Multiple Effects Research Articles

Reduced White Matter Fiber Density in Patients with Multiple Sclerosis.

Introduction: Improved understanding of multiple sclerosis (MS) symptomatology, disease mechanisms, and clinical effectiveness can be achieved by investigating microstructural damage. The aim was to gain deeper insights into changes in white matter (WM) tracts in MS patients. Methods: Diffusion magnetic resonance imaging-based tractography was utilized to segment WM tracts into regions of interest for further quantitative analysis. However, tractography is susceptible to false-positive findings, reducing its specificity and clinical feasibility. To address these limitations, the Convex Optimization Modeling for Microstructure Informed Tractography (COMMIT) technique was used. COMMIT was used to derive measures of intracellular compartment (IC) and isotropic compartments from multishell diffusion data of 40 healthy controls (HCs) and 40 MS patients. Results: The analysis revealed a widespread pattern of significantly decreased IC values in MS patients compared with HCs across 61,581 voxels (pFWE < 0.05, threshold-free cluster enhancement [TFCE] corrected). Similar WM structures studied using the fractional anisotropy (FA) value also showed a reduction in FA among MS patients compared with HCs across 57,304 voxels (pFWE < 0.05, TFCE corrected). Out of the 61,581 voxels exhibiting lower IC, a substantial overlap of 47,251 voxels (76.72%) also demonstrated lower FA in MS patients compared with HCs. Discussion: The data suggested that lower IC values contributed to the explanation of FA reductions. In addition, IC showed promising potential for evaluating microstructural abnormalities in WM in MS, potentially being more sensitive than the frequently used FA value.

Functional roles of CD26/DPP4 in lipopolysaccharide-induced lung injury.

Acute respiratory distress syndrome (ARDS) is characterized by dysregulated inflammation and increased permeability of lung microvascular cells. CD26/dipeptidyl peptidase-4 (DPP4) is a type II membrane protein that is expressed in several cell types and mediates multiple pleiotropic effects. We previously reported that DPP4 inhibition by sitagliptin attenuates lipopolysaccharide (LPS)-induced lung injury in mice. The current study characterized the functional role of CD26/DPP4 expression in LPS-induced lung injury in mice, isolated alveolar macrophages, and cultured lung endothelial cells. In LPS-induced lung injury, inflammatory responses [bronchoalveolar lavage fluid (BALF) neutrophil numbers and several proinflammatory cytokine levels] were attenuated in Dpp4 knockout (Dpp4 KO) mice. However, multiple assays of alveolar capillary permeability were similar between the Dpp4 KO and wild-type mice. TNF-α and IL-6 production was suppressed in alveolar macrophages isolated from Dpp4 KO mice. In contrast, in cultured mouse lung microvascular endothelial cells (MLMVECs), reduction in CD26/DPP4 expression by siRNA resulted in greater ICAM-1 and IL-6 expression after LPS stimulation. Moreover, the LPS-induced vascular monolayer permeability in vitro was higher in MLMVECs treated with Dpp4 siRNA, suggesting that CD26/DPP4 plays a protective role in endothelial barrier function. In summary, this study demonstrated that genetic deficiency of Dpp4 attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential functional roles of CD26/DPP4 expression in resident cellular components of the lung. CD26/DPP4 may be a potential therapeutic target for ARDS and warrants further exploration to precisely identify the multiple functional effects of CD26/DPP4 in ARDS pathophysiology.NEW & NOTEWORTHY We aimed to clarify the functional roles of CD26/DPP4 in ARDS pathophysiology using Dpp4-deficient mice and siRNA reduction techniques in cultured lung cells. Our results suggest that CD26/DPP4 expression plays a proinflammatory role in alveolar macrophages while also playing a protective role in the endothelial barrier. Dpp4 genetic deficiency attenuates inflammatory responses but not permeability in LPS-induced lung injury in mice, potentially through differential roles of CD26/DPP4 expression in the resident cellular components of the lung.

