Portion Of Chain Research Articles

Coordinating the Reverse Factoring System: Buying Back and Bargaining

Reverse factoring is a retailer-led supply chain financing system that can enhance liquidity of suppliers and reduce factoring fraud. This paper proposes a bargaining game theory model to analyze the profit distribution in reverse factoring for a two-echelon supply chain system that comprises a core retailer and a capital-constrained supplier. By taking into account the retailer’s credit loss risk, the impact of buying back and bargaining is investigated. Our study shows that in reverse factoring without buying back, the supplier would rather not bargain but the retailer would like to negotiate the wholesale price if the supplier’s bargaining power is low. If buying back exists and the supplier’s bargaining power is low, the retailer is also willing to negotiate the wholesale price. If there is no bargaining but the supplier takes a large portion of the supply chain’s profit, buying back is preferred. Furthermore, when there is bargaining on the wholesale price, both supplier and retailer can benefit from buying back. In addition, bargaining on the buy-back price in reverse factoring is bargaining-proof. Our study first contributes to the growing body of literature on reverse factoring and bargaining game theory. Two managerial implications for reverse factoring also emerge from the study. We find that bargaining should be considered if the supplier tends to coordinate the supply chain financing system by buying back the retailer’s unsold products. In addition, both supplier and retailer should negotiate the wholesale price as they cannot benefit from bargaining on the buy-back price.

Evaluation of intermodal transport chain: Case of importing tires through a China-Balkans routes

Within the context of global trade, logistics chains face the complex task of bridging significant geographic distances while simultaneously striving to increase their efficiency and sustainability. A significant portion of global logistics chains relies on maritime transport in the initial phase, followed by road, rail, or river transport in the subsequent continental phase. Road transport, however, is associated with various ecological and operational drawbacks. In contrast, intermodal transport (IT) provides an efficient solution by integrating multiple modes of transportation. The key challenge of IT applications remains the determination of the best combination of transport modes, technologies, and routes. Consequently, this paper aims to identify the most favorable alternative to the intermodal transport chain (ITC) for the import of tires from China to Bosnia and Herzegovina (B&H). Since selecting the most favorable alternative to the ITC requires an analysis of conflicting objectives and criteria, the use of multi-criteria decision-making (MCDM) becomes essential in addressing this challenge. The paper presents a new MCDM model that combines the fuzzy DELPHI analytical hierarchy process (fuzzy DAHP) and the fuzzy Axial-Distance-based Aggregated Measurement (fuzzy ADAM) methods. The applicability and effectiveness of the model were demonstrated and confirmed by a case study. The results indicate that the best variants are those that combine maritime, rail, and road transportation through the Port of Koper (with a ranking value of 0.339) and Rijeka (0.289), followed by the variants that combine maritime and road transportation through the same ports (0.241 and 0.222, respectively). The rest of the variants have significantly lower performances.

Diagnostic Utility of Copeptin in Pediatric Patients with Polyuria-Polydipsia Syndrome: A Systematic Review and Meta-Analysis.

Pediatric patients with polyuria polydipsia syndrome (PPS) represent a diagnostic challenge for clinicians because of the technical difficulties in performing the gold standard water deprivation test (WDT). Copeptin, a stable biomarker representing the C-terminal portion of the polypeptide chain of the antidiuretic hormone, is a reliable diagnostic tool. To assess the diagnostic accuracy of baseline copeptin dosing, arginine/hypertonic saline copeptin stimulation tests, and WDT. This study aimed to establish the diagnostic utility of copeptin in pediatric patients by distinguishing between central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia. Comparative and non-comparative primary studies published between January 2018 and August 2024 focusing on children were searched and included in PubMed, Cochrane Library, Web of Science, ScienceDirect, Scopus, and Google Scholar. The QUADAS-2 tool was used to assess the risk of bias and applicability. Meta-analyses used fixed effects models because of low heterogeneity and the HSROC model. Eleven studies were included with an overall low bias and no significant applicability concerns. The mean pooled sensitivity = 0.98 (95% CI: 0.936-1.025), pooled specificity = 0.947 (95% CI: 0.920-0.973), and AUC = 0.972 (95% CI: 0.952-0.992), indicating excellent diagnostic accuracy. Stimulation methods for copeptin dosing represent an effective and less invasive diagnostic test for children with PPS, and future development of standard copeptin testing protocols is needed.

