker for prognoses and a potential therapeutic target for patients with HCC.

Uridine-cytidine kinase 2 upregulation predicts poor prognosis of hepatocellular carcinoma and is associated with cancer aggressiveness.

Patients with advanced hepatocellular carcinoma (HCC) continue to have a dismal prognosis. Potential biomarkers to determine prognosis and select targeted therapies are urgently needed for patients with HCC. This study aimed to elucidate the role of UCK2 in HCC prognosis and tumor progression. We performed a screen of public databases to identify functional genes associated with HCC tumorigenesis, progression, and outcome. We identified uridine-cytidine kinase 2 (UCK2) as a gene of interest for further study. UCK2 promoting HCC aggressiveness was demonstrated by evaluation of clinical samples, in vitro experiments, in vivo tumorigenicity, and transcript analysis. UCK2 expression was generally elevated in HCC and was significantly correlated with poor survival and inferior clinicopathological characteristics of HCC patients. A multivariate analysis revealed that high UCK2 expression was an independent factor for poor prognosis. In HCC cell lines, UCK2 knockdown suppressed cell migration and invasion and inhibited cell proliferation, while UCK2 overexpression had an opposite effect. Animal model experiments confirmed that knockdown of UCK2 suppressed tumor growth in vivo. The bioinformatics analysis demonstrated that UCK2 might associated with metabolsim, splicesome, and adherens junction. UCK2 is highly associated with HCC malignant behavior and is a potential prognostic predictor for HCC patients in the clinic.

Dissimilar responses of fungal and bacterial communities to soil transplantation simulating abrupt climate changes.

Both fungi and bacteria play essential roles in regulating soil carbon cycling. To predict future carbon stability, it is imperative to understand their responses to environmental changes, which is subject to large uncertainty. As current global warming is causing range shifts toward higher latitudes, we conducted three reciprocal soil transplantation experiments over large transects in 2005 to simulate abrupt climate changes. Six years after soil transplantation, fungal biomass of transplanted soils showed a general pattern of changes from donor sites to destination, which were more obvious in bare fallow soils than in maize cropped soils. Strikingly, fungal community compositions were clustered by sites, demonstrating that fungi of transplanted soils acclimatized to the destination environment. Several fungal taxa displayed sharp changes in relative abundance, including Podospora, Chaetomium, Mortierella and Phialemonium. In contrast, bacterial communities remained largely unchanged. Consistent with the important role of fungi in affecting soil carbon cycling, 8.1%-10.0% of fungal genes encoding carbon-decomposing enzymes were significantly (p < 0.01) increased as compared with those from bacteria (5.7%-8.4%). To explain these observations, we found that fungal occupancy across samples was mainly determined by annual average air temperature and rainfall, whereas bacterial occupancy was more closely related to soil conditions, which remained stable 6 years after soil transplantation. Together, these results demonstrate dissimilar response patterns and resource partitioning between fungi and bacteria, which may have considerable consequences for ecosystem-scale carbon cycling.

Efficacy and Safety of Steroid Therapy for Posttransplant Hyperbilirubinemia Caused by Early Allograft Dysfunction: A Randomized Controlled Trial.

BACKGROUND Hyperbilirubinemia is a common event that occurs after liver transplantation. Hyperbilirubinemia is usually caused by early allograft dysfunction. Glucocorticoid is widely used for immunosuppression, but few studies have analyzed the effects of steroid therapy on posttransplantation hyperbilirubinemia. The aim of this study was to assess whether glucocorticoid was beneficial in treating hyperbilirubinemia caused by early allograft dysfunction. MATERIAL AND METHODS Patients with postoperative hyperbilirubinemia (those with conditions such as biliary complications and rejections were excluded) were randomly assigned, in a 2: 1 ratio, to the steroid and control groups. Patients in the steroid group were treated with glucocorticoid combined with ursodeoxycholic acid, whereas patients in the control group were only treated with ursodeoxycholic acid. The primary endpoint was decrease in bilirubin and the secondary endpoint was safety. RESULTS From 1st June 2016 to 30th April 2018, 40 patients were enrolled into the steroid group, and 20 were enrolled into the control group. Donor, recipient, and operative data were similar between the 2 groups. The decrease in bilirubin levels in the steroid group was significantly greater than that in the control group on the first day after the intervention was finished (9.25±1.30 mg/dL vs. 3.11±1.45 mg/dL, p=0.005), and after 2 weeks (15.01±1.20 mg/dL vs. 8.88±1.98 mg/dL, p=0.007). The steroid group did not have a higher complication rate but it did have a shorter postoperative hospital stay than in the control group. CONCLUSIONS Low-dose steroid therapy was effective and safe for treating hyperbilirubinemia caused by early graft dysfunction, and it improved liver function.