Two-way pharmacodynamic modeling of drug combinations and its application to pairs of repurposed Ebola and SARS-CoV-2 agents.

Existing pharmacodynamic (PD) mathematical models for drug combinations discriminate antagonistic, additive, multiplicative, and synergistic effects, but fail to consider how concentration-dependent drug interaction effects may vary across an entire dose-response matrix. We developed a two-way pharmacodynamic (TWPD) model to capture the PD of two-drug combinations. TWPD captures interactions between upstream and downstream drugs that act on different stages of viral replication, by quantifying upstream drug efficacy and concentration-dependent effects on downstream drug pharmacodynamic parameters. We applied TWPD to previously published in vitro drug matrixes for repurposed potential anti-Ebola and anti-SARS-CoV-2 drug pairs. Depending on the drug pairing, the model recapitulated combined efficacies as or more accurately than existing models and can be used to infer efficacy at untested drug concentrations. TWPD fits the data slightly better in one direction for all drug pairs, meaning that we can tentatively infer the upstream drug. Based on its high accuracy, TWPD could be used in concert with PK models to estimate the therapeutic effects of drug pairs in vivo.

Remimazolam Attenuates LPS-Derived Cognitive Dysfunction via Subdiaphragmatic Vagus Nerve Target α7nAChR-Mediated Nrf2/HO-1 Signal Pathway.

Sepsis-induced neuroinflammation is significantly associated with sepsis-related brain dysfunction. Remimazolam is a novel ultra-short-acting benzodiazepine anesthetic with multiple organ protective effects. However, it is unknown whether remimazolam can ameliorate LPS-induced brain impairment. In this study, Lipopolysaccharide (5mg/kg, LPS) severely impaired Sprague-Dawley rats spatial learning ability, memory, and cognitive function. However, remimazolam treatment showed a protective effect on LPS-induced cognitive dysfunction. Remimazolam partly reversed LPS-induced splenomegaly, decreased serum cytokine expression, suppressed hippocampal M1 microglial activation, and mitigated oxidative stress injury and neuroinflammation. Electroacupuncture (EA) or PNU282987 treatment improved LPS-induced cognitive dysfunction and also significantly inhibited neuroinflammation and systemic inflammation. However, MLA, ML385, or subdiaphragmatic vagus nerve (SDV) treatment abolished the protective effects of remimazolam. Further mechanistic studies showed that remimazolam induces protective effects by activating subdiaphragmatic vagus nerve target α7nAChR-mediated Nrf2/HO-1 signaling pathway. These results demonstrate that remimazolam can up-regulate α7nAChR, Cyto-Nrf2, HO-1, and cognitive-related (CREB, BDNF, PSD95) protein expressions, suppress M1 microglia, ameliorate neuroinflammation or systemic inflammation, and reverse cognitive dysfunction. Therefore, this study provides insight into a new therapeutic target for the treatment of sepsis-induced cerebral dysfunction.

Multifunctional sulfur doping in cobalt-based materials for high-energy density supercapacitors

In this study, S-CCO@Co(OH)2 (‘CCO’ representing CuCo2O4/Cu2O; ‘S-’representing sulfur doping) was synthesized by hydrothermal method followed by electrodeposition. The multiple effects of S doping were studied by S doping and constructing 3D core–shell structure. S doping induced the reduction of Cu2+ and Co3+ to Cu+ and Co2+, respectively. Also, S partially replaces O and creates oxygen vacancies, which increases a number of active sites for the redox reaction enhancing the redox reaction activity. After the electrodeposition, S–Co bond is formed between the Co(OH)2 shell and the S-CCO core, which suggests a synergistic effect between S doping and core–shell structure. The formation of S–Co bond is conducive to electron and ion transport, thus improving electrochemical performance. After modification, the specific capacitance of S-CCO@Co(OH)2 is 4.28 times higher than CCO, up to 1730 Fg−1. Furthermore, the assembled S-CCO@Co(OH)2//activated carbon supercapacitor exhibits an energy density of 83.89 Whkg−1 at 848.81 Wkg−1 and a retention rate of 98.48% after 5000 charge and discharge cycles. Therefore, S doping and its mutual effect with the utilization of the core–shell structure considerably enhanced the electrochemical performance of the CCO-based electrodes, endowing its potential in further application.