Crystal structure and enzyme engineering of the broad substrate spectrum l-amino acid oxidase 4 from the fungus Hebeloma cylindrosporum.

l-Amino acid oxidases (LAAOs) catalyze the oxidative deamination of l-amino acids to α-keto acids. Recombinant production of LAAOs with broad substrate spectrum remains a formidable challenge. We previously achieved this for the highly active and thermostable LAAO4 of Hebeloma cylindrosporum (HcLAAO4). Here, we crystallized a proteolytically truncated surface entropy reduction variant of HcLAAO4 and solved its structure in substrate-free form and in complex with diverse substrates. The ability to support the aliphatic portion of a substrate's side chain by an overall hydrophobic active site is responsible for the broad substrate spectrum of HcLAAO4, including l-amino acids with big aromatic, acidic and basic side chains. Based on the structural findings, we generated an E288H variant with increased activity toward pharmaceutical building blocks of high interest.

Resveratrol is converted to the ring portion of coenzyme Q10 and raises intracellular coenzyme Q10 levels in HepG2 cell.

Coenzyme Q10 is an essential lipid in the mitochondrial electron transport system and an important antioxidant. It declines with age and in various diseases, there is a need for a method to compensate for the decrease in coenzyme Q10. Resveratrol, a well-known anti-aging compound, has been shown to undergo metabolism to coenzyme Q10's benzene ring moiety in cells. However, administration of resveratrol did not alter or only slightly increased total intracellular coenzyme Q10 levels in many cell types. Synthesis of coenzyme Q10 requires not only the benzene ring moiety but also the side chain moiety. Biosynthesis of the side chain portion of coenzyme Q10 is mediated by the mevalonic acid pathway. Here, we explore the impact of resveratrol on coenzyme Q10 levels in HepG2 cells, which possess a robust mevalonic acid pathway. As a results, intracellular coenzyme Q10 levels were increased by resveratrol administration. Analysis using 13C6-resveratrol revealed that the benzene ring portion of resveratrol was converted to coenzyme Q10. Inhibition of the mevalonic acid pathway prevented the increase in coenzyme Q10 levels induced by resveratrol administration. These results indicate that resveratrol may be beneficial as a coenzyme Q10-enhancing reagent in cells with a well-developed mevalonic acid pathway.

Comparative characterisation of structural, physicochemical and digestive properties of rice starches isolated from novel high‐amylose mutants

SummaryNovel high‐amylose rice mutants with unique starch properties were developed from a low‐amylose rice variety. The objective of this study was to explore the impacts of apparent amylose content and amylopectin structure on the physical and nutritional properties of rice starch by comparing novel mutants with conventional rice varieties. The rice mutants demonstrated a specific amylopectin characteristic, indicating an extremely lower portion of short chains (15.2%–16.5%) than the other rice varieties (27.3%–31.1%). The starch gel prepared from the rice mutant exhibited significantly higher compressive and breaking stress than the other high‐amylose rice variety with a higher apparent amylose content, indicating that amylopectin characteristics markedly influenced the starch gel structure. The rice mutant demonstrated the highest content of undigested starch after 120 min of digestion in raw starch (50.5%) and starch gel (53.0%). The starch from newly developed rice mutants were found to have markedly high resistance to digestion due to its amylopectin structure and formation of harder gel.

Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery.

MbtI from Mycobacterium tuberculosis (Mtb) is a Mg2+-dependent salicylate synthase, belonging to the chorismate-utilizing enzyme (CUE) family. As a fundamental player in iron acquisition, MbtI promotes the survival and pathogenicity of Mtb in the infected host. Hence, it has emerged in the last decade as an innovative, potential target for the anti-virulence therapy of tuberculosis. In this context, 5-phenylfuran-2-carboxylic acids have been identified as potent MbtI inhibitors. The first co-crystal structure of MbtI in complex with a member of this class was described in 2020, showing the enzyme adopting an open configuration. Due to the high mobility of the loop adjacent to the binding pocket, large portions of the amino acid chain were not defined in the electron density map, hindering computational efforts aimed at structure-driven ligand optimization. Herein, we report a new, high-resolution co-crystal structure of MbtI with a furan-based derivative, in which the closed configuration of the enzyme allowed tracing the entirety of the active site pocket in the presence of the bound inhibitor. Moreover, we describe a new crystal structure of MbtI in open conformation and in complex with the known inhibitor methyl-AMT, suggesting that in vitro potency is not related to the observed enzyme conformation. These findings will prove fundamental to enhance the potency of this series via rational structure-based drug-design approaches.