The first case of ischemia-free organ transplantation in humans: A proof of concept.

Ischemia and reperfusion injury (IRI) is an inevitable event in conventional organ transplant procedure and is associated with significant mortality and morbidity post-transplantation. We hypothesize that IRI is avoidable if the blood supply for the organ is not stopped, thus resulting in optimal transplant outcomes. Here we described the first case of a novel procedure called ischemia-free organ transplantation (IFOT) for patients with end-stage liver disease. The liver graft with severe macrovesicular steatosis was donated from a 25-year-old man. The recipient was a 51-year-old man with decompensated liver cirrhosis and hepatocellular carcinoma. The graft was procured, preserved, and implanted under continuous normothermic machine perfusion. The recipient did not suffer post-reperfusion syndrome or vasoplegia after revascularization of the allograft. The liver function test and histological study revealed minimal hepatocyte, biliary epithelium and vascular endothelium injury during preservation and post-transplantation. The inflammatory cytokine levels were much lower in IFOT than those in conventional procedure. Key pathways involved in IRI were not activated after allograft revascularization. No rejection, or vascular or biliary complications occurred. The patient was discharged on day 18 post-transplantation. This marks the first case of IFOT in humans, offering opportunities to optimize transplant outcomes and maximize donor organ utilization.

Outcomes of Organ Transplantation from Donors with a Cancer History.

BACKGROUND The inherent challenges of selecting an acceptable donor for the increasing number and acuity of recipients has forced programs to take increased risks, including accepting donors with a cancer history (DWCH). Outcomes of organ transplantation using organs from DWCH must be clarified. We assessed transplant outcomes of recipients of organs from DWCH. MATERIAL AND METHODS Retrospective analysis of the Scientific Registry of Transplant Recipients data from January 1, 2000 to December 31, 2014 identified 8385 cases of transplants from DWCH. A Cox-proportional hazard regression model and log-rank test were used to compare patient survival and hazard levels of various cancer types. RESULTS DWCH was an independent risk factor of 5-year patient survival (HR=1.089, 95% CI: 1.009-1.176, P=0.03) and graft survival (HR=1.129, 95% CI: 1.056-1.208, P<0.01) in liver and heart transplantation (patient survival: HR=1.112, 95% CI: 1.057-1.170, P<0.01; graft survival: HR=1.244, 95% CI: 1.052-1.472, P=0.01). There was no remarkable difference between the 2 groups in kidney and lung transplantation. Donors with genitourinary and gastrointestinal cancers were associated with inferior outcomes in kidney transplantation. Transplantation from donors with central nervous system cancer resulted in poorer survival in liver transplant recipients. Recipients of organs from donors with hematologic malignancy and otorhinolaryngologic cancer had poorer survival following heart transplantation. CONCLUSIONS Under the current donor selection criteria, recipients of organs from DWCH had inferior outcomes in liver and heart transplantation, whereas organs from DWCH were safely applied in kidney and lung transplantation. Specific cancer types should be cautiously evaluated before performing certain types of organ transplantation.

Dendritic cells that highly express SOCS1 induce T-cell hypo-responsiveness and prolong islet allograft survival.

The capability of dendritic cells (DCs) to induce an immune response or immune tolerance is dependent on their status. Suppressor of cytokine signaling 1 (SOCS1) is a pivotal regulator that participates in negative feedback of the JAK-STAT pathway, which plays a key role in the differentiation, activation, and maturation of DCs. DCs that highly express SOCS1 may modulate DCs, and induce immune anergy or immune tolerance. In this study, we transduced DCs with the recombinant adenovirus Ad5F35 to highly express SOCS1. The mechanisms by which DC-SOCS1 induces T-cell hypo-responsiveness were analyzed in vivo and in vitro. The data demonstrate that recipients treated with DC-SOCS1 had long islet allograft survival times, with a reduction of Th1 and Tc1 in both spleen and draining lymph nodes in vivo. In vitro assay revealed that DCs transduced with SOCS1 had low expression of major histocompatibility and costimulatory molecules, and potentiated the ability of DC-SOCS1 to induce T-cell hypo-responsiveness. Therefore, genetic modification of DCs with SOCS1 affects DC activation and maturation, inhibits T-cell proliferation and induces hypo-responsiveness, and prolongs islet allograft survival.

