Mutual Antagonism Research Articles

Oligomerization and positive feedback on membrane recruitment encode dynamically stable PAR-3 asymmetries in the C. elegans zygote.

Studies of PAR polarity have emphasized a paradigm in which mutually antagonistic PAR proteins form complementary polar domains in response to transient cues. A growing body of work suggests that the oligomeric scaffold PAR-3 can form unipolar asymmetries without mutual antagonism, but how it does so is largely unknown. Here we combine single molecule analysis and modeling to show how the interplay of two positive feedback loops promote dynamically stable unipolar PAR-3 asymmetries in early C. elegans embryos. First, the intrinsic dynamics of PAR-3 membrane binding and oligomerization encode negative feedback on PAR-3 dissociation. Second, membrane-bound PAR-3 promotes its own recruitment through a mechanism that requires the anterior polarity proteins CDC-42, PAR-6 and PKC-3. Using a kinetic model tightly constrained by our experimental measurements, we show that these two feedback loops are individually required and jointly sufficient to encode dynamically stable and locally inducible unipolar PAR-3 asymmetries in the absence of posterior inhibition. Given the central role of PAR-3, and the conservation of PAR-3 membrane-binding, oligomerization, and core interactions with PAR-6/aPKC, these results have widespread implications for PAR-mediated polarity in metazoa.

Mutual antagonism between CD44 and integrins in glioblastoma cell traction and migration.

Cell migration is the major driver of invasion and metastasis during cancer progression. For cells to migrate, they utilize the actin-myosin cytoskeleton and adhesion molecules, such as integrins and CD44, to generate traction forces in their environment. CD44 primarily binds to hyaluronic acid (HA) and integrins primarily bind to extracellular matrix (ECM) proteins such as collagen. However, the role of CD44 under integrin-mediated conditions and vice versa is not well known. Here, we performed traction force microscopy (TFM) on U251 cells seeded on collagen I-coated polyacrylamide gels to assess the functional mechanical relationship between integrins and CD44. Performing TFM on integrin-mediated adhesion conditions, i.e., collagen, we found that CD44KO U251 cells exerted more traction force than wild-type (WT) U251 cells. Furthermore, untreated WT and CD44-blocked WT exhibited comparable results. Conversely, in CD44-mediated adhesive conditions, integrin-blocked WT cells exerted a higher traction force than untreated WT cells. Our data suggest that CD44 and integrins have a mutually antagonistic relationship where one receptor represses the other's ability to generate traction force on its cognate substrate.

Wound-induced small-peptide-mediated signaling cascade, regulated by OsPSKR, dictates balance between growth and defense in rice

Wounding is a general stress in plants that results from various pest and pathogenic infections in addition to environment-induced mechanical damages. Plants have sophisticated molecular mechanisms to recognize and respond to wounding, with those of monocots being distinct from dicots. Here, we show the involvement of two distinct categories of temporally separated, endogenously derived peptides, namely, plant elicitor peptides (PEPs) and phytosulfokine (PSK), mediating wound responses in rice. These peptides trigger a dynamic signal relay in which a receptor kinase involved in PSK perception named OsPSKR plays a major role. Perturbation of OsPSKR expression in rice leads to compromised development and constitutive autoimmune phenotypes. OsPSKR regulates the transitioning of defense to growth signals upon wounding. OsPSKR displays mutual antagonism with the OsPEPR1 receptor involved in PEP perception. Collectively, our work indicates the presence of a stepwise peptide-mediated signal relay that regulates the transition from defense to growth upon wounding in monocots.

Ontological security and protracted conflict in frontier societies: towards a trans-local turn in peacebuilding

ABSTRACT This article proposes a trans-local turn in peacebuilding in frontier societies. Drawing on René Girard’s concept of ‘mimetic desire’, the article conceptualises how a crisis of ontological insecurity cannot be addressed by rational approaches to institutionalising a process to resolve incompatibilities between conflict parties, but requires de-escalation of the mimetic rivalry between the parties, who are often described as being in conflict over identity. Empirically, the article focuses on the, apparently very different, examples of intractable conflicts in Northern Ireland and Korea, and the trans-local peacebuilding interactions between the two. This article demonstrates how relationships of unresolved mimetic rivalry have intensified ontological insecurity in both cases, creating dynamics of existential anxiety and mutual antagonism, and how the reflexivity based on peacebuilding stories from other frontier societies, which do not impose direct ontological threats, appears to increase hope for change by transcending the endemic sense of ontological insecurity.