Pro-Vaccination Flu and COVID-19 Messages: Evidence of Congenial Targeted and Spillover Effects

Given the plentitude of messages in the public arena that promote vaccination against different diseases or raise the possibility of vaccine mandates, we asked whether message effects in one disease domain might spill over into other domains. Our experiment exposed individuals (N = 1755) recruited from an opt-in online panel (Qualtrics) on influenza or COVID-19 pro-vaccination messages then measured intentions to vaccinate for each disease and intentions to support a vaccine mandate for each disease. Messages that targeted flu (vs. COVID-19) exhibited stronger effects on intentions to vaccinate for corresponding (vs. noncorresponding) disease. We observed positive spillover from intention to vaccinate against one disease to intention to vaccinate against the other disease, as well as from vaccination intention type to support for corresponding and noncorresponding vaccine mandates. Although pro-vaccination flu and COVID-19 messages have multiple effects, those effects are congenial. The results adjudicate differences in spillover theory and suggest synergistic effects between pro-vaccination campaigns.

Transformers enable accurate prediction of acute and chronic chemical toxicity in aquatic organisms.

Environmental hazard assessments are reliant on toxicity data that cover multiple organism groups. Generating experimental toxicity data is, however, resource-intensive and time-consuming. Computational methods are fast and cost-efficient alternatives, but the low accuracy and narrow applicability domains have made their adaptation slow. Here, we present a AI-based model for predicting chemical toxicity. The model uses transformers to capture toxicity-specific features directly from the chemical structures and deep neural networks to predict effect concentrations. The model showed high predictive performance for all tested organism groups-algae, aquatic invertebrates and fish-and has, in comparison to commonly used QSAR methods, a larger applicability domain and a considerably lower error. When the model was trained on data with multiple effect concentrations (EC50/EC10), the performance was further improved. We conclude that deep learning and transformers have the potential to markedly advance computational prediction of chemical toxicity.

Induction of glioblastoma invasion triggered by system Xc−-mediated glutamate release

Abstract Backgrounds Glioblastoma (GBM) is a highly aggressive brain cancer associated with poor prognosis, primarily attributed to its profound invasive characteristics. Glutamate is the main cause of invasion, and invasion is promoted by system Xc− (cystine/glutamate antiporter), which is highly expressed in GBM. To date, no studies have examined the relationship between invasion and the specific downregulation of system Xc− (xCT or SLC7A11) using shRNA in GBM. Objective We aimed to determine the effect of a specific knockdown system, Xc−, in GBM using short hairpin RNA (shRNA) rather than pharmacological approaches. Results Invasion was inhibited in GBM cells treated with sulfasalazine, a system Xc− inhibitor. Our experiments validated a reduction in extracellular glutamate concentration following sulfasalazine treatment, without affecting GBM proliferation or calcium response. However, the efficacy of pharmacological methods is hindered by nonspecific effects and the prevalence of multiple side effects. Therefore, we specifically targeted the system Xc− molecule through shRNA. Downregulation using shRNA demonstrated decreased invasion and extracellular glutamate levels, without affecting the calcium response and proliferation. Conclusion The targeted inhibition of system Xc− using shRNA yields a notable reduction in GBM invasion.

The Simon effect under reversed visual feedback.

