Unraveling transcriptomic signatures and dysregulated pathways in systemic lupus erythematosus across disease states.

OBJECTIVES: This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease remission. METHODS: We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks. RESULTS: Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse. CONCLUSION: Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.

Carbon quantum dots from hemicucur[6]bit and the application for the detection of Pb2.

A macrocyclic compound, hemicucurbit[6]uril (HemiQ[6]), is employed as the carbon source to produce a novel sort of carbon quantum dots (CQDs) with blue fluorescence in aqueous solution. The CQDs are fully identified by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Nuclear Magnetic Resonance (NMR), zeta potential, ultraviolet/visible (UV-vis) and photoluminescence spectroscopy (PL). The nanomaterial is developed for the analysis of Pb2+ in the light of the Resonance Rayleigh scattering (RRS) changes with the increasing Pb2+ concentration. The proposed probe emerges a high selectivity to Pb2+ and excellent sensitivity in the linear concentration range of 0-6 µM with a detection limit low to 0.42 µM, which is superior to the previous values of Pb2+ sensors, as well as the good anti-interference ability is confirmed by the specifical response to Pb2+ in the presence of other metal cations. Therefore, the proposed analysis of Pb2+ is explored for the application in real samples of tap water and lake water, in satisfied results of acceptable recoveries.

Listeria-vectored cervical cancer vaccine candidate strains reduce MDSCs via the JAK-STAT signaling pathway.

BACKGROUND: Immunosuppressive status is prevalent in cancer patients and increases the complexity of tumor immunotherapy. It has been found that Listeria-vectored tumor vaccines had the potential ability of two-side regulatory effect on the immune response during immunotherapy. RESULTS: The results show that the combined immunotherapy with the LM∆E6E7 and LI∆E6E7, the two cervical cancer vaccine candidate strains constructed by our lab, improves the antitumor immune response and inhibits the suppressive immune response in tumor-bearing mice in vivo, confirming the two-sided regulatory ability of the immune response caused by Listeria-vectored tumor vaccines. The immunotherapy reduces the expression level of myeloid-derived suppressor cells (MDSCs)-inducing factors and then inhibits the phosphorylation level of STAT3 protein, the regulatory factor of MDSCs differentiation, to reduce the MDSCs formation ability. Moreover, vaccines reduce the expression of functional molecules associated with MDSCs may by inhibiting the phosphorylation level of the JAK1-STAT1 and JAK2-STAT3 pathways in tumor tissues to attenuate the immunosuppressive function of MDSCs. CONCLUSIONS: Immunotherapy with Listeria-vectored cervical cancer vaccines significantly reduces the level and function of MDSCs in vivo, which is the key point to the destruction of immunosuppression. The study for the first to elucidate the mechanism of breaking the immunosuppression.

Understanding the charge transfer effects of single atoms for boosting the performance of Na-S batteries.

The effective flow of electrons through bulk electrodes is crucial for achieving high-performance batteries, although the poor conductivity of homocyclic sulfur molecules results in high barriers against the passage of electrons through electrode structures. This phenomenon causes incomplete reactions and the formation of metastable products. To enhance the performance of the electrode, it is important to place substitutable electrification units to accelerate the cleavage of sulfur molecules and increase the selectivity of stable products during charging and discharging. Herein, we develop a single-atom-charging strategy to address the electron transport issues in bulk sulfur electrodes. The establishment of the synergistic interaction between the adsorption model and electronic transfer helps us achieve a high level of selectivity towards the desirable short-chain sodium polysulfides during the practical battery test. These finding indicates that the atomic manganese sites have an enhanced ability to capture and donate electrons. Additionally, the charge transfer process facilitates the rearrangement of sodium ions, thereby accelerating the kinetics of the sodium ions through the electrostatic force. These combined effects improve pathway selectivity and conversion to stable products during the redox process, leading to superior electrochemical performance for room temperature sodium-sulfur batteries.

Electronic Spin Alignment within Homologous NiS2/NiSe2 Heterostructures to Promote Sulfur Redox Kinetics in Lithium-Sulfur Batteries.