MicroRNA-146b-5p Identified in Porcine Liver Donation Model is Associated with Early Allograft Dysfunction in Human Liver Transplantation.

BACKGROUND Poor transplant outcome was observed in donation after brain death followed by circulatory death (DBCD), since the donor organs suffered both cytokine storm of brain death and warm ischemia injury. MicroRNAs (miRNAs) have emerged as promising disease biomarkers, so we sought to establish a miRNA signature of porcine DBCD and verify the findings in human liver transplantation. MATERIAL AND METHODS MiRNA expression was determined with miRNA sequencing in 3 types of the porcine model of organ donation, including donation after brain death (DBD) group, donation after circulatory death (DCD) group, and DBCD group. Bioinformatics analysis was performed to reveal the potential regulatory behavior of target miRNA. Human liver graft biopsy samples after reperfusion detected by fluorescence in situ hybridization were used to verify the expression of target miRNA. RESULTS We compared miRNA expression profiles of the 3 donation types. The porcine liver graft miR-146b was significantly increased and selected in the DBCD group versus in the DBD and DCD groups. The donor liver expression of human miR-146b-5p, which is homologous to porcine miR-146b, was further examined in 42 cases of human liver transplantations. High expression of miR-146b-5p successfully predicted the post-transplant early allograft dysfunction (EAD) with the area under the ROC curve (AUC) 0.759 (P=0.004). CONCLUSIONS Our results revealed the miRNA signature of DBCD liver grafts for the first time. The miR-146b-5p may have important clinical implications for monitoring liver graft function and predicating transplant outcomes.

Prognostic value of preoperative peripheral monocyte count in patients with hepatocellular carcinoma after liver transplantation.

Prognostic value of peripheral monocyte, as a member of inflammatory cells, was widely being investigated. The aim of this study was to evaluate the prognostic value of preoperative peripheral blood monocyte count for hepatocellular carcinoma (HCC) patients who underwent liver transplantation (LT) and the relationship between monocyte count and tumor-related characteristics. We retrospectively analyzed the clinical data of 101 HCC patients after LT. Preoperative monocyte count and demographic, clinical, and pathologic data were analyzed. The optimal cutoff value of monocyte count was 456/mm(3), with the sensitivity and specificity of 69.4 and 61.5 %, respectively. Elevated preoperative peripheral blood monocyte count was significantly associated with large tumor size. The 1-, 3-, and 5-year disease-free survival (DFS) (80.9, 70.1, and 53.3 % vs 55.1, 38.7, and 38.7 %, P = 0.007) and overall survival (OS) rates (95.7, 76.6, and 64.8 % vs 72.2, 44.1, and 36.1 %, P = 0.002) of HCC patients in the peripheral blood monocyte count ≤456/mm(3) group were higher than those in the peripheral blood monocyte count >456/mm(3) group. In conclusion, elevated preoperative peripheral blood monocyte count was significantly associated with advanced tumor stage and it can be considered as a prognostic factor for HCC patients after LT.

Adjuvant chemotherapy for patients with primary hepatocellular carcinoma: a meta-analysis.

Numerous studies have investigated the effects of adjuvant chemotherapy for primary hepatocellular carcinoma (HCC) patients. We conducted this analysis to evaluate the efficacy of adjuvant chemotherapy in HCC patients after hepatectomy. PubMed/MEDLINE, EMBASE, Cochrane, and other databases were searched for eligible studies. The major endpoints were overall survival (OS) and disease-free survival (DFS). The pooled odds ratio (OR) was calculated using a random-effects model to summarize the results. In the meta-analysis of 13 randomized control trials (RCTs) and 35 observational studies with 4747 patients, hepatectomy plus adjuvant chemotherapy showed superiority over hepatectomy alone in 1-year DFS (OR = 1.86, 1.38-2.51, p < 0.001), 3-year DFS (OR = 2.37, 1.73-3.24, p < 0.001) and 5-year DFS (OR = 1.99, 1.55-2.55, p < 0.001), as well as 1-year OS (OR = 2.16, 95% confidence interval 1.75-2.68, p < 0.001), 3-year OS (OR = 1.77, 1.48-2.13, p < 0.001) and 5-year OS (OR = 1.92, 1.44-2.56, p < 0.001). Subgroup and sensitivity analysis revealed that only adjuvant TACE had significant survival benefits. The meta-analysis of studies involving patients with portal vein tumor thrombus (PVTT), but not other factors related to recurrence risk, revealed favorable outcomes of the Treatment arm over the Control arm. The present study shows that adjuvant chemotherapy can improve outcomes for HCC patients. The benefits of adjuvant TACE have been confirmed whereas the effects of other adjuvant chemotherapy modalities remain uncertain. Adjuvant chemotherapy is likely to be more applicable to certain patient populations for instance those with PVTT, but further research in identifying these patient factors is of importance for tailoring adjuvant therapies to individual patients in the future.

