Direct design of ground-state probabilistic logic using many-body interactions for probabilistic computing.

In this work, an innovative design model aimed at enhancing the efficacy of ground-state probabilistic logic with a binary energy landscape (GSPL-BEL) is presented. This model enables the direct conversion of conventional CMOS-based logic circuits into corresponding probabilistic graphical representations based on a given truth table. Compared to the conventional approach of solving the configuration of Ising model-basic probabilistic gates through linear programming, our model directly provides configuration parameters with embedded many-body interactions. For larger-scale probabilistic logic circuits, the GSPL-BEL model can fully utilize the dimensions of many-body interactions, achieving minimal node overhead while ensuring the simplest binary energy landscape and circumventing additional logic synthesis steps. To validate its effectiveness, hardware implementations of probabilistic logic gates were conducted. Probabilistic bits were introduced as Ising cells, and cascaded conventional XNOR gates along with passive resistor networks were precisely designed to realize many-body interactions. HSPICE circuit simulation results demonstrate that the probabilistic logic circuits designed based on this model can successfully operate in free, forward, and reverse modes, exhibiting the simplest binary probability distributions. For a 2-bit × 2-bit integer factorizer involving many-body interactions, compared to the logic synthesis approach, the GSPL-BEL model significantly reduces the number of consumed nodes, the solution space (in the free-run mode), and the number of energy levels from 12, 4096, and 9-8, 256, and 2, respectively. Our findings demonstrate the significant potential of the GSPL-BEL model in optimizing the structure and performance of probabilistic logic circuits, offering a new robust tool for the design and implementation of future probabilistic computing systems.

Acquired immune thrombotic thrombocytopenic purpura (TTP) associated with inactivated COVID-19 vaccine CoronaVac.

Corona virus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the whole world. Acquired thrombotic thrombocytopenic purpura (TTP) has been reported after administration of mRNA- or adenoviral vector-based COVID-19 vaccines, including Ad26.COV2-S, BNT162b2, mRNA-1273, and ChAdOx1 nCov-19. However, whether inactivated vaccines, such as CoronaVac, could cause TTP and whether the symptoms in TTPs caused by inactivated vaccines are different from previously reported cases are unknown. In this study, two cases were reported. Both cases developed TTP after the second CoronaVac vaccination shot, but not the first. They demonstrated symptoms of fever, neurological abnormalities, renal dysfunction, thrombocytopenia, and hemolysis. Both patients achieved complete remission through several sessions of plasma exchanges and immune suppression. The incidence of TTP in Nanjing area was analyzed. The number of patients with TTP was 12 in 2019, 6 in 2020, 16 in 2021, and 19 in 2022. To the authors' knowledge, this report is the first report of TTP associated with inactivated COVID-19 vaccine (CoronaVac). The rarity and delayed onset may be due to the relatively milder immune response caused by the inactivated vaccines than mRNA-based ones. Timely plasma exchange is a vital treatment for CoronaVac-related TTP, similar to activated vaccine-related TTP.

Correction: Current overview on the genetic basis of key genes involved in soybean domestication.

[This corrects the article DOI: 10.1007/s42994-022-00074-5.].

Initial soil condition, stand age, and aridity alter the pathways for modifying the soil carbon under afforestation.

Afforestation is a crucial pathway for ecological restoration and has the potential to modify soil microbial community, thereby impacting the cycling and accumulation of carbon in soil across diverse patterns. However, the overall patterns of how afforestation impacts below-ground carbon cycling processes remain uncertain. In this comprehensive meta-analysis, we systematically evaluated 7045 observations from 210 studies worldwide to evaluate the influence of afforestation on microbial communities, enzyme activities, microbial functions, and associated physicochemical properties of soils. Afforestation increases microbial biomass, carbon and nitrogen hydrolase activities, and microbial respiration, but not carbon oxidase activity and nitrogen decomposition rate. Conversely, afforestation leads to a reduction in the metabolic quotient, with significant alteration of bacterial and fungal community structures and positive effects on the fungi: bacteria ratio rather than alpha and beta diversity metrics. We found a total 77 % increase in soil organic carbon (SOC) content after afforestation, which varied depending on initial SOC content before afforestation, afforestation stand age, and aridity index of afforestation sites. The modified SOC is associated with bacterial community composition along with intracellular metabolic quotient and extracellular carbon degrading enzyme activity playing a role. These findings provide insights into the pathways through which afforestation affects carbon cycling via microorganisms, thus improving our knowledge of soil carbon reservoir's responses to afforestation under global climate change.