Quantifying and normalizing the combined phytotoxicity of mixed-valence chromium in soil integrated by toxicity equivalence

When Cr(VI) and Cr(III) coexist, the reasonable assessment of the combined toxicity of chromium in soil and its ecological risk is still not well resolved. In the present study, exogenous mixed concentration combinations were set up to determine the interaction and combined toxicity of Cr(VI) and Cr(III), which were quantified as measured total and resin extractable forms for dose-response experiments with barley root elongation. The concept of toxicity equivalence "α" (the ratio of toxicity intensity coefficient between Cr(VI) and Cr(III), which can be expressed as the relative toxic strength of Cr(VI) to Cr(III)) was proposed for the toxicity assessment of mixed-valence chromium in soil. The results showed that the dose-response relationship was determined more precisely by the extended independent action model (e-IA) than traditional models (e.g., concentration addition model), and the mutual antagonism for resin extractable form (Resin-Cr) was stronger than the measured total form (T-Cr). The values of toxicity equivalence (α) between coexisting Cr(VI) and Cr(III) as Resin-Cr and T-Cr were 0.74 and 160, respectively, which indicated Resin-Cr(III) had relatively stronger toxicity than Resin-Cr(VI), while T-Cr(III) was much less than T-Cr(VI). The α values between Cr(VI) and Cr(III) decreased with their more active forms (decreased to about 0.5% of the original), even as total concentration and activity in solutions, making a dialectical view of the toxicity of both in different forms necessary. Finally, the log-logistic models were developed, enabling mixed-valence Cr toxicity to be assessed from a unilateral perspective using the Cr(III) equivalence concentration (Cr(III)-eq). This work provided innovative ideas for ecological threshold studies for mixed-valence metals in soils.

Impacts of Central Administration of the Novel Peptide, LEAP-2, in Different Food Intake Models in Conscious Rats.

Liver-expressed antimicrobial peptide-2 (LEAP-2) has mutual antagonism with ghrelin, which evokes food intake under a freely fed state. Nevertheless, the impact of LEAP-2 on ghrelin under time-restricted feeding (TRF), which has benefits in the context of metabolic disease, is still unknown. This study aims to explore the impact of central administration of LEAP-2 on the ingestion behavior of rats, which was evaluated using their cumulative food intake in the TRF state. Before intracerebroventricular (ICV) administration of O-n-octanoylated ghrelin (0.1 nmol/rat), as a food-stimulatory model, the rats received various doses of LEAP-2 (0.3, 1, 3 nmol/rat, ICV). Cumulative food intake was recorded at 1, 2, 4, 8, 12, and 24 h after ICV injection under 12 h freely fed and TRF states in a light phase. In 12 h freely fed and TRF states, central administration of ghrelin alone induced feeding behavior. Pre-treatment with LEAP-2 (1 and 3 nmol/rat, ICV) suppressed ghrelin-induced food intake in a dose-dependent manner in a 12 h freely fed state instead of a TRF state, which may have disturbed the balance of ghrelin and LEAP-2. This study provides neuroendocrine-based evidence that may explain why TRF sometimes fails in fighting obesity/metabolic dysfunction-associated steatotic liver disease in clinics.

