Comparison of clinical efficacy of different colon anastomosis methods in laparoscopic radical resection of colorectal cancer.

OBJECTIVE: The objective of this study was to investigate the clinical effect of overlap anastomosis and functional end-to-end anastomosis (FEEA) in laparoscopic radical resection of colorectal cancer (CRC). METHODS: The clinical data of 180 patients who underwent laparoscopic radical resection of CRC and side-to-side anastomosis were retrospectively collected; the patients were divided into the Overlap group and FEEA group, according to the anastomosis method that was used to treat them. RESULTS: The Overlap group had a shorter operation time, anastomosis time, post-operative hospital stay, post-operative feeding time, and post-operative exhaust time than the FEEA group (p < 0.05). The total incidence of post-operative complications was 14.4% (13/90) in the FEEA group and 0.7% (6/90) in the Overlap group, and there was no significant difference between the two groups (p > 0.05). CONCLUSIONS: Overlapping anastomosis can shorten the operation time and accelerate the recovery of intestinal function without increasing the incidence of post-operative complications, and it will not affect the quality of life and survival of patients in the short term after surgery.

OBJETIVO: Investigar el efecto clínico de la anastomosis superpuesta y de la anastomosis funcional de extremo a extremo (AFEE) en la resección radical laparoscópica del cáncer colorrectal (CCR). MÉTODO: Se recolectaron retrospectivamente los datos clínicos de 180 pacientes sometidos a resección radical laparoscópica de CCR y anastomosis de lado a lado. Los pacientes se dividieron en grupo de anastomosis superpuesta y grupo AFEE, según el método de anastomosis que se utilizó para tratarlos. RESULTADOS: El grupo de anastomosis superpuesta tuvo un tiempo de operación, un tiempo de anastomosis, una estancia hospitalaria posoperatoria, un tiempo de alimentación posoperatorio y un tiempo de escape posoperatorio más cortos que el grupo AFEE (p < 0.05). La incidencia total de complicaciones posoperatorias fue del 14.4% (13/90) en el grupo AFEE y del 0.7% (6/90) en el grupo de anastomosis superpuesta, y no hubo diferencias significativas entre los dos grupos (p > 0.05). CONCLUSIONES: La anastomosis superpuesta puede acortar el tiempo operatorio y acelerar la recuperación de la función intestinal sin aumentar la incidencia de complicaciones posoperatorias, y sin afectar la calidad de vida y la supervivencia de los pacientes a corto plazo después de la cirugía.

Microbial Sulfur and Arsenic Oxidation Facilitate the Establishment of Biocrusts during Reclamation of Degraded Mine Tailings.

Degraded tailings generated by the mining of metal ores are major environmental threats to the surrounding ecosystems. Tailing reclamation, however, is often impeded due to adverse environmental conditions, with depleted key nutrients (i.e., nitrogen (N) and phosphorus (P)) and elevated sulfur and metal(loid) concentrations. Formation of biocrusts may significantly accelerate nutrient accumulation and is therefore an essential stage for tailing reclamation. Although suggested to play an important role, the microbial community composition and key metabolisms in biocrusts remain largely unknown and are therefore investigated in the current study. The results suggested that sulfur and arsenic oxidation are potential energy sources utilized by members of predominant biocrust bacterial families, including Beijerinckiaceae, Burkholderiaceae, Hyphomicrobiaceae, and Rhizobiaceae. Accordingly, the S and As oxidation potentials are elevated in biocrusts compared to those in their adjacent tailings. Biocrust growth, as proxied by chlorophyll concentrations, is enhanced in treatments supplemented with S and As. The elevated biocrust growth might benefit from nutrient acquisition services (i.e., nitrogen fixation and phosphorus solubilization) fueled by microbial sulfur and arsenic oxidation. The current study suggests that sulfur- and arsenic-oxidizing microorganisms may play important ecological roles in promoting biocrust formation and facilitating tailing reclamation.

Microbially mediated sulfur oxidation coupled with arsenate reduction within oligotrophic mining-impacted habitats.