Soybean hypocotyl elongation is regulated by a MYB33-SWEET11/21-GA2ox8c module involving long-distance sucrose transport.

The length of hypocotyl affects the height of soybean and lodging resistance, thus determining the final grain yield. However, research on soybean hypocotyl length is scarce, and the regulatory mechanisms are not fully understood. Here, we identified a module controlling the transport of sucrose, where sucrose acts as a messenger moved from cotyledon to hypocotyl, regulating hypocotyl elongation. This module comprises four key genes, namely MYB33, SWEET11, SWEET21 and GA2ox8c in soybean. In cotyledon, MYB33 is responsive to sucrose and promotes the expression of SWEET11 and SWEET21, thereby facilitating sucrose transport from the cotyledon to the hypocotyl. Subsequently, sucrose transported from the cotyledon up-regulates the expression of GA2ox8c in the hypocotyl, which ultimately affects the length of the hypocotyl. During the domestication and improvement of soybean, an allele of MYB33 with enhanced abilities to promote SWEET11 and SWEET21 has gradually become enriched in landraces and cultivated varieties, SWEET11 and SWEET21 exhibit high conservation and have undergone a strong purified selection and GA2ox8c is under a strong artificial selection. Our findings identify a new molecular pathway in controlling soybean hypocotyl elongation and provide new insights into the molecular mechanism of sugar transport in soybean.

Mechanism of Bile Acid in Regulating Platelet Function and Thrombotic Diseases.

Platelets play a key role in physiological hemostasis and pathological thrombosis. Based on the limitations of current antiplatelet drugs, it's important to elucidate the mechanisms of regulating platelet activation. In addition to dissolving lipid nutrients, bile acids (BAs) can regulate platelet function. However, the specific mechanisms underlying BAs-mediated effects on platelet activation and thrombotic diseases remain unknown. Therefore, the effects of BAs on platelets and intracellular regulatory mechanisms are explored. It is showed that the inhibitory effect of secondary BAs is more significant than that of primary BAs; lithocholic acid (LCA) shows the highest inhibitory effect. In the process of platelet activation, BAs suppress platelet activation via the spleen tyrosine kinase (SYK), protein kinase B (Akt), and extracellular signal-regulated kinase1/2 (Erk1/2) pathways. Nck adaptor proteins (NCK1) deficiency significantly suppress the activity of platelets and arterial thrombosis. Phosphorylated proteomics reveal that LCA inhibited phosphorylation of syntaxin-11 at S80/81 in platelets. Additional LCA supplementation attenuated atherosclerotic plaque development and reduced the inflammation in mice. In conclusion, BAs play key roles in platelet activation via Syk, Akt, ERK1/2, and syntaxin-11 pathways, which are associated with NCK1. The anti-platelet effects of BAs provide a theoretical basis for the prevention and therapy of thrombotic diseases.

UAV-Assisted Mobile Edge Computing: Dynamic Trajectory Design and Resource Allocation.

The recent advancements of mobile edge computing (MEC) technologies and unmanned aerial vehicles (UAVs) have provided resilient and flexible computation services for ground users beyond the coverage of terrestrial service. In this paper, we focus on a UAV-assisted MEC system in which the UAV equipped with MEC servers is used to assist user devices in computing their tasks. To minimize the weighted average energy consumption and delay in the UAV-assisted MEC system, a LQR-Lagrange-based DDPG (LLDDPG) algorithm, which jointly optimizes the user task offloading and the UAV trajectory design, is proposed. To be specific, the LLDDPG algorithm consists of three subproblems. The DDPG algorithm is used to address the issue of UAV desired trajectory planning, and subsequently, the LQR-based algorithm is employed to achieve the real-time tracking control of UAV desired trajectory. Finally, the Lagrange duality method is proposed to solve the optimization problem of computational resource allocation. Simulation results indicate that the proposed LLDDPG algorithm can effectively improve the system resource management and realize the real-time UAV trajectory design.