Our aim was to study the processes involved in the spatial coding of the body during actions producing multiple simultaneous effects. We specifically aimed to challenge the intentional-based account, which proposes that the effects used to code responses are those deemed relevant to the agent's goal. Accordingly, we used a Simon paradigm (widely recognized as a suitable method to investigate the spatial coding of responses) combined with a setup inducing a multimodal discrepancy between visual and tactile/proprioceptive effects (known to be crucial for body schema construction and action control). To be more precise, the setup allowed to horizontally reverse the visual effects of the hands compared to the tactile/proprioceptive effects (e.g., the right hand was seen as being on the left). In Experiment 1, the visual effects were not reversed. However, in Experiment 2, the visual effects were reversed, and the task emphasized the relevance of these effects to the participants. In Experiment 3, the visual effects were also reversed, but the task emphasized the relevance of tactile/proprioceptive effects. A Simon effect, based on the location of the tactile/proprioceptive effects, was observed in Experiments 1 and 3. However, in Experiment 2, the Simon effect was partially driven by the location of the visual effects. These findings collectively support that the agent's intention plays a prominent role in the representation of their body during action. This work also suggests a promising avenue for research in linking action and body representations.

The Ten-Year Guarantee of the Contractor and the Engineer on Ensuring the Durability of the Building in the System of Applying the Saudi Building Code: A Comparative Study

This study aims to clarify the personal civil liability of the contractor and engineer for the damage and demolition in buildings and facilities and the defects that may appear during the warranty period. The general rules in civil liability were not sufficient in construction and building. During a warrant on the building, the negative result may appear as complete or partial demolition or defects that threaten its safety and durability. This changes the purpose for which it was established, whether in the national economy or compromising public security and public tranquillity. This also varies from a threat to individuals and their money. This pushed the legislators, including the Saudi regulator, to decide on a set of exceptional guarantees characterized by strictness consistent with the tragedies resulting from the collapse of buildings in whole or in part, from multiple aspects and effects. The most important of these guarantees is the decimal responsibility or the decimal guarantee that the Saudi regulator has imposed in Article (8) of the Saudi Building Code application system and clarified by Article (29) of the Executive Regulations for the Saudi Building Code Application System. We have adopted in the research: the descriptive, analytical, and comparative approach of the relevant texts in the system of application of the Saudi building code on which the study is focused, which is the case of the responsibility of the contractor and the engineer, for any demolition or defect in the construction after the issuance of the occupancy certificate, compared to some Arab legislation, which is the Egyptian Jordanian and Bahraini. This study discusses the nature of the decimal guarantee and its duration. Then, we focus on the provisions of the decimal guarantee. The study recommended that the Saudi regulator stipulates the warranty claim against the contractor and engineer. The lawsuit occurs after three years have passed since the demolition occurred or the defect was discovered, contrary to what was mentioned in the Saudi Civil Transactions System, which requires ten years to pass, because the ten-year liability is a private liability. The solidarity between the contractor and the engineer should not be limited to joint liability but should extend to include solidarity in the guarantee. &#x0D; &#x0D; Received: 16 December 2023 / Accepted: 19 February 2024 / Published: 5 March 2024

Causal Effects of COVID-19 on the Risk of Thrombosis: A Two-Sample Mendel Randomization Study.

Coronavirus disease 2019 (COVID-19) and thrombosis are linked, but the biomolecular mechanism is unclear. We aimed to investigate the causal relationship between COVID-19 and thrombotic biomarkers. We used two-sample Mendelian randomization (MR) to assess the effect of COVID-19 on 20 thrombotic biomarkers. We estimated causality using inverse variance weighting with multiplicative random effect, and performed sensitivity analysis using weighted median, MR-Egger regression and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods. All the results were examined by false discovery rate (FDR) with the Benjamin and Hochberg method for this correction to minimize false positives. We used R language for the analysis. All COVID-19 classes showed lower levels of tissue factor pathway inhibitor (TFPI) and interleukin-1 receptor type 1 (IL-1R1). COVID-19 significantly reduced TFPI (odds ratio [OR] = 0.639, 95% confidence interval [CI]: 0.435-0.938) and IL-1R1 (OR = 0.603, 95% CI = 0.417-0.872), nearly doubling the odds. We also found that COVID-19 lowered multiple coagulation factor deficiency protein 2 and increased C-C motif chemokine 3. Hospitalized COVID-19 cases had less plasminogen activator, tissue type (tPA) and P-selectin glycoprotein ligand 1 (PSGL-1), while severe cases had higher mean platelet volume (MPV) and lower platelet count. These changes in TFPI, tPA, IL-1R1, MPV, and platelet count suggested a higher risk of thrombosis. Decreased PSGL-1 indicated a lower risk of thrombosis. TFPI, IL-1R, and seven other indicators provide causal clues of the pathogenesis of COVID-19 and thrombosis. This study demonstrated that COVID-19 causally influences thrombosis at the biomolecular level.