Dissipative Particle Dynamics Simulation for the Self-Assembly of Symmetric Pentablock Terpolymers Melts under 1D Confinements.

The phase behavior of CBABC pentablock terpolymers confined in thin films is investigated using the Dissipative Particle Dynamic method. Phase diagrams are constructed and used to reveal how chain length (i-block length), block composition and wall selectivity influence the self-assembly structures. Under neutral walls, four categories of morphologies, i.e., perpendicular lamellae, core-shell types of microstructures, complex networks, and half-domain morphologies, are identified with the change in i-block length. Ordered structures are more common at weak polymer-polymer interaction strengths. For polymers of a consistent chain length, when one of the three components has a relatively smaller length, the morphologies transition is sensitive to block composition. With selective walls, parallel lamellae structures are prevalent. Wall selectivity also impacts chain conformations. While a large portion of chains form loop conformations under A-selective walls, more chains adopt bridge conformation when the wall prefers C-blocks. These findings offer insights for designing nanopatterns using symmetric pentablock terpolymers.

Molecular Simulations of Controlled Polymer Crystallization in Polyethylene.

Multilamella polymer crystals are grown from the melt for the first time, in molecular dynamics simulations of a united-monomer model, with in excess of 1500000 united-monomers. Two-component systems comprised of equal weight fractions of 2000 united-monomer long chains and 200 united-monomer short chains are considered, with varying numbers of short butyl branches placed along the long chains. Utilizing two different cooling protocols, continuous-cooling and self-seeding, drastically different multilamella structures are revealed, which depend heavily on the branch content and crystallization protocol used. By self-seeding, well-aligned multilamella crystals are grown, which more clearly reveal the subtle alterations an increasing number of branches create on the size and shape of the crystallites in the early stages of spherulite formation. Under continuous cooling, this observation is almost completely obscured. At maximum thickness, chain portions as long as 100 united-monomers (200 carbons) are extended inside the crystalline lamella.

A blockchain‐based framework to optimize shipping container flows in the hinterland

AbstractWe address two interrelated issues affecting the hinterland portion of the maritime container supply chain: reducing the movement of empty containers and reducing empty trips by trucks carrying these containers. In this paper, we show that empty container flow optimization can be implemented via a blockchain based on the proof‐of‐useful‐work concept where the proof of work requires the solution of an ‐hard optimization problem whose solution benefits the blockchain participants. Accordingly, we propose that anonymous miners compete to solve the container truck routing problem, which seeks to find the most efficient routes for trucks. We show that this problem is ‐hard. Miners must also solve the problem of optimally matching consignees and shippers, which will reduce transportation and storage costs for empty containers. In essence, the proposed framework turns blockchain into a massive optimization engine that directly benefits the hinterland container supply chain ecosystem.

Amyloidogenic and non-amyloidogenic molten globule conformation of β-lactoglobulin in self-crowded regime

Molecular insights on the β-lactoglobulin thermal unfolding and aggregation are derived from FTIR and UV Resonance Raman (UVRR) investigations. We propose an in situ and in real-time approach that thanks to the identification of specific spectroscopic markers can distinguish the two different unfolding pathways pursued by β-lactoglobulin during the conformational transition from the folded to the molten globule state, as triggered by the pH conditions. For both the investigated pH values (1.4 and 7.5) the greatest conformational variation of β-lactoglobulin occurs at 80 °C and a high degree of structural reversibility after cooling is observed. In acidic condition β-lactoglobulin exposes to the solvent its hydrophobic moieties in a much higher extent than in neutral solution, resulting on a highly open conformation. Moving from the diluted to the self-crowded regime, the solution pH and consequently the different molten globule conformation select the amyloid or non-amyloid aggregation pathway. At acidic condition the amyloid aggregates form during the heating cycle leading to the formation of transparent hydrogel. On the contrary, in neutral condition the amyloid aggregates never form. Information on the secondary structure conformational change of β-lactoglobulin and the formation of amyloid aggregates are obtained by FTIR spectroscopy and are related to the information of the structural changes localized around the aromatic amino acid sites by UVRR technique. Our results highlight a strong involvement of the chain portions where tryptophan is located on the formation of amyloid aggregates.