Sonocatalytic oncolysis microbiota curb intrinsic microbiota lactate metabolism and blockade CD24-Siglec10 immune escape to revitalize immunological surveillance.

Intrinsic lactate retention of chemically- or genetically-engineered bacteria therapy aggravates tumor immunosuppression, which will collaborate with immune escape to cause immunological surveillance failure. To address them, sonocatalytic oncolysis Escherichia coli (E.coli) that chemically chelated anti-CD24 and TiO1+x have been engineered to blockade CD24-siglec10 interaction, regulate microbiota colonization and curb its lactate metabolism, which are leveraged to revitalize immunological surveillance and repress breast cancer. The chemically-engineered E.coli inherited their parent genetic information and expansion function. Therefore, their intrinsic hypoxia tropism and CD24 targeting allow them to specifically accumulate and colonize in solid breast cancer to lyse tumor cells. The conjugated CD24 antibody is allowed to blockade CD24-Siglec10 signaling axis and revitalize immunological surveillance. More significantly, the chelated TiO1+x sonosensitizers produce ROS to render bacteria expansion controllable and curb immunosuppression-associated lactate birth that are usually neglected. Systematic experiments successfully vlaidate hypoxia-objective active targeting, sonocatalytic therapy, microbiota expansion-enabled oncolysis, CD24-Siglec10 communication blockade and precise microbiota abundance & lactate metabolism attenuations. These actions contribute to the potentiated anti-tumor immunity and activated anti-metastasis immune memory against breast cancer development. Our pioneering work provide a route to sonocatalytic cancer immunotherapy.

Transforming waste into valuables: Preparation and evaluation of dual-ligand hydrophobic charge-induction chromatography using two poor performing ligands.

In conventional chromatographic ligand screening, underperforming ligands are often dismissed. However, this practice may inadvertently overlook potential opportunities. This study aims to investigate whether these underperforming ligands can be repurposed as valuable assets. Hydrophobic charge-induction chromatography (HCIC) is chosen as the validation target for its potential as an innovative chromatographic mode. A novel dual-ligand approach is employed, combining two suboptimal ligands (5-Aminobenzimidazole and Tryptamine) to explore enhanced performance and optimization prospects. Various dual-ligand HCIC resins with different ligand densities were synthesized by adjusting the ligand ratio and concentration. The resins were characterized to assess appearance, functional groups, and pore features using SEM, FTIR, and ISEC techniques. Performance assessments were conducted using single-ligand mode resins as controls, evaluating the selectivity against human immunoglobulin G and human serum albumin. Static adsorption experiments were performed to understand pH and salt influence on adsorption. Breakthrough experiments were conducted to assess dynamic adsorption capacity of the novel resin. Finally, chromatographic separation using human serum was performed to evaluate the purity and yield of the resin. Results indicated that the dual-ligand HCIC resin designed for human antibodies demonstrates exceptional selectivity, surpassing not only single ligand states but also outperforming certain high-performing ligand types, particularly under specific salt and pH conditions. Ultimately, a high yield of 83.9 % and purity of 96.7 % were achieved in the separation of hIgG from human serum with the dual-ligand HCIC, significantly superior to the single-ligand resins. In conclusion, through rational design and proper operational conditions, the dual-ligand mode can revitalize underutilized ligands, potentially introducing novel and promising chromatographic modes.

A meta-analysis of antibiotic residues in the Beibu Gulf.