Neuropsychiatric effects of glucocorticoids

Neuropsychiatric effects of glucocorticoids

GFRAL Is Widely Distributed in the Brain and Peripheral Tissues of Mice.

In 2017, four independent publications described the glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as receptor for the growth differentiation factor 15 (GDF15, also MIC-1, NAG-1) with an expression exclusively in the mice brainstem area postrema (AP) and nucleus tractus solitarii (NTS) where it mediates effects of GDF15 on reduction of food intake and body weight. GDF15 is a cell stress cytokine with a widespread expression and pleiotropic effects, which both seem to be in contrast to the reported highly specialized localization of its receptor. This discrepancy prompts us to re-evaluate the expression pattern of GFRAL in the brain and peripheral tissues of mice. In this detailed immunohistochemical study, we provide evidence for a more widespread distribution of this receptor. Apart from the AP/NTS region, GFRAL-immunoreactivity was found in the prefrontal cortex, hippocampus, nucleus arcuatus and peripheral tissues including liver, small intestine, fat, kidney and muscle tissues. This widespread receptor expression, not taken into consideration so far, may explain the multiple effects of GDF-15 that are not yet assigned to GFRAL. Furthermore, our results could be relevant for the development of novel pharmacological therapies for physical and mental disorders related to body image and food intake, such as eating disorders, cachexia and obesity.

Macroscale TiO2 Microspherical Arrays with Multiple Synergistic Effect for Highly Sensitive Surface‐Enhanced Raman Scattering

AbstractSemiconductor materials represent an ideal choice for designing surface‐enhanced Raman scattering (SERS)‐based sensors due to their superior thermal and chemical stability compared to conventional metal materials. However, current SERS‐active semiconductor substrates have limitations such as low detection sensitivity and often complicated preparation steps, which restrict their real‐life applications. In this work, for the first time the feasibility of large‐area fabricating SERS‐active semiconductor substrates based on screen‐printing of micron‐sized TiO2 ink synthesized through a simple flame thermal‐assisted method is demonstrated. The resultant TiO2 microspherical arrays (MSAs) exhibit extraordinary SERS sensitivity with an enhancement factor of 3.28 × 107, which represents one of the highest sensitivity and are the easiest strategy among the reported SERS‐active semiconductor substrates. Both experiments and simulations rationalize the observed enhancement factor and propose that multiple synergistic resonances, including Mie resonance, charge‐transfer resonance, and molecular resonance significantly boost the performance of semiconductor substrates. Dye‐modified TiO2 MSAs are further exploited as the sensing platform for the development of a ratiometric SERS sensor, enabling the highly sensitive, selective, low cost, and stable detection of Hg2+ ions. This study opens up new possibilities for preparing a large‐scale SERS‐active semiconductor array, ultimately advancing the fields of semiconductor‐based SERS sensing technology.

Multiple Slip Effects on the Time Independent MHD Flow of a UCM Fluid over an Elongating Surface That Has Higher-Grade Chemical Reaction

Multiple Slip Effects on the Time Independent MHD Flow of a UCM Fluid over an Elongating Surface That Has Higher-Grade Chemical Reaction

Innovative thermodynamic modeling for enhanced yeast dough mixing: energy perspectives and applications