Olfactory perceptual interactions of maltol with key food odorants in binary mixtures: Scatter matrix statistical analysis of odor intensity in heterogeneous perceptual situation

To study the olfactory perceptual interaction of odorants (OPIO) in binary mixtures containing maltol, a simple and efficient analysis method was developed. This method correlated three variables of the binary mixture: two rates of change in perceived odor intensities of two odorants within the binary mixtures, and the degree of overall odor synergy exhibited by the binary mixtures. By creating a three-dimensional scatter matrix with the variables, the changes in odor intensity of the binary mixture due to OPIO were visualized. The results revealed that the proportions of mutual antagonism, opposite effect, mutual independence, and mutual synergy in the binary mixtures were 64.7%, 32.9%, 1.9%, and 0.5%, respectively. The odor of maltol was mainly masked, and those of esters (68%), aldehydes and ketones (33%) in the mixture were enhanced. In terms of overall odor intensity, 67% of cases involved partial addition, followed by 22.2% overshadowing, and 19.6% stronger component effect.

The Tick Saliva Peptide HIDfsin2 TLR4-Dependently Inhibits the Tick-Borne Severe Fever with Thrombocytopenia Syndrome Virus in Mouse Macrophages.

Ticks transmit a variety of pathogens to their hosts by feeding on blood. The interactions and struggle between tick pathogens and hosts have evolved bilaterally. The components of tick saliva can directly or indirectly trigger host biological responses in a manner that promotes pathogen transmission; however, host cells continuously develop strategies to combat pathogen infection and transmission. Moreover, it is still unknown how host cells develop their defense strategies against tick-borne viruses during tick sucking. Here, we found that the tick saliva peptide HIDfsin2 enhanced the antiviral innate immunity of mouse macrophages by activating the Toll-like receptor 4 (TLR4) signaling pathway, thereby restricting tick-borne severe fever with thrombocytopenia syndrome virus (SFTSV) replication. HIDfsin2 was identified to interact with lipopolysaccharide (LPS), a ligand of TLR4, and then depolymerize LPS micelles into smaller particles, effectively enhancing the activation of the nuclear factor kappa-B (NF-κB) and type I interferon (IFN-I) signaling pathways, which are downstream of TLR4. Expectedly, TLR4 knockout completely eliminated the promotion effect of HIDfsin2 on NF-κB and type I interferon activation. Moreover, HIDfsin2 enhanced SFTSV replication in TLR4-knockout mouse macrophages, which is consistent with our recent report that HIDfsin2 hijacked p38 mitogen-activated protein kinase (MAPK) to promote the replication of tick-borne SFTSV in A549 and Huh7 cells (human cell lines) with low expression of TLR4. Together, these results provide new insights into the innate immune mechanism of host cells following tick bites. Our study also shows a rare molecular event relating to the mutual antagonism between tick-borne SFTSV and host cells mediated by the tick saliva peptide HIDfsin2 at the tick-host-virus interface.

Mutual Antagonism of NF-ΚB and P53 - Major Phenomenon for Targeted Drug Therapies

Mutual Antagonism of NF-ΚB and P53 - Major Phenomenon for Targeted Drug Therapies

OsNAC120 balances plant growth and drought tolerance by integrating GA and ABA signaling in rice

The crosstalk between gibberellin (GA) and abscisic acid (ABA) signaling is crucial for balancing plant growth and adaption to environmental stress. Nevertheless, the molecular mechanism of their mutual antagonism still remains to be fully clarified. In this study, we found that knockout of the rice NAC (NAM, ATAF1/2, CUC2) transcription factor gene OsNAC120 inhibits plant growth but enhances drought tolerance, whereas OsNAC120 overexpression produces the opposite results. Exogenous GA can rescue the semi-dwarf phenotype of osnac120 mutants, and further study showed that OsNAC120 promotes GA biosynthesis by transcriptionally activating the GA biosynthetic genes OsGA20ox1 and OsGA20ox3. The DELLA protein SLENDER RICE1 (SLR1) interacts with OsNAC120 and impedes its transactivation ability, and GA treatment can remove the inhibition of transactivation activity caused by SLR1. On the other hand, OsNAC120 negatively regulates rice drought tolerance by repressing ABA-induced stomatal closure. Mechanistic investigation revealed that OsNAC120 inhibits ABA biosynthesis via transcriptional repression of the ABA biosynthetic genes OsNCED3 and OsNCED4. Rice OSMOTIC STRESS/ABA-ACTIVATED PROTEIN KINASE 9 (OsSAPK9) physically interacts with OsNAC120 and mediates its phosphorylation, which results in OsNAC120 degradation. ABA treatment accelerates OsNAC120 degradation and reduces its transactivation activity. Together, our findings provide evidence that OsNAC120 plays critical roles in balancing GA-mediated growth and ABA-induced drought tolerance in rice. This research will help us to understand the mechanisms underlying the trade-off between plant growth and stress tolerance and to engineer stress-resistant, high-yielding crops.