Antibiotic residue stands as a significant ongoing environmental issue, with aquaculture being a major source of annual antibiotic discharge into the ocean. Nevertheless, there is still an incomplete evaluation of antibiotic residues in the Beibu Gulf, an area encompassed by two prominent aquaculture nations, China and Vietnam. The present systematic review and meta-analysis was conducted to examine the presence antibiotic residues in the Beibu Gulf based on published studies. Data were obtained through eight databases up to December 19th, 2023, and were updated on April 15th, 2024. The pooled concentration of antibiotic residues in seawater was 5.90 (ng/L), ranging from 5.73 to 6.06 (ng/L), and was 8.03 (ng/g), ranging from 7.77 to 8.28 (ng/g) in sediments. Fluoroquinolones, tetracyclines, and macrolides were identified as the main antibiotics found in both seawater and sediment samples. The Beibu Gulf showed higher antibiotic levels in its western and northeastern areas. Additionally, the nearshore mangrove areas displayed the highest prevalence of antibiotic residues. It is strongly advised to conduct regular long-term monitoring of antibiotic residues in the Beibu Gulf. Collaborative surveys covering the entire Beibu Gulf involving China and Vietnam are recommended.

The impact of fear of cancer recurrence on the quality of life of breast cancer patients: A longitudinal study of the mediation effect of cortisol and hope.

OBJECTIVE: This longitudinal study sought to explore the impact of cortisol and hope levels on Fear of Cancer Recurrence (FCR) and Quality of Life (QOL) in a cohort of 552 breast cancer patients from three centers in Wuhan City. METHOD: A longitudinal study involving 552 breast cancer patients from three centers in Wuhan City utilized Chinese versions of the Fear of Progression Questionnaire-Short Form (FoP-Q-SF), the Herth Hope Index (HHI), and the Functional Assessment of Cancer Therapy-Breast (FACT-B) scale. Cortisol levels were measured thrice daily, and data was collected longitudinally three times. Data analysis was conducted using SPSS 26.0 and Mplus 8.3, employing a longitudinal path model constructed via the cross-lagged method. RESULTS: The results showed there were significant correlations between FCR, cortisol levels, and QOL at different time points. A significant mediating model was found with outcomes related to hope levels. Specifically, FCR predicted a decrease in hope levels (ß = -0.163, p < 0.001), which in turn led to a decrease in overall QOL (ß = -0.078, p < 0.001), with a mediation effect accounting for 10.34%. Although there were correlations between FCR, cortisol levels, and QOL at different time points, further analysis revealed that cortisol levels did not exhibit a mediating effect between the two (95% confidence interval: -0.002 to 0.001). CONCLUSION: This study demonstrated there were significant correlations among FCR, QOL, and hope levels. Considering hope as a crucial mediator between FCR and QOL, potential intervention strategies for optimizing the QOL of breast cancer patients are proposed.

Wrecking neutrophil extracellular traps and antagonizing cancer-associated neurotransmitters by interpenetrating network hydrogels prevent postsurgical cancer relapse and metastases.

Tumor-promoting niche after incomplete surgery resection (SR) can lead to more aggressive local progression and distant metastasis with augmented angiogenesis-immunosuppressive tumor microenvironment (TME). Herein, elevated neutrophil extracellular traps (NETs) and cancer-associated neurotransmitters (CANTs, e.g., catecholamines) are firstly identified as two of the dominant inducements. Further, an injectable fibrin-alginate hydrogel with high tissue adhesion has been constructed to specifically co-deliver NETs inhibitor (DNase I)-encapsulated PLGA nanoparticles and an unselective ß-adrenergic receptor blocker (propranolol). The two components (i.e., fibrin and alginate) can respond to two triggers (thrombin and Ca2+, respectively) in postoperative bleeding to gelate, shaping into an interpenetrating network (IPN) featuring high strength. The continuous release of DNase I and PR can wreck NETs and antagonize catecholamines to decrease microvessel density, blockade myeloid-derived suppressor cells, secrete various proinflammatory cytokines, potentiate natural killer cell function and hamper cytotoxic T cell exhaustion. The reprogrammed TME significantly suppress locally residual and distant tumors, induce strong immune memory effects and thus inhibit lung metastasis. Thus, targetedly degrading NETs and blocking CANTs enabled by this in-situ IPN-based hydrogel drug depot provides a simple and efficient approach against SR-induced cancer recurrence and metastasis.