A thermodynamic model for the calculation of energy exchange in the chamber of a new mixer with effective use of structural and technological parameters of the mixing process without the necessary introduction of experimental data correlations in the distribution of fluid velocities is proposed, which determines the relevance of this direction of calculation with the perspective of its development. The purpose of the presented work is to determine the specific power by substantiating the effective mode parameters of the preparation of the mixture (dough) as a result of evaluating the thermodynamic energy parameters of the kneading process. The assessment was carried out by developing a methodology for determining specific costs for creating a viscous medium when mixing components, which allows you to establish the required power depending on the design and technological parameters of the new mixer. The considered principle of the proposed open-type thermodynamic system of the description of the working process of mixing made it possible to reveal and determine the ways of converting energy into useful work of interphase heat and mass transfer of a heterogeneous medium. In the conditions of circulation mixing with multiple mechanical effects on the mixture of components in the closed circuit of the cylindrical working chamber, which is an effective way to achieve homogeneity of the environment, it was possible to obtain an analytical determination of the specific work and power of the drive in the absence of a clear description of the model of the interconnection of components. The proposed thermodynamic description of the system's energy balance allows to perform only a few experiments. In general, the practical value of the given calculations is of practical importance for improving productivity and efficiency and minimizing energy consumption for the process while reducing the dynamic loads of the designed mixer.

Co–HOAT Complexes Change Their Antibacterial and Physicochemical Properties with Morphological Evolution

Antibacterial coordination compounds have attracted tremendous attention ascribed to their excellent designability. However, how the morphological evolution of these complexes influences their antibacterial and physicochemical properties has never been investigated based on proposed mechanisms. Thus, a series of Co–HOAT coordination compounds synthesized from inorganic to organic cobalt sources were prepared. We propose that with the same HOAT ligand, inorganic Co–HOAT nanosheets possess higher sterilization rates compared with organic Co–HOAT nanoparticles. This is explained by the different steric hindrance of cobalt sources. Relatively small steric hindrance could lead to ample active positions for inorganic cobalt ions to coordinate with both N and O atoms in HOAT. Meanwhile, organic Co2+ ions could only unite with N atoms in HOAT. Furthermore, by theoretical calculation, cobalt ions with adequate coordination sites are beneficial for developing nanosheet morphologies. Meanwhile, the Co–HOAT complexes with a lower density of electron clouds present higher sterilization rates due to the anchoring effect of electrostatic attraction. The proposed mechanism is that Co2+ released from compounds could cause multiple toxic effects to bacteria anchored by Co–HOATs. Finally, Co–HOATs’ behaviors have excellent antimicrobial properties without environmental limitations. In conclusion, the Co–HOATs appear to be a potential antibacterial catalyst in the antimicrobial field.

Trophic cascades within and across ecosystems: The role of anti-predatory defences, predator type and detritus quality.

Species in one ecosystem can indirectly affect multiple biodiversity components and ecosystem functions of adjacent ecosystems. The magnitude of these cross-ecosystem effects depends on the attributes of the organisms involved in the interactions, including traits of the predator, prey and basal resource. However, it is unclear how predators with cross-ecosystem habitat interact with predators with single-ecosystem habitat to affect their shared ecosystem. Also, unknown is how such complex top-down effects may be mediated by the anti-predatory traits of prey and quality of the basal resource. We used the aquatic invertebrate food webs in tank bromeliads as a model system to investigate these questions. We manipulated the presence of a strictly aquatic predator (damselfly larvae) and a predator with both terrestrial and aquatic habitats (spider), and examined effects on survival of prey (detritivores grouped by anti-predator defence), detrital decomposition (of two plant species differing in litter quality), nitrogen flux and host plant growth. To evaluate the direct and indirect effects each predator type on multiple detritivore groups and ultimately on multiple ecosystem processes, we used piecewise structural equation models. For each response variable, we isolated the contribution of different detritivore groups to overall effects by comparing alternate model formulations. Alone, damselfly larvae and spiders each directly decreased survival of detritivores and caused multiple indirect negative effects on detritus decomposition, nutrient cycling and host plant growth. However, when predators co-occurred, the spider caused a negative non-consumptive effect on the damselfly larva, diminishing the net direct and indirect top-down effects on the aquatic detritivore community and ecosystem functioning. Both detritivore traits and detritus quality modulated the strength and mechanism of these trophic cascades. Predator interference was mediated by undefended or partially defended detritivores as detritivores with anti-predatory defences evaded consumption by damselfly larvae but not spiders. Predators and detritivores affected ecosystem decomposition and nutrient cycling only in the presence of high-quality detritus, as the low-quality detritus was consumed more by microbes than invertebrates. The complex responses of this system to predators from both recipient and adjacent ecosystems highlight the critical role of maintaining biodiversity components across multiple ecosystems.