The catalytic activation of the Li-S reaction is fundamental to maximize the capacity and stability of Li-S batteries (LSBs). Current research on Li-S catalysts mainly focuses on optimizing the energy levels to promote adsorption and catalytic conversion, while frequently overlooking the electronic spin state influence on charge transfer and orbital interactions. Here, hollow NiS2/NiSe2 heterostructures encapsulated in a nitrogen-doped carbon matrix (NiS2/NiSe2@NC) are synthesized and used as a catalytic additive in sulfur cathodes. The NiS2/NiSe2 heterostructure promotes the spin splitting of the 3d orbital, driving the Ni3+ transformation from low to high spin. This high spin configuration raises the electronic energy level and activates the electronic state. This accelerates the charge transfer and optimizes the adsorption energy, lowering the reaction energy barrier of the polysulfides conversion. Benefiting from these characteristics, LSBs based on NiS2/NiSe2@NC/S cathodes exhibit high initial capacity (1458 mAh·g⁻1 at 0.1C), excellent rate capability (572 mAh·g⁻1 at 5C), and stable cycling with an average capacity decay rate of only 0.025% per cycle at 1C during 500 cycles. Even at high sulfur loadings (6.2 mg·cm⁻2), high initial capacities of 1173 mAh·g⁻1 (7.27 mAh·cm⁻2) are measured at 0.1C, and 1058 mAh·g⁻1 is retained after 300 cycles.

Electrochemical coupling in subnanometer pores/channels for rechargeable batteries.

Subnanometer pores/channels (SNPCs) play crucial roles in regulating electrochemical redox reactions for rechargeable batteries. The delicately designed and tailored porous structure of SNPCs not only provides ample space for ion storage but also facilitates efficient ion diffusion within the electrodes in batteries, which can greatly improve the electrochemical performance. However, due to current technological limitations, it is challenging to synthesize and control the quality, storage, and transport of nanopores at the subnanometer scale, as well as to understand the relationship between SNPCs and performances. In this review, we systematically classify and summarize materials with SNPCs from a structural perspective, dividing them into one-dimensional (1D) SNPCs, two-dimensional (2D) SNPCs, and three-dimensional (3D) SNPCs. We also unveil the unique physicochemical properties of SNPCs and analyse electrochemical couplings in SNPCs for rechargeable batteries, including cathodes, anodes, electrolytes, and functional materials. Finally, we discuss the challenges that SNPCs may face in electrochemical reactions in batteries and propose future research directions.

Association of genetic variation on X chromosome with systemic lupus erythematosus in both Thai and Chinese populations.

OBJECTIVES: X chromosome has been considered as a risk factor for SLE, which is a prototype of autoimmune diseases with a significant sex difference (female:male ratio is around 9:1). Our study aimed at exploring the association of genetic variants in X chromosome and investigating the influence of trisomy X in the development of SLE. METHODS: X chromosome-wide association studies were conducted using data from both Thai (835 patients with SLE and 2995 controls) and Chinese populations (1604 patients with SLE and 3324 controls). Association analyses were performed separately in females and males, followed by a meta-analysis of the sex-specific results. In addition, the dosage of X chromosome in females with SLE were also examined. RESULTS: Our analyses replicated the association of TMEM187-IRAK1-MECP2, TLR7, PRPS2 and GPR173 loci with SLE. We also identified two loci suggestively associated with SLE. In addition, making use of the difference in linkage disequilibrium between Thai and Chinese populations, a synonymous variant in TMEM187 was prioritised as a likely causal variant. This variant located in an active enhancer of immune-related cells, with the risk allele associated with decreased expression level of TMEM187. More importantly, we identified trisomy X (47,XXX) in 5 of 2231 (0.22%) females with SLE. The frequency is significantly higher than that found in the female controls (0.08%; two-sided exact binomial test P=0.002). CONCLUSION: Our study confirmed previous SLE associations in X chromosome, and identified two loci suggestively associated with SLE. More importantly, our study indicated a higher risk of SLE for females with trisomy X.