Indole Alkaloids from Chaetomium globosum.

Two new indole alkaloids chaetocochin J (1) and chaetoglobinol A (8), along with chetomin (2), chetoseminudin A (3), cochliodinol (9), and semicochliodinol (10), were isolated from the rice culture of the fungus Chaetomium globosum. Their structures were elucidated by spectral analysis. Three new epipolythiodioxopiperazines, chaetocochins G-I (5-7), were identified by the combination of UPLC and mass spectrometric analysis. Chaetocochin I contained two sulfur bridges, one formed by three sulfur atoms between C-3 and C-11a, and the other formed by four sulfur atoms between C-3' and C-6'. Chaetocochin I was readily transformed into chetomin (2), chetoseminudin A (3), chaetocochin D (4), chaetocochin G (5), and chaetocochin H (6) by losing sulfur atoms. Compounds 1-3, and 8 exhibited antibacterial activities against Bacillus subtilis with MICs of 25, 0.78, 0.78, and 50 µg/mL, respectively, but not against Gram-negative bacterium (Escherichia coli). Compounds 2 and 8 were inactive against Candida albicans, Fusarium graminearum, Fusarium vasinfectum, Saccharomyces cerevisiae, and Aspergillus niger even at the high concentrations of 200 and 100 µg/mL, respectively. Compound 8 showed free radical scavenging capacity against the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical (ABTS(+•)), with IC50 values of 143.6 and 45.2 µM, respectively. The free radical scavenging capacity rates of compounds 1-3 on the DPPH and ABTS(+•) were less than 20% at the test concentrations (89.9-108.3 µM). The superoxide anion radical scavenging assay indicated that compounds 1-3, and 8 showed 14.8% (90.9 µM), 18.1% (90.9 µM), 51.5% (88.3 µM), and 30.4% (61.3 µM) superoxide anion radical scavenging capacity, respectively.

Liver transplantation using organs from deceased organ donors: a single organ transplant center experience.

BACKGROUND: In 2011, a pilot program for deceased organ donation was initiated in China. We describe the first successful series of liver transplants in the pilot program. METHODS: From July 2011 to August 2012, our center performed 26 liver transplants from a pool of 29 deceased donors. All organ donation and allograft procurement were conducted according to the national protocol. The clinical data of donors and recipients were collected and summarized retrospectively. RESULTS: Among the 29 donors, 24 were China Category II donors (organ donation after cardiac death), and five were China Category III donors (organ donation after brain death followed by cardiac death). The recipients were mainly the patients with hepatocellular carcinoma. The one-year patient survival rate was 80.8% with a median follow-up of 422 (2-696) days. Among the five mortalities during the follow-up, three died of tumor recurrence. In terms of post-transplant complications, 9 recipients (34.6%) experienced early allograft dysfunction, 1 (3.8%) had non-anastomotic biliary stricture, and 1 (3.8%) was complicated with hepatic arterial thrombosis. None of these complications resulted in patient death. Notably, primary non-function was not observed in any of the grafts. CONCLUSION: With careful donor selection, liver transplant from deceased donors can be performed safely and plays a critical role in overcoming the extreme organ shortage in China.

Quorum sensing bacteria improve microbial networks stability and complexity in wastewater treatment plants.