Covalent binding of reactive anhydride of cantharidin to biological amines.

Cantharidin is a terpenoid from coleoptera beetles. Cantharidin has been used to treat molluscum contagiosum and some types of tumors. Cantharidin is highly toxic and cantharidin poisoning and fatal cases have been reported worldwide. The mechanisms underlying cantharidin-induced toxicity remain unclear. Cantharidin contains anhydride, which may react with biological amines. This study aimed to examine the chemical reactivity of cantharidin toward nucleophiles and characterize adducts of cantharidin with biological amines in vitro and in mice. Here, two types of conjugates were formed in the incubation of cantharidin under physiologic conditions with free amino acids, a mimic peptide, or amine-containing compounds, respectively. Amide-type conjugates were produced by the binding of cantharidin anhydride with the primary amino group of biological amines. Imide-type conjugates were generated from the dehydration and cyclization of amide-type conjugates. The structure of the conjugates was characterized by using the high-resolution mass spectrometry. We introduced the 14N/15N and 79Br/81Br isotope signatures to confirm the formation of conjugates using L-(ε)15N-lysine, L-lysine-15N2, and bromine-tagged hydrazine, respectively. The structure of imide conjugate was also confirmed by NMR experiments. Furthermore, the amide and imide conjugates of cantharidin with amino acids or N-acetyl-lysine were detected in mouse liver and urine. Cantharidin was found to modify lysine residue proteins in mouse liver. Pan-P450 inhibitor 1-aminobenzotriazole significantly increased the urine cantharidin-N-acetyl-lysine conjugates whereas decreased cantharidin metabolites. In summary, cantharidin anhydride can covalently bind to biological amines nonenzymatically, which facilitates a better understanding of the role of nonenzymatic reactivity in cantharidin poisoning. Significance Statement Anhydride moiety of cantharidin can covalently bind to the primary amino group of biological amines nonenzymatically. Amide and imide conjugates were generated after the covalent binding of cantharidin anhydride with the primary amino groups of amino acids, a mimic peptide, and protein lysine residues. The structure of conjugates was confirmed by 14N/15N and 79Br/81Br isotope signatures using isotope-tagged reagents and NMR experiments. This study will facilitate the understanding of the role of nonenzymatic reactivity in cantharidin poisoning.

Progesterone Enhances Niraparib Efficacy in Ovarian Cancer by Promoting Palmitoleic-Acid-Mediated Ferroptosis.

Poly (adenosine 5'-diphosphate-ribose) polymerase inhibitors (PARPi) are increasingly important in the treatment of ovarian cancer. However, more than 40% of BRCA1/2-deficient patients do not respond to PARPi, and BRCA wild-type cases do not show obvious benefit. In this study, we demonstrated that progesterone acted synergistically with niraparib in ovarian cancer cells by enhancing niraparib-mediated DNA damage and death regardless of BRCA status. This synergy was validated in an ovarian cancer organoid model and in vivo experiments. Furthermore, we found that progesterone enhances the activity of niraparib in ovarian cancer through inducing ferroptosis by up-regulating palmitoleic acid and causing mitochondrial damage. In clinical cohort, it was observed that progesterone prolonged the survival of patients with ovarian cancer receiving PARPi as second-line maintenance therapy, and high progesterone receptor expression combined with low glutathione peroxidase 4 (GPX4) expression predicted better efficacy of PARPi in patients with ovarian cancer. These findings not only offer new therapeutic strategies for PARPi poor response ovarian cancer but also provide potential molecular markers for predicting the PARPi efficacy.

A Customized Biohybrid Presenting Cascade Responses to Tumor Microenvironment.