Arsenate reduction is a major cause of As release from soils which threatens more than 200 million people worldwide. While heterotrophic As(V) reduction has been investigated extensively, the mechanism of chemolithotrophic As(V) reduction is less studied. Since As is frequently found as sulfidic minerals in the environment, microbial mediated sulfur oxidation coupled to As(V) reduction (SOAsR), a chemolithotrophic process, may be more favorable in oligotrophic mining-impacted sites (e.g., As-contaminated mine tailings). While SOAsR is thermodynamically favorable, knowledge regarding this biogeochemical process is still limited. The current study suggested that SOAsR was a more prevalent process compared to heterotrophic As(V) reduction in oligotrophic sites, such as mine tailings. The water-soluble reduced sulfur concentration was predicted as one of the major geochemical parameters that substantially impacted SOAsR potentials. A combination of DNA-SIP and metagenome binning revealed members of the genera Sulfuricella, Ramlibacter, and Sulfuritalea as sulfur oxidizing As(V)-reducing bacteria (SOAsRB) in mine tailings. Genome mining further expanded the list of potential SOAsRBs to diverse phylogenetic lineages such as members associated with Burkholderiaceae and Rhodocyclaceae. Metagenome analysis using multiple tailing samples across southern China confirmed that the putative SOAsRB were the dominant As(V) reducers in these sites. Together, the current findings expand our knowledge regarding the chemolithotrophic As(V) reduction process, which may be harnessed to facilitate future remediation practices in mine tailings.

Yersinia infection induces glucose depletion and AMPK-dependent inhibition of pyroptosis in mice.

Nutritional status and pyroptosis are important for host defence against infections. However, the molecular link that integrates nutrient sensing into pyroptosis during microbial infection is unclear. Here, using metabolic profiling, we found that Yersinia pseudotuberculosis infection results in a significant decrease in intracellular glucose levels in macrophages. This leads to activation of the glucose and energy sensor AMPK, which phosphorylates the essential kinase RIPK1 at S321 during caspase-8-mediated pyroptosis. This phosphorylation inhibits RIPK1 activation and thereby restrains pyroptosis. Boosting the AMPK-RIPK1 cascade by glucose deprivation, AMPK agonists, or RIPK1-S321E knockin suppresses pyroptosis, leading to increased susceptibility to Y. pseudotuberculosis infection in mice. Ablation of AMPK in macrophages or glucose supplementation in mice is protective against infection. Thus, we reveal a molecular link between glucose sensing and pyroptosis, and unveil a mechanism by which Y. pseudotuberculosis reduces glucose levels to impact host AMPK activation and limit host pyroptosis to facilitate infection.

Differential Mechanisms of Microbial As(III) and Sb(III) Oxidation and Their Contribution to Tailings Reclamation.

Mine tailings are extremely oligotrophic environments frequently contaminated with elevated As and Sb, making As(III) and Sb(III) oxidation potentially important energy sources for the tailing microbiome. Although they have been proposed to share similar metabolic pathways, a systemic comparison of the As(III) and Sb(III) oxidation mechanisms and energy utilization efficiencies requires further elucidation. In this study, we employed a combination of physicochemical, molecular, and bioinformatic analyses to compare the kinetic and genetic mechanisms of As(III) and Sb(III) oxidation as well as their respective energy efficiencies for fueling the key nutrient acquisition metabolisms. Thiobacillus and Rhizobium spp. were identified as functional populations for both As(III) and Sb(III) oxidation in mine tailings by DNA-stable isotope probing. However, these microorganisms mediated As(III) and Sb(III) oxidation via different metabolic pathways, resulting in preferential oxidation of Sb(III) over As(III). Notably, both As(III) and Sb(III) oxidation can facilitate nitrogen fixation and phosphate solubilization in mine tailings, with Sb(III) oxidation being more efficient in powering these processes. Thus, this study provided novel insights into the microbial As(III) and Sb(III) oxidation mechanisms and their respective nutrient acquisition efficiencies, which may be critical for the reclamation of mine tailings.

Controlling factors of heavy metal(loid) accumulation in rice: Main and interactive effects.