The HH 24 Complex: Jets, Multiple Star Formation, and Orphaned Protostars

The HH 24 complex harbors five collimated jets emanating from a small protostellar multiple system. We have carried out a multiwavelength study of the jets, their driving sources, and the cloud core hosting the embedded stellar system, based on data from the Hubble Space Telescope, Gemini, Subaru, Apache Point Observatory 3.5 m, Karl G. Jansky Very Large Array, and Atacama Large Millimeter/submillimeter Array (ALMA) telescopes. The data show that the multiple system, SSV 63, contains at least 7 sources, ranging in mass from the hydrogen-burning limit to proto-Herbig Ae stars. The stars are in an unstable nonhierarchical configuration, and one member, a borderline brown dwarf, is moving away from the protostellar system with 25 km s−1, after being ejected ∼5800 yr ago as an orphaned protostar. Five of the embedded sources are surrounded by small, possibly truncated, disks resolved at 1.3 mm with ALMA. Proper motions and radial velocities imply jet speeds of 200–300 km s−1. The two main HH 24 jets, E and C, form a bipolar jet system that traces the innermost portions of parsec-scale chains of Herbig–Haro and H2 shocks with a total extent of at least 3 pc. H2CO and C18O observations show that the core has been churned and continuously fed by an infalling streamer. 13CO and 12CO trace compact, low-velocity, cavity walls carved by the jets and an ultracompact molecular outflow from the most embedded object. Chaotic N-body dynamics likely will eject several more of these objects. The ejection of stars from their feeding zones sets their masses. Dynamical decay of nonhierarchical systems can thus be a major contributor to establishing the initial mass function.

Use the Value Chain Analysis to Improve the Quality of Health Service

Quality is currently one of the most important strategies adopted by WHO in to gain time to please and deal with the client for the greatest possible benefit to auditors, In health service, quality and value have become convergent ideas, and the importance of patients as clients has grown as a result of a focus on quality management and value delivery.The supply chain idea also aids marketing by showcasing the ties that make up a network of firms that manufacture products for customers, as well as shifting the attention away from individual transactions and toward a more holistic view of the entire system. The value chain idea in marketing broadens the perception of the supply chain in a significant way. It describes the value created at each level of the chain and, for marketers, is a critical tool in satisfying customers for a portion of the value chain. This research looks at numerous value approaches that are critical for the value chain's success, then identifies key aspects of the value chain and follows them as they relate to services. Finally, it looks at one of the most complicated services, the health services system. Finally, the research reveals some crucial implications for health-service marketers by evaluating the critical aspects determining the performance of the health-service process.

Recapitulating protein vectorial appearance enhances folding to the native structure in vitro.

In the cell, protein folding starts vectorially, in a specific direction determined by protein synthesis (N- to C-terminus) or secretion (either N- to C- or C- to N-terminus, depending on the secretion mechanism). In contrast, during a typical in vitro protein refolding experiment, the abrupt removal of a chemical denaturant enables refolding to begin with interactions formed between any portions of a full-length polypeptide chain. The vectorial appearance of the polypeptide chain enables proteins to begin folding by exploring a simple energy landscape that increases in size and complexity as the amino acid chain lengthens. However, currently little is known regarding the impact of vectorial folding on protein folding kinetics and/or aggregation avoidance, in part because no simple method exists to test the impact of vectorial appearance on protein folding mechanisms in vitro. In this study, we adapted the ring-shaped AAA+ translocase ClpX to create an experimental platform with which to study vectorial protein folding in vitro. Crucially, translocation through the central nanometer-sized pore of ClpX enables us to recapitulate vectorial appearance of polypeptide chains from either N- to C- or C- to N-terminus. We used this approach to study the impact of vectorial folding of three diverse fluorescent proteins. Whereas these proteins are highly prone to misfolding and aggregation under traditional in vitro refolding conditions, initiating folding by translocation through ClpX led to robust folding to the native structure. We are currently adapting this assay to study the impact of vectorial chain appearance on protein folding mechanisms.