Quorum-sensing bacteria (QSB) are crucial factors for microbial communication, yet their ecological role in wastewater treatment plants (WWTPs) remains unclear. Here, we developed a method to identify QSB by comparing 16S rRNA gene sequences. QSB in 388 activated sludge samples collected from 130 WWTPs across China primarily were identified as rare taxa and conditionally rare taxa. A co-occurrence network shared by all sludge communities revealed that QSB exhibited higher average clustering coefficient (0.46) than non-QSB (0.15). Individual sludge networks demonstrated that quorum sensing microbiomes were positively correlated with network robustness and network complexity, including average clustering coefficient and link density. We confirmed that QSB keystones and QSB nodes have a positive impact on network complexity by influencing network modularity through a structural equation model. Meanwhile, QSB communities directly contributed to maintaining network robustness (r = 0.29, P < 0.05). Hence, QSB play an important role in promoting network complexity and stability. Furthermore, QSB communities were positively associated with the functional composition of activated sludge communities (r = 0.33, P < 0.01), especially the denitrification capacity (r = 0.45, P < 0.001). Overall, we elucidated the ecological significance of QSB and provided support for QS-based regulation of activated sludge microbial communities.

B7-H3 enhances colorectal cancer progression by regulating HB-EGF via HIF-1α.

Background: B7-H3 (or CD276) represents an important costimulatory molecule expressed in many malignant solid tumors, including colorectal cancer (CRC). The receptor of B7-H3 is not known, and the intracellular function of B7-H3 remains obscure. Herein, we report that B7-H3 upregulated the epidermal growth factor heparin-binding epidermal growth factor (HB-EGF), likely by regulating hypoxia-inducible factor 1α (HIF-1α) and thereby promoting the progression of CRC. Methods: Lentiviral transfection was performed on CRC cells to establish stable low-B7-H3 expression cells. A mechanistic analysis with an Agilent human gene expression profiling chip was conducted on them. Clinical data and specimens were collected to detect the connection between B7-H3 and HB-EGF in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the messenger RNA (mRNA) level of B7-H3, HB-EGF, and HIF-1α. Chromatin immunoprecipitation (ChIP) quantitative real-time PCR was conducted. The protein level of HIF-1α and the phosphatidylinositide 3-kinases (PI3K)-protein kinase B (AKT) pathway were detected by western blot. HIF-1α was recovered by lentiviral transfection, and the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis ability were detected. Results: B7-H3 promoted tumor progression through HB-EGF and the PI3K-AKT pathway. As B7-H3 was downregulated, HB-EGF levels were significantly reduced simultaneously, a growth trend that was shown by both CRC cell lines and cancer tissues. In addition, B7-H3 and HB-EGF had significant associations with tumor-node-metastasis (TNM) stage and lymph node metastasis in 50 CRC patients. The binding ability of HIF-1α to the HB-EGF promoter region was significantly decreased in the shB7-H3 RKO group. Western blot revealed that PI3K, AKT, and mammalian target of rapamycin (mTOR) protein amounts and p-AKT and p-mTOR phosphorylation were also downregulated in shB7-H3 RKO cells, suggesting that B7-H3 may regulate HIF-1α via PI3K-AKT signaling. After recovery of the HIF-1α level by lentiviral transfection, the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis in CRC cells recovered as well. Conclusions: B7-H3 may transmit intracellular signals through PI3K-AKT-mTOR-HIF-1α signaling, upregulating HB-EGF. As the final transcription factor of the pathway, HIF-1α regulates the transcription of the HB-EGF gene, thereby promoting HB-EGF expression, which eventually mediates cell proliferation, invasion, and angiogenesis and promotes the progression of CRC.

Metagenomic insights into microbial community structure and metabolism in alpine permafrost on the Tibetan Plateau.

Permafrost, characterized by its frozen soil, serves as a unique habitat for diverse microorganisms. Understanding these microbial communities is crucial for predicting the response of permafrost ecosystems to climate change. However, large-scale evidence regarding stratigraphic variations in microbial profiles remains limited. Here, we analyze microbial community structure and functional potential based on 16S rRNA gene amplicon sequencing and metagenomic data obtained from an ∼1000 km permafrost transect on the Tibetan Plateau. We find that microbial alpha diversity declines but beta diversity increases down the soil profile. Microbial assemblages are primarily governed by dispersal limitation and drift, with the importance of drift decreasing but that of dispersal limitation increasing with soil depth. Moreover, genes related to reduction reactions (e.g., ferric iron reduction, dissimilatory nitrate reduction, and denitrification) are enriched in the subsurface and permafrost layers. In addition, microbial groups involved in alternative electron accepting processes are more diverse and contribute highly to community-level metabolic profiles in the subsurface and permafrost layers, likely reflecting the lower redox potential and more complicated trophic strategies for microorganisms in deeper soils. Overall, these findings provide comprehensive insights into large-scale stratigraphic profiles of microbial community structure and functional potentials in permafrost regions.