Triple Modulation Research Articles

Efficient Electrosynthesis of Valuable para-Benzoquinone from Aqueous Phenol on NiRu Hybrid Catalysts.

Electrocatalytic oxidation of aqueous phenol to para-benzoquinone (p-BQ) offers a sustainable approach for both pollutant abatement and value-added chemicals production. However, achieving high phenol conversion and p-BQ yield under neutral conditions remains challenging. Herein, we report a Ni(OH)2-supported Ru nanoparticles (NiRu) hybrid electrocatalyst, which exhibits a superior phenol conversion of 96.5% and an excellent p-BQ yield of 83.4% at pH 7.0, significantly outperforming previously reported electrocatalysts. This exceptional performance benefits from the triple synergistic modulation of the NiRu catalyst, including enhanced phenol adsorption, increased p-BQ desorption, and suppressed oxygen evolution. By coupling a flow electrolyzer with an extraction-distillation separation unit, the simultaneous phenol removal and p-BQ recovery are realized. Additionally, the developed electrocatalytic system with the NiRu/C anode displays good stability, favorable energy consumption, and reduced greenhouse gas emissions for phenol-containing wastewater treatment, demonstrating its potential for practical applications. This work offers a promising strategy for achieving low-carbon emissions in phenol wastewater treatment.

Efficient Electrosynthesis of Valuable para‐Benzoquinone from Aqueous Phenol on NiRu Hybrid Catalysts

Electrocatalytic oxidation of aqueous phenol to para‐benzoquinone (p‐BQ) offers a sustainable approach for both pollutant abatement and value‐added chemicals production. However, achieving high phenol conversion and p‐BQ yield under neutral conditions remains challenging. Herein, we report a Ni(OH)2‐supported Ru nanoparticles (NiRu) hybrid electrocatalyst, which exhibits a superior phenol conversion of 96.5% and an excellent p‐BQ yield of 83.4% at pH 7.0, significantly outperforming previously reported electrocatalysts. This exceptional performance benefits from the triple synergistic modulation of the NiRu catalyst, including enhanced phenol adsorption, increased p‐BQ desorption, and suppressed oxygen evolution. By coupling a flow electrolyzer with an extraction‐distillation separation unit, the simultaneous phenol removal and p‐BQ recovery are realized. Additionally, the developed electrocatalytic system with the NiRu/C anode displays good stability, favorable energy consumption, and reduced greenhouse gas emissions for phenol‐containing wastewater treatment, demonstrating its potential for practical applications. This work offers a promising strategy for achieving low‐carbon emissions in phenol wastewater treatment.

Heightened mitochondrial respiration in CF cells is normalised by triple CFTR modulator therapy through mechanisms involving calcium

BackgroundCystic fibrosis (CF) is associated with increased resting energy expenditure. However, the introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has resulted in a paradigm shift in nutritional status for many people with CF, with increase body mass index and reduction in the need for nutritional support. While these changes are likely to reflect improved clinical status and an associated downregulation of energy expenditure, they may also reflect drug-induced alterations in metabolic perturbations within CF cells. We hypothesise that some of these changes relate to normalisation of mitochondrial respiration in CF. MethodsUsing wild-type (WT) and F508del/F508del CFTR human bronchial epithelial cell lines (HBE cell lines) and baby hamster kidney (BHK) cells we examined the impact of ETI on cellular metabolism. We monitored mitochondrial respiration, using Seahorse extracellular flux assays and monitored mitochondrial reactive oxygen species (mROS) and intracellular calcium levels by flow cytometry. ResultsIncreased mitochondrial respiration was found in HBE cell lines and BHK cells expressing CFTR F508del/F508del when assessing basal, maximal, spare respiratory capacities and ATP production, as well as increased mitochondrial ROS generated via forward electron transport. ETI significantly decreased basal, maximal, spare respiratory capacity and ATP production to WT levels or below. Calcium blocker, BAPTA-AM normalised mitochondrial respiration, suggesting a calcium-mediated mechanism. ETI decreased intracellular calcium levels in CF cells to the same extent as BAPTA-AM, highlighting the importance of calcium and chloride in mitochondrial respiration in CF. ConclusionsCF cell lines exhibit increased mitochondrial respiration, which can be downregulated by ETI therapy through mechanisms involving calcium.

BOS-318 treatment enhances elexacaftor-tezacaftor-ivacaftor (ETI)-mediated improvements in airways hydration and mucociliary transport

BackgroundCFTR triple modulator therapy, elexacaftor-tezacaftor-ivacaftor (ETI) has transformed care for people with cystic fibrosis (pwCF) who have eligible mutations. It is, however, not curative. Response to treatment also varies and lung disease although slowed, remains progressive. We have previously demonstrated that inhibition of the epithelial sodium channel (ENaC) by selective furin inhibition offers an alternative, mutation-agnostic approach to enhance airways hydration and restore mucociliary transport (MCT) in CF. Inhibition of furin therefore, offers a potential therapeutic strategy for those ineligible, intolerant or non-responsive to ETI and may provide a further opportunity for clinical benefit for those currently treated with ETI. The aim of this study was to determine the impact of furin inhibition on ETI responses to assess its utility as an adjunct therapy.MethodsDifferentiated primary human CF bronchial epithelial cells (CF HBECs) were treated with the highly selective furin inhibitor, BOS-318 and ETI. Ion channel function was measured using a 24-channel Transepithelial Current Clamp (TECC-24) system and airways surface hydration was investigated by measuring airway surface liquid (ASL) height and MCT rate.ResultsThe presence of BOS-318 had no effect on the ability of ETI to stimulate CFTR-mediated Cl−secretion but contributed a reduced Na+transportviarobust inhibition of ENaC. This altered ion transport profile effected an improved ASL height and MCT rate which were significantly greater than improvements observed with ETI alone, demonstrating the benefits of the dual approach.ConclusionsSelective furin inhibition has potential to further improve clinical outcomes for all pwCF and offers opportunity as an adjunct to improve responses to currently available CFTR modulator therapies.