Identifying the key determinants of heavy metal(loid) accumulation in rice and quantifying their contributions are critical for precise prediction of heavy metal(loid) concentrations in rice and the formulation of effective pollution control strategies. The accumulation of heavy metal(loid)s in rice can be influenced by both natural and anthropogenic factors, which may interact with each other. However, distinguishing the independent roles (main effects) from interactive effects and quantifying their impacts separately pose challenges. To address this knowledge gap, we employed TreeExplainer-based SHAP and random forest algorithms in this study to quantitatively estimate the primary influencing factors and their main and interactive effects on heavy metal(loid)s in rice. Our findings reveal that soil cadmium (SCd) and rice cultivation time (C_TIME) were the primary contributors to rice cadmium (RCd) and rice arsenic (RAs), respectively. Soil lead (SPb) and sampling distances from roads significantly contributed to rice lead (RPb). Additionally, we identified significant interactive effects of SCd and C_TIME, C_TIME and RCd, and RCd and rice variety on RCd, RAs, and RPb, respectively, emphasizing their significance. These insights are pivotal in improving the accuracy of heavy metal(loid) concentration predictions in rice and offering theoretical guidance for the formulation of pollution control measures.

Bacteria associated with Comamonadaceae are key arsenite oxidizer associated with Pteris vittata root.

Pteris vittata (P. vittata), an arsenic (As) hyperaccumulator commonly used in the phytoremediation of As-contaminated soils, contains root-associated bacteria (RAB) including those that colonize the root rhizosphere and endosphere, which can adapt to As contamination and improve plant health. As(III)-oxidizing RAB can convert the more toxic arsenite (As(III)) to less toxic arsenate (As(V)) under As-rich conditions, which may promote plant survial. Previous studies have shown that microbial As(III) oxidation occurs in the rhizospheres and endospheres of P. vittata. However, knowledge of RAB of P. vittata responsible for As(III) oxidation remained limited. In this study, members of the Comamonadaceae family were identified as putative As(III) oxidizers, and the core microbiome associated with P. vittata roots using DNA-stable isotope probing (SIP), amplicon sequencing and metagenomic analysis. Metagenomic binning revealed that metagenome assembled genomes (MAGs) associated with Comamonadaceae contained several functional genes related to carbon fixation, arsenic resistance, plant growth promotion and bacterial colonization. As(III) oxidation and plant growth promotion may be key features of RAB in promoting P. vittata growth. These results extend the current knowledge of the diversity of As(III)-oxidizing RAB and provide new insights into improving the efficiency of arsenic phytoremediation.

Enhancing the relative abundance of comammox nitrospira in ammonia oxidizer community decreases N2O emission in nitrification exponentially.

Comammox Nitrospira and canonical ammonia-oxidizing bacteria (cAOB) generally coexist in activated sludge. In present study, the effect of comammox Nitrospira on N2O production during nitrification of activated sludge was investigated. Comammox Nitrospira and cAOB were separately enriched in two nitrifying reactors, with respective relative abundance of approximately 98% in ammonia oxidizer community. The N2O emission factor (EF) of nitrification in comammox Nitrospira dominated reactor was 0.35%, consistently lower than that (2.2%) in cAOB dominated reactor. When increasing the relative abundance of comammox Nitrospira in ammonia oxidizer community, the N2O EF of nitrification decreased exponentially, which suggested that comammox Nitrospira not only decreased N2O production directly but also might have reduced N2O yield by cAOB. When cAOB dominated the ammonia oxidizer community of sludge, decreasing pH to 6.3, lowering DO to less than 0.5 mg/L, and increasing nitrite concentration enhanced N2O EF dramatically. When comammox Nitrospira became the dominant ammonia oxidizer, however, the N2O EF correlated to nitrite insignificantly and a low DO of 0.2 mg/L and weakly acidic pH (6.3) decreased N2O EF by approximately 70% and 60%, respectively. These results imply that enhancing the relative abundance of comammox Nitrospira in sludge is an effective way to reducing N2O emissions and can also offset the promoting effects of acidic pH, low DO, and high nitrite concentration on N2O production during nitrification.

Maximum chirality of THz metasurfaces with quasi-bound states in the continuum.