Boron nanosheets as a phosphatase mimicking nanozyme with ultrahigh catalytic activity for prodrug-based cancer therapy.

Boron nanosheets (BNSs) are reported as a new phosphatase mimicking nanozyme. Surprisingly, the catalytic rate of BNSs is up to 17 times those of known phosphatase mimicking nanozymes. By adding polyols and Lewis bases, the catalytic activity of BNSs was attributed to the Lewis acidity of the B centers of the BNSs. Theoretical investigation shows that the B centers are responsible for the catalytic hydrolysis of phosphoesters. Moreover, the biomimetic activity of the BNSs was further explored for enhancing anticancer therapy through nanozyme-catalyzed prodrug conversion.

Linearly Interlinked Fe-Nx -Fe Single Atoms Catalyze High-Rate Sodium-Sulfur Batteries.

Linearly interlinked single atoms offer unprecedented physiochemical properties, but their synthesis for practical applications still poses significant challenges. Herein, linearly interlinked iron single-atom catalysts that are loaded onto interconnected carbon channels as cathodic sulfur hosts for room-temperature sodium-sulfur batteries are presented. The interlinked iron single-atom exhibits unique metallic iron bonds that facilitate the transfer of electrons to the sulfur cathode, thereby accelerating the reaction kinetics. Additionally, the columnated and interlinked carbon channels ensure rapid Na+ diffusion kinetics to support high-rate battery reactions. By combining the iron atomic chains and the topological carbon channels, the resulting sulfur cathodes demonstrate effective high-rate conversion performance while maintaining excellent stability. Remarkably, even after 5000 cycles at a current density of 10 A g-1 , the Na-S battery retains a capacity of 325 mAh g-1 . This work can open a new avenue in the design of catalysts and carbon ionic channels, paving the way to achieve sustainable and high-performance energy devices.

Transcriptomic Features of systemic lupus erythematosus Patients in Flare and Changes during Acute In-Hospital Treatment.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with varying symptoms and multi-organ damage. Relapse-remission cycles often persist for many patients for years with the current treatment. Improved understanding of molecular changes caused by SLE flare and intensive treatment may result in more targeted therapies. METHODS: RNA-sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 65 SLE patients in flare, collected both before (SLE1) and after (SLE2) in-hospital treatment, along with 15 healthy controls (HC). Differentially expressed genes (DEGs) were identified among the three groups. Enriched functions and key molecular signatures of the DEGs were analyzed and scored to elucidate the transcriptomic changes during treatment. RESULTS: Few upregulated genes in SLE1 vs HC were affected by treatment (SLE2 vs SLE1), mostly functional in interferon signalling (IFN), plasmablasts, and neutrophils. IFN and plasmablast signatures were repressed, but the neutrophil signature remained unchanged or enhanced by treatment. The IFN and neutrophil scores together stratified the SLE samples. IFN scores correlated well with leukopenia, while neutrophil scores reflected relative cell compositions but not cell counts. CONCLUSIONS: In-hospital treatment significantly relieved SLE symptoms with expression changes of a small subset of genes. Notably, IFN signature changes matched SLE flare and improvement, while enhanced neutrophil signature upon treatment suggested the involvement of low-density granulocytes (LDG) in disease development.

Biomechanical Analysis of Titanium Dental Implants in the All-on-4 Treatment with Different Implant-Abutment Connections: A Three-Dimensional Finite Element Study.

The type of implant-abutment connection is one of the factors influencing the distribution of occlusal forces. This study aims to investigate the biomechanical performance of the mandibular all-on-4 treatment with different implant-abutment connections. Two connection types with 30° abutments and 18-mm implant fixtures were chosen for the posterior implants of the all-on-4 assembly. For the external hexagon connection (EHC) group, the implants with 4 mm in diameter were used. For the internal hexagon connection (IHC) group, we selected implants with 4.3 mm in diameter. A vertical force of 190 N was applied to the cantilever region. The FEA results indicated that the most stressed region in the two groups was prosthetic screws, followed by multi-unit abutments (MUAs). The lowest values of von Mises stress were both observed on the bone. The peak stress value of the implant screw and implant fixture in the EHC group were 37.75% and 33.03% lower than the IHC group, respectively. For stress distribution patterns, the load force tended to be concentrated at locations where components were interconnected. The EHC and IHC are clinically durable under the tested loading conditions, but the prosthetic screws and MUAs can be the weak point on the posterior implant within the mandibular all-on-four assembly. The peak stress values of implant screw and implant fixture in the EHC groups were lower than the IHC group.