Involvement of a Rarely Used Splicing SD2b Site in the Regulation of HIV-1 vif mRNA Production as Revealed by a Growth-Adaptive Mutation.

We have previously reported an HIV-1 mutant designated NL-Y226tac that expresses Vif at an ultra-low level, being replication-defective in high-APOBEC3G cells, such as H9. It carries a synonymous mutation within the splicing SA1 site relative to its parental clone. In order to determine whether a certain mutant(s) emerges during multi-infection cycles, we maintained H9 cells infected with a relatively low or high input of NL-Y226tac for extended time periods. Unexpectedly, we reproducibly identified a g5061a mutation in the SD2b site in the two independent long-term culture experiments that partially increases Vif expression and replication ability. Importantly, the adaptive mutation g5061a was demonstrated to enhance vif mRNA production by activation of the SA1 site mediated through increasing usage of a rarely used SD2b site. In the long-term culture initiated by a high virus input, we additionally found a Y226Fttc mutation at the original Y226tac site in SA1 that fully restores Vif expression and replication ability. As expected, the adaptive mutation Y226Fttc enhances vif mRNA production through increasing the splicing site usage of SA1. Our results here revealed the importance of the SD2b nucleotide sequence in producing vif mRNA involved in the HIV-1 adaptation and of mutual antagonism between Vif and APOBEC3 proteins in HIV-1 adaptation/evolution and survival.

Zanubrutinib, Polatuzumab Vedotin and Rituximab (ZPR) Combination Regimen for Relapsed/Refractory Patients with Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous and invasive lymphoma. About 30% of patients are difficult to cure or relapse after R-CHOP treatment, known as relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Patients who are not suitable for high-dose chemotherapy followed by autologous stem cell rescue, rely more on the discovery of new drugs and proposals of new treatment plans. Polatuzumab vedotin (Pola) is an antibody-drug conjugate that targets the B-cell antigen CD79b and delivers monomethyl auristatin E (MMAE). It is recently available in China and approved in combination with Bendamustine and Rituximab for r/r DLBCL. However, real-world data on Pola-based regimens are limited. Here, we propose ZPR (combination of Zanubrutinib, Polatuzumab vedotin and Rituximab) as a potential salvage treatment in r/r DLBCL patients, aiming to explore its efficacy and safety in our single center. Response characteristics in patients received ZPR therapy There were already eight r/r DLBCL patients treated with ZPR regimen at our institution between April 1 and July 31, 2023. Informed consent and biological sample donation informed consent were both signed by each participant. Patients were 69 years old on median and half of them were non-GCB type. Seven patients are classified as stage IV. The median number of treatment lines is two. Patients were given Zanubrutinib 160mg bid daily; Polatuzumab vedotin 1.8 mg/kg and Rituximab 375 mg/m 2 on the first day of each cycle (every 21 days per cycle). Four patients completed 3 cycles of ZPR and three underwent a mid-term evaluation. Results showed that the complete remission (CR) rate was 100% (Figure 1). In terms of adverse events, hematological toxicity grade is not greater than level 2 of Common Terminology Criteria for Adverse Events (CTCAE). One patient developed a pulmonary infection during the treatment. The Rationale for the combination of Polatuzumab vedotin, Rituximab and Zanubrutinib The combination therapy of bruton's tyrosine kinase inhibitor (BTKi) with anti-CD20 therapy has been used in many B-cell lymphomas. It was proposed that combining these two drugs will target and clear blood lymphocytes and shorten the time to respond in chronic lymphocytic leukemia patients. Compared with the first generation BTKi the new generation BTKi Zanubrutinib has a higher selectivity and fewer off-target effects on BTK. Meanwhile, Natsumi Kawasaki et al discovered that Pola increased the expression of CD20 and sensitized Pola refractory cells to Rituximab-induced complement-dependent cytotoxicity (CDC). While the release of MMAE, a chemical component of Pola, results in microtubule disruption and cycle arrest. These findings provide a scientific rationale for employing the Pola-Rituximab combination therapy to treat DLBCL patients. However, the combination of Pola and Zanubrutinib does not show a clear mutual antagonism effect. The molecular rationale for the combination of these two drugs needs further exploration. Who are suitable for ZPR regimen? Patients who are diagnosed with r/r DLBCL after standard first-line treatment failure: ECOG≥2Age≥70As a bridging therapy for patients waiting for ASCT or CAR-T therapyAge＜70 expect a high quality of life, still need working, or going to schoolUnable to tolerate standard-dose of chemotherapy due to hematological toxicity (need a blood transfusion, treatment delay, or dosage reduction) Prospective study to be continued Due to the good response of our three r/r DLBCL patients, we intended to conduct a “Prospective single-arm, single-center clinical study of Zanubrutinib, Polatuzumab vedotin and Rituximab (ZPR) regimen in relapsed/refractory patients with diffuse large B-cell lymphoma” to learn more about the impact of the ZPR regimen in the treatment of r/r DLBCL. We got the approval from the Investigator-Initiated Trial (IIT) Scientific Review Board of Zhongshan Hospital after discussing the risks and benefits of ZPR regimen with them. This protocol has also been reviewed and approved by the Institutional Review Board (IRB) of Zhongshan Hospital Affiliated to Fudan University (B2023-186R) and will follow the principles of the Helsinki Declaration. The protocol was previously registered on ClinicalTrials. gov (NCT05940051) . We illustrated the flowchart of our study in Figure 2.