Metasurfaces hold great promise for terahertz (THz) chiral-optical devices. Here, we proposed a chiral THz metasurface with quasi-bound state in the continuum (BIC) for maximum chirality. By exploiting structural perturbations of the dipole displacement and the diverging angle for the THz metasurface, the symmetry-protected BIC transforms into quasi-BIC. The critical coupling condition is satisfied by the introduction of graphene, enabling the theoretical maximum absorption of the quasi-BIC. Subsequently, the perturbations are balanced to obtain maximum chirality. The numerical simulations show that the THz metasurface exhibits strong linear chirality with the circular dichroism (CD) of 0.99 at the quasi-BIC. Additionally, the chiral third harmonic generation (THG) is achieved, characterized by high efficiency up to 19% and strong THG-CD as high as 0.99. It is expected that the THz metasurfaces has great potential for applications in chiral sensing and imaging.

Phototrophic Nitrogen Fixation, a Neglected Biogeochemical Process in Mine Tailings?

Biological nitrogen fixation (BNF) has important ecological significance in mine tailing by contributing to the initial accumulation of nitrogen. In addition to chemolithotrophic and heterotrophic BNF, light may also fuel BNF in oligotrophic mine tailings. However, knowledge regarding the occurrence and ecological significance of this biogeochemical process in mine tailings remains ambiguous. The current study observed phototrophic BNF in enrichment cultures established from three primary successional stages (i.e., original tailings, biological crusts, and pioneer plants) of tailings. Notably, phototrophic BNF in tailings may be more active at vegetation stages (i.e., biological crusts and pioneering plants) than in bare tailings. DNA-stable isotope probing identified Roseomonas species as potential aerobic anoxygenic phototrophs responsible for phototrophic BNF. Furthermore, metagenomic binning as well as genome mining revealed that Roseomonas spp. contained essential genes involved in nitrogen fixation, anoxygenic photosynthesis, and carbon fixation, suggesting their genetic potential to mediate phototrophic BNF. A causal inference framework equipped with the structural causal model suggested that the enrichment of putative phototrophic diazotrophic Roseomonas may contribute to an elevated total nitrogen content during primary succession in these mine tailings. Collectively, our findings suggest that phototrophic diazotrophs may play important roles in nutrient accumulation and hold the potential to facilitate ecological succession in tailings.

Bisphenol A affects microbial interactions and metabolic responses in sludge anaerobic digestion.

The widespread use of bisphenol A (BPA) has resulted in the emergence of new pollutants in various environments, particularly concentrated in sewage sludge. This study investigated the effects of BPA on sludge anaerobic digestion, focusing specifically on the interaction of microbial communities and their metabolic responses. While the influence of BPA on methane accumulation is not significant, BPA still enhanced the conversion of soluble COD, protein, and polysaccharides. BPA also positively influenced the hydrolysis-acidogenesis process, leading to 17% higher concentrations of volatile fatty acids (VFAs). Lower BPA levels (0.2-0.5 mg/kg dw) led to decreased hydrolysis and acidogenesis gene abundance, indicating metabolic inhibition; conversely, higher concentrations (1-5 mg/kg dw) increased gene abundance, signifying metabolic enhancement. Diverse methane metabolism was observed and exhibited alterations under BPA exposure. The presence of BPA impacted both the diversity and composition of microbial populations. Bacteroidetes, Proteobacteria, Firmicutes, and Chloroflexi dominated in BPA-treated groups and varied in abundance among different treatments. Changes of specific genera Sedimentibacter, Fervikobacterium, Blvii28, and Coprothermobacter in response to BPA, affecting hydrolysis and acetogenesis. Archaeal diversity declined while the hydrogenotrophic methanogen Methanospirillum thrived under BPA exposure. BPA exposure enabled microorganisms to form structured community interaction networks and boost their metabolic activities during anaerobic digestion. The study also observed the enrichment of BPA biodegradation pathways at high BPA concentrations, which could interact and overlap to ensure efficient BPA degradation. The study provides insights into the digestion performance and interactions of microbial communities to BPA stress and sheds light on the potential effect of BPA during anaerobic digestion.

Metagenomic insights into the toxicity of carbamazepine to functional microorganisms in sludge anaerobic digestion.