Membrane vesicles derived from Listeria monocytogenes might be a potential antigen delivery vector.

Membrane vesicles (MVs) derived from Listeria monocytogenes (LM) have a natural nanoscale size and contain a variety of bacterial components. We speculated that LM MVs may be a novel delivery vector, but it is necessary to evaluate the safety and immunogenicity of LM MVs in vivo. Here, we isolated LM MVs and tested their safety and immunogenicity both in vitro and in vivo. The results showed that LM MVs stimulated RAW264.7 cells and DC2.4 cells to secrete the inflammatory cytokines IL-1ß, TNF-α, IL-6 and IL-10. Intraperitoneal injection of LM MVs at 80 µg per C57BL/6 mouse did not cause lethal effects or irreversible pathological changes in major organs, indicating that LM MVs were safe. Intraperitoneal immunization of C57BL/6 mice twice with LM MVs mainly induced a high level of LM MV-specific IgG antibodies. In addition, we subcutaneously injected C57BL/6 mice with a mixture of ovalbumin and LM MVs and found that LM MVs exhibited a humoral immune adjuvant effect equal to that of the same amount of alum. The results of this study indicated that LM MVs have good safety and effective immunogenicity and may act as humoral immune adjuvants. Therefore, LM MVs are a potential new choice for antigen and drug delivery vectors.

Ratiometric fluorescent detection of total phosphates in frozen shrimp samples using catalytic active Zr(IV) modified gold nanoclusters.

Phosphate salts are important food additives in a variety of foods. In this study, the Zr(IV) modified gold nanoclusters (Au NCs) were prepared for ratiometric fluorescent sensing of phosphate additives in seafood samples. Compared with bare Au NCs, the synthesized Zr(IV)/Au NCs showed stronger orange fluorescence at 610 nm. On the other hand, the Zr(IV)/Au NCs retained the phosphatase-like activity of Zr(IV) ions and could catalyze the hydrolysis of fluorescent substrate 4-methylumbelliferyl phosphate to produce blue emission at 450 nm. The addition of phosphate salts could effectively inhibit the catalytic activity of Zr(IV)/Au NCs, resulting the fluorescence decrease at 450 nm. However, the fluorescence at 610 nm almost unchanged upon the addition of phosphates. Based on this finding, the ratiometric detection of phosphates using the fluorescence intensity ratio (I450/I610) was demonstrated. The method has been further applied for sensing total phosphates in frozen shrimp samples with satisfactory results.

In-Hover Aerodynamic Analysis of a Small Rotor with a Thin Circular-Arc Airfoil and a Convex Structure at Low Reynolds Number.

This study focused on the in-hover aerodynamics of a small rotor with a thin circular-arc airfoil and a convex structure at a low Reynolds number. The method combined computational fluid dynamics (CFD) with the blade element momentum theory (BEMT). The former was used for studying the two-dimensional parametric aerodynamics of the airfoil at a low Reynolds number and the latter was used for the prediction of the rotor's hover performance. A novel thin circular-arc airfoil with a convex structure with a high aerodynamic performance, high structural strength, light weight and easy manufacturing process is presented in this paper. A convex curve on the upper surface was adopted to increase the thickness of the airfoil at partial chord, and a stiffener in the airfoil was installed to improve the structural strength of rotor span-wise. The aerodynamic performance of the airfoil was numerically simulated by the two-dimensional steady and incompressible Navier-Stokes equations. The in-hover performance of the rotor for small-scale vehicles was predicted by an improved version of the blade element momentum theory (BEMT). Finally, a carbon-fiber rotor with the presented airfoil was manufactured that had a diameter of 40 cm and a pitch of 6.2 inches. The analysis results were verified by experiments. It was shown that the maximum calculation errors were below 6%. The improved BEMT can be used in the analysis of in-hover micro-rotor aerodynamics at low Reynolds numbers.