Mutual antagonism of mouse-adaptation mutations in HA and PA proteins on H9N2 virus replication

Avian H9N2 viruses have wide host range among the influenza A viruses. However, knowledge of H9N2 mammalian adaptation is limited. To explore the molecular basis of the adaptation to mammals, we performed serial lung passaging of the H9N2 strain A/chicken/Hunan/8.27 YYGK3W3-OC/2018 (3W3) in mice and identified six mutations in the hemagglutinin (HA) and polymerase acidic (PA) proteins. Mutations L226Q, T511I, and A528V of HA were responsible for enhanced pathogenicity and viral replication in mice; notably, HA-L226Q was the key determinant. Mutations T97I, I545V, and S594G of PA contributed to enhanced polymerase activity in mammalian cells and increased viral replication levels in vitro and in vivo. PA-T97I increased viral polymerase activity by accelerating the viral polymerase complex assembly. Our findings revealed that the viral replication was affected by the presence of PA-97I and/or PA-545V in combination with a triple-point HA mutation. Furthermore, the double- and triple-point PA mutations demonstrated antagonistic effect on viral replication when combined with HA-226Q. Notably, any combination of PA mutations, along with double-point HA mutations, resulted in antagonistic effect on viral replication. We also observed antagonism in viral replication between PA-545V and PA-97I, as well as between HA-528V and PA-545V. Our findings demonstrated that several antagonistic mutations in HA and PA proteins affect viral replication, which may contribute to the H9N2 virus adaptation to mice and mammalian cells. These findings can potentially contribute to the monitoring of H9N2 field strains for assessing their potential risk in mammals.