FRET-Mediated Collective Blinking of Self-Assembled Stacks of CdSe Semiconducting Nanoplatelets

Förster resonant energy transfer (FRET) can be an efficient energy transfer mechanism between densely packed fluorescent emitters. It plays a key role in photosynthesis but may also be detrimental. In optoelectronic devices for instance, FRET funnels energy to quenching sites and favors losses. Here, we image individual self-assembled chains of stacked CdSe nanoplatelets and demonstrate fluorescence intermittency (blinking) of chain portions corresponding to a few tens of platelets. This collective blinking is attributed to the fluctuations of a quencher site, to which excitons are transferred by FRET migration from the surrounding platelets. We develop an analytical random walk model of the chain and show that an ensemble of platelets can be quenched collectively by a single site provided that its quenching (nonradiative recombination) rate is faster than the geometric mean of the radiative recombination rate and the transfer rate, which for self-assembled platelets would be of the order of (100 ps)−1.

Medicinal plants as a cellulose source for the fabrication of poly(lactic acid) composites: A mini-review

More recently, natural polymers produced by living organisms have received considerable attention due to their unique properties such as eco-friendliness, biodegradability, and biocompatibility. These polymers possess similar properties to conventional plastics, making them suitable potential plastic substitutes for sustainable development and conservation of finite oil resources. Poly(lactic acid) (PLA) is comparable to commonly used plastics but is inferior, thus limited applications. However, PLA can benefit from the incorporation of various polymer components with complementary properties to yield improved physical properties. The fabrication of fully bio-based nanocomposites such as that of PLA and cellulose is of particular interest to research scientists. Incorporating organic fillers such as nanocellulose in a PLA matrix gives rise to improved composite properties. Because plant cell walls comprise semicrystalline cellulose molecules embedded in matrices, the crystalline portion of the stiff chains extracted from medicinal plants is currently exploited for potential filler roles. In this review, the use of medicinal plants in bio-based composite applications is covered. Several medicinal plants as sources of cellulose, different cellulose extraction methods, as well as the resulting fiber properties, are discussed. Although tremendous progress has been made in developing biocomposites, a lot of research still needs to be carried out.

New insights on Pseudomonas aeruginosa exotoxin A-based immunotoxins in targeted cancer therapeutic delivery.

Pseudomonas aeruginosa exotoxin A-based immunotoxins (PE-ITs) are fusion proteins that harness targeting and toxin moieties. Structural optimizations in PE and targeting moieties were implemented to lower their immunogenicity and alleviate undesirable side effects. PE moiety was engineered to lack its cell-binding domain and T cell epitope regions, whereas single chain (scFv) and disulfide Fv portions (dsFv), nanobodies, and monobodies were utilized as targeting moieties. This review discusses applications of PE-ITs on different types of cancer, structural optimizations to reduce PE-ITs drawbacks, and recent modifications applied for efficient therapeutic delivery. Finally, we draw attention to the possibility of combining radiotherapy, radionuclides, and RGDs with PE-IT to improve overall response rates of IT-based treatments and reduce cancer cell resistance.

Detecting temperature breaks in the initial stages of the citrus export cold chain: A case study

Background: Fruit is an important export commodity for South Africa and accounts for 35% of its agricultural exports. South Africa is the second largest citrus exporter in the world, behind Spain. Maintaining the postharvest cold chain is key to ensuring that fruit quality meets export standards.Objectives: The main objectives of this research were to investigate the frequency, location, magnitude and duration of temperature deviations in the South African leg of the clementine and navel orange cold chain.Method: Temperature trials were conducted on two consignments of clementines and two consignments of navels. Each consignment contained 36 iButtons®, of which 18 measured pulp temperature and 18 measured ambient temperature. Data were successfully retrieved from 130 of the 144 iButtons®.Results: This research identified areas where the temperature went outside the prescribed range along the South African portion of the export cold chain of navel oranges and clementines from Citrusdal, South Africa to the Port of Newark, United States of America.Conclusion: The temperature incidents identified could result in a breach of the cold sterilisation (steri) protocols and quality defects. Recommendations were made to address these deficiencies to improve the South African citrus industry’s global competitiveness.Contribution: This research allowed the citrus industry to investigate and adjust current cold chain practices to improve the integrity of the entire export cold chain, potentially resulting in a higher quality product and increased revenue.