Study on the effect of additives on microbial diversity, predicted functional profiles, and fermentation quality of Broussonetia papyrifera and Pennisetum sinese mixed ensilage in the karst region.

In this research, we evaluated the effect of exogenous lactic acid bacteria and Amomum villosum essential oil (AVEO) on the chemical composition, microbial community composition, microbial functional diversity, and fermentation quality of Broussonetia papyrifera (BP) and Pennisetum sinese (PS) mixed silages. The BP:PS mixing ratios were 100:0, 70:30, 50:50, 30:70, and 0:100. After 3 and 30 days of ensiling at 22°C-25°C, microbial diversity and function, and fermentation quality, were assessed. Increasing PS content resulted in decreased ammoniacal nitrogen and pH, increased water-soluble carbohydrate content, increased relative abundance of Lactococcus and Acinetobacter, and reduced relative abundance of Caproiciproducens and Pseudomonas. A 50:50 BP:PS ratio effectively improved the fermentation quality compared to anaerobic fermentation with BP or PS alone, while AVEO treatment further improved fermentation quality by increasing Lactococcus relative abundance. Moreover, as fermentation proceeded, ensiling enhanced the 'Human diseases', 'Environmental information processing', and 'Cellular processes' functions at the first level, as well as the 'Two-component system' and 'ABC transporters' functions at the third level. Different additives affected the fermentation of BP and PS mixed silage by regulating microbial community succession and metabolic pathways during ensiling.

Bacterial outer membrane vesicle based versatile nanosystem boosts the efferocytosis blockade triggered tumor-specific immunity.

Efferocytosis inhibition is emerging as an attractive strategy for antitumor immune therapy because of the subsequent leak of abundant immunogenic contents. However, the practical efficacy is seriously impeded by the immunosuppressive tumor microenvironments. Here, we construct a versatile nanosystem that can not only inhibit the efferocytosis but also boost the following antitumor immunity. MerTK inhibitor UNC2025 is loaded into the bacterial outer membrane vesicles (OMVs), which are then modified with maleimide (mU@OMVs). The prepared mU@OMVs effectively inhibits the efferocytosis by promoting the uptake while preventing the MerTK phosphorylation of tumor associated macrophages, and then captures the released antigens through forming universal thioether bonds. The obtained in situ vaccine effectively transfers to lymph nodes by virtue of the intrinsic features of OMVs, and then provokes intense immune responses that can efficiently prevent the growth, metastasis and recurrence of tumors in mice, providing a generalizable strategy for cancer immunotherapy.

Fermentation quality, bacterial community, and predicted functional profiles in silage prepared with alfalfa, perennial ryegrass and their mixture in the karst region.

There is little information regarding the dynamics of fermentation products and the bacterial community in silage prepared with alfalfa (MS), perennial ryegrass (LP), and their mixture in the karst region. In this study, we explored the effects of combining MS with LP in different ratios (100% MS, 70% MS + 30% LP, 50% MS + 50% LP, 30% MS + 70% LP and 100% LP; fresh matter basis) on silage chemical composition, fermentation quality, bacterial communities and predicted functions during the ensiling process. Each treatment was prepared in triplicate and stored at room temperature (22-25°C) for 7, 15, and 45 days. The dry matter (DM) and water-soluble carbohydrate content of the silages increased as the LP proportion in the mixed silage increased; at 45 days, the 70% MS + 30% LP, 50% MS + 50% LP and 30% MS + 70% LP silages contained higher (p < 0.05) CP content than the 100% MS and 100% LP silages. The 30% MS + 70% LP and 100% LP silages exhibited lower (p < 0.05) pH and higher (p < 0.05) LA content than the other silages; at 45 days, none of the silages contained PA or BA. As fermentation proceeded, the abundance of harmful (Enterobacteriaceae and Sphingomonas) and beneficial (Lentilactobacillus, Lactiplantibacillus, Secundilactobacillus, and Levilactobacillus) microorganisms decreased and increased, respectively, as the LP proportion in the mixed silage increased. The predicted functional distribution of microbial communities and metabolic pathways revealed that the 30% MS + 70% LP and 100% LP silages had a stronger capacity for fermentation and a weaker capacity for nitrate reduction than the other silages. Moreover, as the fermentation proceeded, the 30% MS + 70% LP and 100% LP treatments enhanced the functions of "Metabolism," "Genetic information processing" and "Organismal systems" at level 1, the functions of "Amino acid metabolism" and "Nucleotide metabolism" at level 2, and the functions of "Metabolic pathways," "Biosynthesis of secondary metabolites," "Biosynthesis of antibiotics" and "Purine metabolism" at level 3. Thus, adding LP could improve the fermentation quality of MS silage by changing the composition and metabolic function of microbes; furthermore, ensiling 30% alfalfa with 70% ryegrass can produce high-quality silage in the karst region.