Insights into synergistic metabolism of phenol and ammonium pollutants in treating coal gasification wastewater by algal-microbial fuel cell

The coexistence of phenol and ammonium induced mutual antagonism largely and hindered the application of biological treatment in coal gasification wastewater (CGW). A novel algal-microbial fuel cell (AMFC) was employed to separate and cleanse phenol and ammonium pollutants, and the insights into biological process were explored. Two types of AMFCs were developed to simultaneously remove phenol and ammonium from CGW, with cyanobacteria and green algal as the cathodes, respectively. The AMFC with Synechocystis cathode exhibited superior performance, removing COD and NH4+-N of 94.82 % and 20.16 %, about 1.12 and 1.06 times higher than the AFMC with Chlorella cathode. Meanwhile, the maximum power density of the AMFC with Synechocystis cathode was enhanced by 40.34 %. The conductive Synechocystis on the cathode and generated biomass on the anode might cooperate to facilitate extracellular electron transfer (EET), which consequently accelerated the separation and cooperative removal of phenol and ammonium in AMFC. By microbial community analysis, the microbiota in biofilm and generated biomass was respective keystone contributor to phenolic degradation and biomass transformation. Meanwhile, Chryseobacterium was the leading bacteria and might dominate both phenol degrading and the generated biomass formation.

Antagonism between viral infection and innate immunity at the single-cell level.

When infected with a virus, cells may secrete interferons (IFNs) that prompt nearby cells to prepare for upcoming infection. Reciprocally, viral proteins often interfere with IFN synthesis and IFN-induced signaling. We modeled the crosstalk between the propagating virus and the innate immune response using an agent-based stochastic approach. By analyzing immunofluorescence microscopy images we observed that the mutual antagonism between the respiratory syncytial virus (RSV) and infected A549 cells leads to dichotomous responses at the single-cell level and complex spatial patterns of cell signaling states. Our analysis indicates that RSV blocks innate responses at three levels: by inhibition of IRF3 activation, inhibition of IFN synthesis, and inhibition of STAT1/2 activation. In turn, proteins coded by IFN-stimulated (STAT1/2-activated) genes inhibit the synthesis of viral RNA and viral proteins. The striking consequence of these inhibitions is a lack of coincidence of viral proteins and IFN expression within single cells. The model enables investigation of the impact of immunostimulatory defective viral particles and signaling network perturbations that could potentially facilitate containment or clearance of the viral infection.

A system of mutual dependence and antagonism: exploring the potential of uneven and combined development within Global Political Economy

U&CD scholarship has made vital conceptual and analytical contributions to international relations and international historical sociology scholarship during recent decades. However, so far, it has mainly focused on the longue durée of capitalist transitions rather than contemporary analyses of the dynamics, crises and policy shifts within the global political economy. A small body of literature has recently begun to apply a U&CD conceptual toolkit towards just such ends. In this special issue, we showcase a range of original thought and empirical work which advances the U&CD perspective within the growing and critically oriented field of global political economy. Transcending the pitfalls of orthodox liberal and realist approaches, U&CD draws a direct link between ruptures, contradictions and crises in the global economy and its ongoing division into a multiplicity of nominally sovereign territorial political units. Focusing on a breadth of divisions and antagonisms across lines of class, race, gender and nationality, the articles contained herein point to the immense potential for creative applications of U&CD to play a role in GPE scholarship as it emerges from the grip of the stifling orthodoxies of international political economy.

Совместное культивирование азотфиксирующего штамма Azomonas macrocytogenes и штамма-антагониста Bacillus atrophaeus

The possibility of co-cultivation of the nitrogen-fixing strain Azomonas macrocytogenes OSV-2 and the antagonist strain of phytopathogenic fungi Bacillus atrophaeus B-13893 for the purpose of using it in a complex biological preparation with nitrogen-fixing and antimycotic activity was studied. Both strains were isolated by the authors from agricultural soils and identified by the nucleotide sequence of the 16S rRNA gene. It has been established that the strains do not show mutual antagonism and grow well in a joint culture on an artificial nutrient medium. When measuring microcolonies, no statistically significant growth inhibition of the nitrogen-fixing strain A. macrocytogenes OSV-2 was found in the presence of the antagonist strain B. atrophaeus B-13893. Thus, both strains can be used together to improve the nitrogen nutrition of plants and the biological protection of plants from fungal diseases. Keywords: BIOLOGICAL PROTECTION OF PLANTS FROM DISEASES, ANTAGONIST STRAINS, NITROGEN-FIXING STRAINS, BACILLUS ATROPHAEUS, AZOMONAS MACROCYTOGENES, CO-CULTURATION