Verification of nanoparticle formation, skin permeation, and apoptosis using nobiletin as a methoxyflavonoid derivative

PurposeNobiletin (NOB), a polymethoxyflavonoid, is known for its antioxidant and anti-inflammatory effects and has antitumor activity. However, its poor solubility and low bioavailability pose a significant challenge in its delivery. In this experiment, NOB was added to Soluplus® (Sol)/l-ascorbyl 2,6-dipalmitate (ASC-DP) as a ternary system, and Sol/ASC-DP/NOB nanoparticles were obtained using the hydration method. The purpose of this study was to enhance the solubility of NOB, apply it for skin permeation, and improve antitumor activity.MethodsThe preparation of Sol/ASC-DP/NOB nanoparticles was attempted using the hydration method, and particle size, zeta potential, and stability tests were performed to evaluate the formation of nanoparticles. 1H-1H NOESY/ROESY NMR spectral measurements were also performed to identify molecular interaction between NOB and Sol/ASC-DP. To evaluate its functionality, DPPH radical scavenging, skin permeation, fluorescence microscopy, and cell viability analyses were performed.ResultsThe particles were approximately 100 nm in size in the ternary system (weight ratio (Sol/ASCDP/NOB=8/1/1)) and were relatively stable for approximately 7 days at 25 °C under light-shielded conditions. From the NMR spectrum measurements of Sol/ASCDP/NOB, a cross-peak was observed between the –OCH3 group: C6,8 (3.8 ppm) derived from NOB, the methyl group (2.0 ppm) derived from Sol, and the side chain portion (1.2 ppm) derived from ASC-DP. Cross-peaks were observed between the polyethylene glycol (PEG) backbone of Sol (3.6 ppm) and the side chain of ASC-DP (0.8–1.2 ppm). The formation of Sol/ASC-DP/NOB nanoparticles facilitated its skin permeation, and fluorescence microscopy confirmed improved permeation. The DPPH radical scavenging test revealed that Sol/ASC-DP/NOB had an IC50 of 46.7 μg/mL. Cell viability assays showed a 20–40% decrease in cell viability with the addition of Sol/ASC-DP/NOB at 0.1 mg/mL.ConclusionSol/ASC-DP/NOB nanoparticles were successfully prepared, and these were found to inhibit melanin formation and have antitumor activity.

Extraction, characterization and epoxidation of Cassia fistula (Indian laburnum) seed oil: A bio-based material

Vegetable oils are rich source for obtaining most sustainable and green chemical compounds for various industrial applications. Oil from the seeds of locally grown plant Cassia fistula was extracted using Soxhlet apparatus using n-hexane as solvent. The fatty acid composition of the extracted oil (CFSO) was established by GC analysis. The epoxidation of the unsaturated fatty acids of triglyceride nature was carried out to get the epoxidated compound (ECFSO). Both the compounds were characterized by FTIR and 1H NMR spectra. The physicochemical properties such as acid value, iodine value, epoxy equivalent and oxirane oxygen content of both the compounds were measured. The results confirm the complete epoxidation on the unsaturated double bond portion of the alkyl chains of triglyceride. Thermal decomposition stability of the samples was established from the dynamic thermo gravimetric analysis (TGA) and derivative thermogravimetry (DTG). The decomposition of the samples occurred in a single step. ECFSO has relatively more thermal stability over the precursor CFSO. Integral and differential methods were used in the thermokinetic analysis of the data at different heating rates to calculate the activation energies (Ea) for the decomposition. It was revealed that the ECFSO sample decomposes with high Ea than its precursor. High sensitive differential scanning calorimetric (DSC) traces were used to determine the melting, pour, and cloud points. The pristine oil sample has displayed both the pour and cloud points while ECFSO showed only pour point, indicating the presence of cohesive intermolecular forces among the molecules of later. The Density functional theory (DFT) calculations were performed on CFSO, ECFSO, and the methyl esters of the fatty acids of triglyceride to get the information on the changes in the IR characteristics upon epoxidation and also to calculate the HOMO-LUMO energies, band gap, molecular electrostatic potentials and quantum chemical descriptors to assess the effect of epoxidation and influence of fatty acids of triglyceride on the reactivity.