A Listeria ivanovii balanced-lethal system may be a promising antigen carrier for vaccine construction.

Expressing heterologous antigens by plasmids may cause antibiotic resistance. Additionally, antigen expression via plasmids is unstable due to the loss of the plasmid. Here, we developed a balanced-lethal system. The Listeria monocytogenes (LM) balanced-lethal system has been previously used as an antigen carrier to induce cellular immune response. However, thus far, there has been no reports on Listeria ivanovii (LI) balanced-lethal systems. The dal and dat genes from the LI-attenuated LIΔatcAplcB (LIΔ) were deleted consecutively, resulting in a nutrient-deficient LIΔdd strain. Subsequently, an antibiotic resistance-free plasmid carrying the LM dal gene was transformed into the nutrient-deficient strain to generate the LI balanced-lethal system LIΔdd:dal. The resultant bacterial strain retains the ability to proliferate in phagocytic cells, as well as the ability to adhere and invade hepatocytes. Its genetic composition was stable, and compared to the parent strain, the balanced-lethal system was substantially attenuated. In addition, LIΔdd:dal induced specific CD4+ /CD8+ T-cell responses and protected mice against LIΔ challenge. Similarly, we constructed an LM balanced-lethal system LMΔdd:dal. Sequential immunization with different recombinant Listeria strains will significantly enhance the immunotherapeutic effect. Thus, LIΔdd:dal combined with LMΔdd:dal, or with other balanced-lethal systems will be more promising alternative for vaccine development.

Phase Transition between Crystalline Variants of Ordinary Ice.

Water is one of the most abundant molecules on Earth. However, this common and "simple" material has more than 18 different phases, which poses a great challenge to theoretically study the nature of water and ice. We designed two reaction coordinates that can distinguish between water and various ice states and used them to efficiently sample all possible states of the system in all-atom molecular dynamics simulation at ambient temperature and pressure. Various structural and thermodynamics properties, including the water-ice phase diagrams, can thus be calculated. We also present a simple model that successfully explains the thermodynamic stability of different ice states. Our work provides effective methods and data for theoretical studies of different phases of water and ice.

Locating Transition Zone in Phase Space.

Understanding the reaction mechanism is required for better control of chemical reactions and is usually achieved by locating transition states (TSs) along a proper one-dimensional coordinate called reaction coordinate (RC). The identification of RC can be very difficult for high-dimensional realistic systems. A number of methods have been proposed to tackle this problem. A machine learning method is developed here to incorporate the influence of velocity on the reaction process. The method is also free of the unbalanced label problem resulting from the rather low fraction of configurations near the TS and can be easily extended to large systems. It locates the transition zone in the phase space and defines the dividing surface with a high transmission coefficient. Moreover, considering that the reaction environment can not only change the reaction path but also activate the reactive mode through energy transfer, we devise two measures to quantify the influence of these two factors on the reaction process and find that solvents can assist the reaction by directly doing work along the reactive mode. Not surprisingly, there is a positive correlation between the efficiency of energy transfer into the reactive mode and the reaction rate.