Rationally designed chimeric PI3K-BET bromodomain inhibitors elicit curative responses in MYC-driven lymphoma

Targeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signaling demonstrate potent but self-limited antilymphoma activity as single agents in the context of cellular Myelocytomatosis (cMYC) oncogene-dysregulation. However, combined PI3K and BET inhibition imparts synergistic anticancer activity with the potential for more sustained disease responses due to the mutual antagonism of compensatory epigenetic and signaling networks. Here, we describe the mechanistic and therapeutic validation of rationally designed dual PI3K/BET bromodomain inhibitors, built by linkage of established PI3K and BET inhibitor pharmacophores. The lead candidate demonstrates high selectivity, nanomolar range cellular potency, and compelling in vivo efficacy, including curative responses in the aggressive Eµ-Myc lymphoma model. These studies further support the therapeutic strategy of combined PI3K and BET inhibition and provide a potential step-change in approach to orthogonal MYC antagonism using optimized chimeric small-molecule technology.

A Computational Fluid Dynamics‐Thermodynamics Coupled Approach to Simulate Desulfurization in Ladle Furnace Based on Interface Equilibrium Assumption

This study proposes a coupled computational fluid dynamics and thermodynamics model based on the assumption of interface equilibrium at the steel–slag interface to simulate the desulfurization process in a ladle furnace. The species transport equation is solved to analyze the kinetic behavior and chemical content variation in the melt. The sulfur distribution ratio is calculated based on the slag sulfide capacity and oxygen activity. Subsequently, the solutions are coupled by introducing the species transfer and source terms generated by comparing the initial and predicted thermodynamic equilibrium states at the steel–slag interface cell. The model is validated by experimentally comparing the sulfur content. Furthermore, the model is applied under different kinetics and thermodynamics conditions. With an increase in the gas flow rate, the in‐phase effective diffusion coefficient increases, but the number of interface cells involved in the sulfur transfer process decreases. The complex relationship between the desulfurization process and the gas flow rate results from the mutual antagonism between these two factors. Moreover, the study findings demonstrate that a higher slag basicity enhances the calculated sulfur distribution ratio and final desulfurization ratio.

Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70

Although it has been established that cannabidiol (CBD), the major non-psychoactive constituent of cannabis, exerts antitumoral activities, the exact mechanism(s) via which tumor cells are killed by CBD are not well understood. This study provides new insights into the potential mechanisms of CBD-induced mutual antagonism of apoptosis and macroautophagy using wild type (HCT116 p53wt, LS174T p53wt), knockout (HCT116 p53−/−) and mutant (SW480 p53mut) human colorectal cancer cells (CRC). CBD causes a more pronounced loss in the viability of p53wt cells than p53−/− and p53mut cells, and a 5-week treatment with CBD reduced the volume of HCT116 p53wt xenografts in mice, but had no effect on the volume of HCT116 p53−/− tumors. Mechanistically, we demonstrate that CBD only significantly elevates ROS production in cells harboring wild-type p53 (HCT116, LS174T) and that this is associated with an accumulation of PARP1. CBD-induced elevated ROS levels trigger G0/G1 cell cycle arrest, a reduction in CDK2, a p53-dependent caspase-8/9/3 activation and macroautophagy in p53wt cells. The ROS-induced macroautophagy which promotes the activation of keap1/Nrf2 pathway might be positively regulated by p53wt, since inhibition of p53 by pifithrin-α further attenuates autophagy after CBD treatment. Interestingly, an inhibition of heat shock protein 70 (Hsp70) expression significantly enhances caspase-3 mediated programmed cell death in p53wt cells, whereas autophagy—which is associated with a nuclear translocation of Nrf2—was blocked. Taken together, our results demonstrate an intricate interplay between apoptosis and macroautophagy in CBD-treated colorectal cancer cells, which is regulated by the complex interactions of p53wt and Hsp70.