Contaminants of emerging concern (CECs) contained in sludge, such as carbamazepine, may be toxic to microorganisms and affect the biogenesis of methane during anaerobic digestion. In this study, different scales of anaerobic digesters were constructed to investigate the inhibitory effect of carbamazepine. Results showed that carbamazepine reduced methane production by 11.3 % and 62.1 % at concentrations of 0.4 and 2 mg/g TS, respectively. Carbamazepine hindered the dissolution of organic matter and the degradation of protein. Carbamazepine inhibited some fermentative bacteria, especially uncultured Aminicenantales, whose abundance decreased by 9.5-93.4 % under carbamazepine stress. It is worth noting that most prior studies investigated the effects of CECs only based on well-known microorganisms, ignoring the metabolisms of uncultured microorganisms. Genome-predicted metabolic potential suggested that 54 uncultured metagenome-assembled genomes (MAGs) associated with acidogenesis or acetogenesis. Therein, uncultured Aminicenantales related MAGs were proved to be acetogenic fermenters, their significant reduction may be an important reason for the decrease of methane production under carbamazepine stress. The toxicity of carbamazepine to microorganisms was mainly related to the overproduction of reactive oxygen species. This study elucidates the inhibition mechanism of carbamazepine and emphasizes the indispensable role of uncultured microorganisms in anaerobic digestion.

Microbial-mediated oxidative dissolution of orpiment and realgar in circumneutral aquatic environments.

Arsenic (As) is a toxic metalloid that causes severe environmental contamination worldwide. Upon exposure to aqueous phases, the As-bearing minerals, such as orpiment (As2S3) and realgar (As4S4), undergo oxidative dissolution, in which biotic and abiotic activities both contributed significant roles. Consequently, the dissolved As and S are rapidly discharged through water transportation to broader regions and contaminate surrounding areas, especially in aquatic environments. Despite both orpiment and realgar are frequently encountered in carbonate-hosted neutral environments, the microbial-mediated oxidative dissolution of these minerals, however, have been primarily investigated under acidic conditions. Therefore, the current study aimed to elucidate microbial-mediated oxidative dissolution under neutral aquatic conditions. The current study demonstrated that the dissolution of orpiment and realgar is synergistically regulated by abiotic (i.e., specific surface area (SSA) of the mineral) and biotic (i.e., microbial oxidation) factors. The initial dissolution of As(III) and S2- from minerals is abiotically impacted by SSA, while the microbial oxidation of As(III) and S2- accelerated the overall dissolution rates of orpiment and realgar. In As-contaminated environments, members of Thiobacillus and Rhizobium were identified as the major populations that mediated oxidative dissolution of orpiment and realgar by DNA-stable isotope probing. This study provides novel insights regarding the microbial-mediated oxidative dissolution process of orpiment and realgar under neutral conditions.

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.

Mechanisms of low cadmium accumulation in crops: A comprehensive overview from rhizosphere soil to edible parts.

Cadmium (Cd) is a toxic heavy metal often found in soil and agricultural products. Due to its high mobility, Cd poses a significant health risk when absorbed by crops, a crucial component of the human diet. This absorption primarily occurs through roots and leaves, leading to Cd accumulation in edible parts of the plant. Our research aimed to understand the mechanisms behind the reduced Cd accumulation in certain crop cultivars through an extensive review of the literature. Crops employ various strategies to limit Cd influx from the soil, including rhizosphere microbial fixation and altering root cell metabolism. Additional mechanisms include membrane efflux, specific transport, chelation, and detoxification, facilitated by metalloproteins such as the natural resistance-associated macrophage protein (Nramp) family, heavy metal P-type ATPases (HMA), zinc-iron permease (ZIP), and ATP-binding cassette (ABC) transporters. This paper synthesizes differences in Cd accumulation among plant varieties, presents methods for identifying cultivars with low Cd accumulation, and explores the unique molecular biology of Cd accumulation. Overall, this review provides a comprehensive resource for managing agricultural lands with lower contamination levels and supports the development of crops engineered to accumulate minimal amounts of Cd.

Selective pressure of arsenic and antimony co-contamination on microbial community in alkaline sediments.