Intrinsic characteristics of microorganisms, including non-specific metabolism sites, toxic byproducts, and uncontrolled proliferation constrain their exploitation in medical applications such as tumor therapy. Here, the authors report an engineered biohybrid that can efficiently target cancerous sites through a pre-determined metabolic pathway to enable precise tumor ablation. In this system, DH5α Escherichia coli is engineered by the introduction of hypoxia-inducible promoters and lactate oxidase genes, and further surface-armored with iron-doped ZIF-8 nanoparticles. This bioengineered E. coli can produce and secrete lactate oxidase to reduce lactate concentration in response to hypoxic tumor microenvironment, as well as triggering immune activation. The peroxidase-like functionality of the nanoparticles extends the end product of the lactate metabolism, enabling the conversion of hydrogen peroxide (H2O2) into highly cytotoxic hydroxyl radicals. This, coupled with the transformation of tirapazamine loaded on nanoparticles to toxic benzotriazinyl, culminates in severe tumor cell ferroptosis. Intravenous injection of this biohybrid significantly inhibits tumor growth and metastasis.

Heterogenetic mechanism in high-temperature Daqu fermentation by traditional craft and mechanical craft: From microbial assembly patterns to metabolism phenotypes.

The mechanical process has a widely usage in large-scale high-temperature Daqu (HTD) enterprises, however, the quality of the mechanical HTD is gapped with the HTD by traditional process. Currently, the understanding of the mechanism behind this phenomenon is still over-constrained. To this end, the discrepancies in fermentation parameters, enzymatic characteristics, microbial assembly and succession patterns, metabolic phenotypes were compared between traditional HTD and mechanical HTD in this paper. The results showed that mechanical process altered the temperature ramping procedure, resulting in a delayed appearance of the peak temperature. This alteration shifted the assembly pattern of the initial bacterial community from determinism to stochasticity, while having no impact on the stochastic assembly pattern of the fungal community. Concurrently, mechanical pressing impeded the accumulation of arginase, tetramethylpyrazine, trimethylpyrazine, 2-methoxy-4-vinylphenol, and butyric acid, as the target dissimilarities in metabolism between traditional HTD and mechanical HTD. Pearson correlation analysis combined with the functional prediction further demonstrated that Bacillus, Virgibacillus, Oceanobacillus, Kroppenstedtia, Lactobacillus, and Monascus were mainly contributors to metabolic variances. The Redundancy analysis (RDA) of fermented environmental factors on functional ASVs indicated that high temperature, high acid and low moisture were key positive drivers on the microbial metabolism for the characteristic flavor in HTD. Based on these results, heterogeneous mechanisms between traditional HTD and mechanical HTD were explored, and controllable metabolism targets were as possible strategies to improve the quality of mechanical HTD.

Identification of Susceptibility Genes Underlying Bovine Respiratory Disease in Xinjiang Brown Cattle Based on DNA Methylation.

DNA methylation is a form of epigenetic regulation, having pivotal parts in controlling cellular expansion and expression levels within genes. Although blood DNA methylation has been studied in humans and other species, its prominence in cattle is largely unknown. This study aimed to methodically probe the genomic methylation map of Xinjiang brown (XJB) cattle suffering from bovine respiratory disease (BRD), consequently widening cattle blood methylome ranges. Genome-wide DNA methylation profiling of the XJB blood was investigated through whole-genome bisulfite sequencing (WGBS). Many differentially methylated regions (DMRs) obtained by comparing the cases and controls groups were found within the CG, CHG, and CHH (where H is A, T, or C) sequences (16,765, 7502, and 2656, respectively), encompassing 4334 differentially methylated genes (DMGs). Furthermore, GO/KEGG analyses showed that some DMGs were involved within immune response pathways. Combining WGBS-Seq data and existing RNA-Seq data, we identified 71 significantly differentially methylated (DMGs) and expressed (DEGs) genes (p < 0.05). Next, complementary analyses identified nine DMGs (LTA, STAT3, IKBKG, IRAK1, NOD2, TLR2, TNFRSF1A, and IKBKB) that might be involved in the immune response of XJB cattle infected with respiratory diseases. Although further investigations are needed to confirm their exact implication in the involved immune processes, these genes could potentially be used for a marker-assisted selection of animals resistant to BRD. This study also provides new knowledge regarding epigenetic control for the bovine respiratory immune process.

Cobalt-based hybrid nanoparticles loaded with curcumin for ligand-enhanced synergistic nanocatalytic therapy/chemotherapy combined with calcium overload.