Whole Body Cryostimulation: A New Adjuvant Treatment in Central Sensitization Syndromes? An Expert Opinion.

Central sensitisation is defined as a multifactorial etiopathogenetic condition involving an increase in the reactivity of nociceptive neurons and alterations in pain transmission and perception in the central nervous system. Patients may present with widespread chronic pain, fatigue, sleep disturbance, dizziness, psychological (e.g., depression, anxiety, and anger) and social impairment. Pain can be spontaneous in onset and persistence, characterised by an exaggerated response and spread beyond the site of origin, and sometimes triggered by a non-painful stimulus. Whole-body cryostimulation (WBC) could be an adjuvant therapy in the management of this type of pain because of its global anti-inflammatory effect, changes in cytokines and hormone secretion, reduction in nerve conduction velocity, autonomic modulation, and release of neurotransmitters involved in the pain pathway. In several conditions (e.g., fibromyalgia, rheumatoid arthritis, and chronic musculoskeletal pain), WBC affects physical performance, pain perception, and psychological aspects. Given its multiple targets and effects at different organs and levels, WBC appears to be a versatile adjuvant treatment for a wide range of conditions of rehabilitation interest. Further research is needed to fully understand the mechanisms of analgesic effect and potential actions on pain pathways, as well as to study long-term effects and potential uses in other chronic pain conditions.

Formation and strengthening mechanism of equiaxial cellular grain zone in AA2195-T8 Al–Cu–Li alloy twin-wire P-VPPA welded joint with Ti–Zr microalloying

A novel method involving twin-wire pulsed VPPA (P-VPPA) welding was combined with Ti–Zr microalloying to improve the mechanical properties of AA2195-T8 Al–Cu–Li alloy variable polarity plasma arc (VPPA) welded joints. This method aimed to increase the width of the equiaxial cellular grain zone (ECZ) by adding higher content of Ti–Zr and reducing heat input. The microstructure evolution process was established to understand the formation and strengthening mechanism of the ECZ. The results showed that the strength of the ECZ was higher than that of the dendrite in the weld zone (WZ). The twin-wire VPPA welding led to the formation of a wider ECZ near the fusion zone (FZ). This ECZ was continuously distributed throughout the thickness direction of the welded joint. Combined with higher Ti–Zr microalloying, the maximum width of ECZ increased to 2.5 mm and extended to the WZ. Consequently, the proportion of cracks passing through the ECZ during tensile fracture increased from 27.6% to 88.7%. Moreover, the ultimate tensile strength (UTS) of the welded joint exhibited a notable improvement, rising from 328 MPa to 370 MPa, while the elongation also increased to 5%. The UTS of the welded joint achieved 66% of the base metal. Additionally, the average grain size in the ECZ was 14 μm. The formation of the ECZ was primarily attributed to the nucleation precursors of Al3(Ti, Zr) and β′ phase, as well as less welding heat input near the FZ. The widening of the ECZ was mainly due to the presence of more Al3(Ti, Zr) phases. Moreover, the grain boundary of the ECZ exhibited the distribution of Al–Cu eutectic, θ(Al2Cu), Ω, T2(Al6CuLi3), and ω(Al7Cu2Fe) phases, while a small amount of T1(Al2CuLi) phase precipitated within the grain. The strengthening mechanism of ECZ is the result of multiple strengthening effects, including the reduction of element segregation and microcracks, the precipitation of the T1 phase, and the fine grain strengthening.