Although response of microbial community to arsenic (As) and antimony (Sb) co-contamination has been investigated in neutral and acidic environments, little is known in alkaline environment. Herein, the microbial response and survival strategies under the stress of As and Sb co-contamination were determined in the alkaline sediments. Elevated concentrations of As (13700 ± 5012 mg/kg) and Sb (10222 ± 1619 mg/kg) were introduced into the alkaline sediments by the mine drainage, which was partially adopted in the aquatic environment and resulted in a relatively lower contamination (As, 6633 ± 1707 mg/kg; Sb, 6108 ± 1095 mg/kg) in the downstream sediments. The microbial richness was significantly damaged and the microbial compositions were dramatically shifted by the As and Sb co-contamination. Metagenomic analysis shed light on the survival strategies of the microbes under the pressure of As and Sb co-contamination including metal oxidation coupled with denitrification, metal reduction, and metal resistance. The representative microbes were revealed in the sediments with higher (Halomonas) and lower (Thiobacillus, Hydrogenophaga and Flavihumibacter) As and Sb concentration, respectively. In addition, antibiotic resistance genes were found to co-occur with metal resistance genes in the assembled bins. These findings might provide theoretical guidance for bioremediation of As and Sb co-contamination in alkaline environment.

Lab-on-fiber: laser-induced micro-cavity for a relative humidity measurement.

The lab-on-fiber design philosophy is the foundation for creating high-performance integrated fiber sensors. Hence, this Letter proposes an ultra-compact Fabry-Perot interferometer (FPI) based on a laser-induced micro-cavity (LIMC-FPI) on a fiber end for measuring relative humidity. To our knowledge, this novel approach, named the fiber-end photopolymerization (FEP) technique, is applied to create a micro-cavity. Specifically, a pair of humidity-sensitive polymer pillars and a resin end cap obtained by FEP are integrated to generate the cavity. As the ambient humidity changes, the pillars lengthen or shorten, resulting in the spectral evolution of the LIMC-FPI. A typical humidity sensitivity of 0.18 nm/%RH is obtained experimentally. For monitoring the human breathing process, the LIMC-FPI is responsive in the breathing frequency range of 0.2 to 0.5 Hz, allowing a response and recovery time of less than 0.388 s and 1.171 s, respectively. This work introduces a fresh and cost-effective approach for developing lab-on-fiber concept-based sensors.

Highly-sensitive temperature sensor based on photopolymerized-waveguide embedded Mach-Zehnder interferometer.

Biology, medicine, and chemistry all rely heavily on highly sensitive optical fiber temperature sensors. To the best of our knowledge, this research introduces a unique design framework for high-performance fiber temperature sensors that helps eliminate the all-fiber interferometers' sensitivity bottleneck. A section of photopolymerized waveguide is embedded in a typical Mach-Zehnder interferomenter framework with multimode fiber-single mode fiber-multimode fiber (MSM) structure. The thermal-optical coefficient (TOC) of the photopolymerized waveguide core, which is created via the fiber-end lithography technique, differs dramatically from that of the resin cladding. Due to the considerable TOC difference, the phase difference between the interfering beams significantly increases as the temperature changes. The fundamental variables affecting temperature sensitivity are conceptually explored and experimentally verified. The suggested device achieves a typical temperature sensitivity of 1.15 nm/ ∘C in the range of 30-100 ∘C, which is about 10 times as high as that of the all-fiber MSM sensors. The suggested designing framework offers a fresh thought for creating high-performing fiber optic temperature sensors.

Small molecule activators of TAK1 promotes its activity-dependent ubiquitination and TRAIL-mediated tumor cell death.

TAK1 is a key modulator of both NF-κB signaling and RIPK1. In TNF signaling pathway, activation of TAK1 directly mediates the phosphorylation of IKK complex and RIPK1. In a search for small molecule activators of RIPK1-mediated necroptosis, we found R406/R788, two small molecule analogs that could promote sustained activation of TAK1. Treatment with R406 sensitized cells to TNF-mediated necroptosis and RIPK1-dependent apoptosis by promoting sustained RIPK1 activation. Using click chemistry and multiple biochemical binding assays, we showed that treatment with R406 promotes the activation of TAK1 by directly binding to TAK1, independent of its original target Syk kinase. Treatment with R406 promoted the ubiquitination of TAK1 and the interaction of activated TAK1 with ubiquitinated RIPK1. Finally, we showed that R406/R788 could promote the cancer-killing activities of TRAIL in vitro and in mouse models. Our studies demonstrate the possibility of developing small molecule TAK1 activators to potentiate the effect of TRAIL as anticancer therapies.