The therapeutic efficacy of Fenton or Fenton-like nanocatalysts is usually restricted by the inappropriate pH value and limited concentration of hydrogen peroxide (H2O2) at the tumor site. Herein, calcium carbonate (CaCO3)-mineralized cobalt silicate hydroxide hollow nanocatalysts (CSO@CaCO3, CC) were synthesized and loaded with curcumin (CCC). This hybrid system can simultaneously realize nanocatalytic therapy, chemotherapy and calcium overload. With the stabilization of liposomes, CCC is able to reach the tumor site smoothly. The CaCO3 shell first degrades in an acidic tumor environment, releasing Cur and Ca2+, and the pH value of the tumor is increased simultaneously. Then the exposed CSO catalyzes the Fenton-like reaction to convert H2O2 into ˙OH and enhances the cytotoxicity of curcumin (Cur) by catalytically oxidizing it to a ˙Cur radical. Curcumin not only induces the chemotherapy effect but also serves as a nucleophilic ligand and an electron donor in the catalytic system, enhancing the Fenton-like activity of CCC by electron transfer. In addition, calcium overload also amplifies the efficacy of ROS-based therapy. In vitro and in vivo results show that CCC exhibited an excellent synergistic tumor inhibition effect without any clear side effect. This work proposes a novel concept of nanocatalytic therapy/chemotherapy synergistic mechanism by the ligand-induced enhancement of Fenton-like catalytic activity, and inspires the construction of combined therapeutic nanoplatforms and multifunctional nanocarriers for drug and ion delivery in the future.

PPP2CA Inhibition Promotes Ferroptosis Sensitivity Through AMPK/SCD1 Pathway in Colorectal Cancer.

PURPOSE: Colorectal cancer (CRC) is a very common malignancy of the digestive system. Despite a variety of treatments including surgery, chemotherapeutic and targeted drugs, the prognosis for patients with CRC is still unsatisfactory and the mortality remains high. Protein phosphorylation plays an essential role in tumorigenesis and progression and is also crucial for protein to act with proper functions. Ferroptosis is found widely involved in various diseases especially tumors as a newly identified programmed cell death. METHODS: In our study, we aimed at PPP2CA as a prospective target which may play a crucial role in CRC progression. In one hand, knockdown of PPP2CA significantly enhanced the malignant phenotype in HCT116. In the other hand, knockdown of PPP2CA significantly enhanced Erastin-induced ferroptosis as well. RESULTS: Specifically, knockdown of PPP2CA in HCT116 significantly increased the relative level of malondialdehyde (MDA), reactive oxygen species (ROS) and Fe2+, and decreased GSH/GSSG ratio after the treatment of certain concentration of Erastin. Besides, we found that the inhibition of PPP2CA further led to the suppression of SCD1 expression in CRC cells in a AMPK-dependent way. CONCLUSION: Ultimately, we conclude that PPP2CA may regulate Erastin-induced ferroptosis through AMPK/SCD1 signaling pathway.

Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis.

The essence of difference between hemostasis and thrombosis is that the clotting reaction is a highly fine-tuned process. Vascular protein disulfide isomerase (PDI) represents a critical mechanism regulating the functions of hemostatic proteins. Herein we show that histidine-rich glycoprotein (HRG) is a substrate of PDI. Reduction of HRG by PDI enhances the procoagulant and anticoagulant activities of HRG by neutralization of endothelial heparan sulfate (HS) and inhibition of factor XII (FXIIa) activity, respectively. Murine HRG deficiency (Hrg-/-) leads to delayed onset but enhanced formation of thrombus compared to WT. However, in the combined FXII deficiency (F12-/-) and HRG deficiency (by siRNA or Hrg-/-), there is further thrombosis reduction compared to F12-/- alone, confirming HRG's procoagulant activity independent of FXIIa. Mutation of target disulfides of PDI leads to a gain-of-function mutant of HRG that promotes its activities during coagulation. Thus, PDI-HRG pathway fine-tunes thrombosis by promoting its rapid initiation via neutralization of HS and preventing excessive propagation via inhibition of FXIIa.