Performance Analysis of Electric Vehicle Fast Charging System with Dual Active Bridge Converter using Triple Phase Shift Modulation

Performance Analysis of Electric Vehicle Fast Charging System with Dual Active Bridge Converter using Triple Phase Shift Modulation

Kidney effects of triple CFTR modulator therapy in people with cystic fibrosis.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a new cystic fibrosis transmembrane conductance regulator (CFTR) modulator that has transformed the respiratory prognosis of people with cystic fibrosis (pwCF). However, its impact on other organs such as the kidneys, where CFTR is expressed, remains unclear. Since pwCF are risk of both kidney disease and urolithiasis, we aimed to study the potential effects of ETI on renal function, volume status, and risk factors for urolithiasis. This prospective, observational, single-center, before-after cohort study, involved adult pwCF eligible for ETI. The changes in plasma and urinary profiles were assessed by comparing renal function (using 2021 CKD-EPIcreatinine and 2021 CKD-EPIcreatinine-cystatin C formulas), volume status (using aldosterone/renin ratio and blood pressure), and risk factors for urolithiasis, at the time of ETI introduction (M0) and 7 months after (M7). Nineteen pwCF were included. No significant change in renal function was observed between M0 and M7 (2021 CKD-EPIcreatinine: 105.5ml/min/1.73 m² at M0 vs. 103.3ml/min/1.73 m² at M7; P=.17). There was a significant reduction in aldosterone level (370.3pmol/l at M0 vs. 232.4pmol/l at M7; P=.02) and aldosterone/renin ratio (33.6 at M0 vs. 21.8 at M7; P=.03). Among the risk factors for urolithiasis, a significant reduction in magnesuria level was found (4.6mmol/d at M0 vs. 3.8mmol/d at M7; P=.01). These findings suggest that ETI seem to have no short-term impact on the renal function of adult pwCF and appears to correct secondary hyperaldosteronism due to excessive sweat losses. Further investigations are needed to determine the potential impact of decreased magnesuria observed under ETI therapy on the risk of urolithiasis.

Epidemiology of advanced cystic fibrosis lung disease in the modulator era.

Advanced cystic fibrosis lung disease remains the main cause of death in people with cystic fibrosis (pwCF). Cystic fibrosis transmembrane regulator (CFTR) modulators have changed the disease burden for eligible pwCF with access to this therapy. Real-world data show that there are no safety concerns for patients with advanced cystic fibrosis lung disease treated with highly effective triple CFTR modulator therapy. The improvements are comparable to those in other people with cystic fibrosis and in part even better. Mortality and rates of lung transplantation have decreased since the approval of CFTR modulator therapy and, especially, highly effective triple CFTR modulator therapy. Nevertheless, at least 10% of people with cystic fibrosis are not eligible for highly effective CFTR modulator therapy, and the development of alternative treatments remains important. The approval of highly effective CFTR modulator therapies has been a breakthrough in treatment for most people with cystic fibrosis, especially those with advanced lung disease, improving survival and reducing the burden of the disease.

The effect of triple CFTR modulator therapy and azithromycin on ion channels and inflammation in cystic fibrosis

Inflammation in cystic fibrosis (CF) airways is difficult to treat with well-established regimens often including azithromycin (AZ) as an immunomodulatory drug. As AZ has been reported to require CFTR to be able to reduce IL-8 and given the emergence of highly effective CFTR “triple” modulator therapy (elexacaftor/tezacaftor/ivacaftor; ETI), the aim of this study was to investigate the effect of AZ and ETI, singly and in combination, on ion channel activity and to assess potential anti-inflammatory effects. Electrophysiological assessment of ETI and AZ was performed on 3D cultures of primary CF human bronchial epithelial (HBE) cells using Multi Trans-Epithelial Current Clamp (MTECC). IL-8 from NuLi-1 (non-CF) and CuFi-1 (CF) cells treated with AZ was measured by ELISA. Inflammatory mediators from primary CF HBE cells exposed to tumour necrosis factor-alpha (TNF-α) in the presence of AZ, ETI and their combination, were screened using the Proteome Profiler™ Human Cytokine Array Kit, with selected targets validated by ELISA. AZ did not alter CFTR chloride efflux, nor did it have any synergistic/antagonistic effect in combination with ETI. AZ reduced IL-8 in NuLi-1 but not CuFi-1 cells. The Proteome Profiler™ screen identified several disease-relevant cytokines that were modulated by treatment. Subsequent analysis by ELISA showed IL-8, IL-6, CXCL1 and GM-CSF to be significantly reduced by treatment with ETI, but not by AZ. Incorporating ETI into the standard of CF care provides an opportunity to re-evaluate therapeutic regimens to reduce treatment burden and safely discontinue chronic treatments such as AZ, without loss of clinical benefit. Identification of redundant treatments in the era of CFTR modulation may improve medication adherence and overcome potential adverse effects associated with the chronic use AZ and other drugs.

Cystic fibrosis.

Cystic fibrosis is a rare genetic disease caused by mutations in CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). The discovery of CFTR in 1989 has enabled the unravelling of disease mechanisms and, more recently, the development of CFTR-directed therapeutics that target the underlying molecular defect. The CFTR protein functions as an ion channel that is crucial for correct ion and fluid transport across epithelial cells lining the airways and other organs. Consequently, CFTR dysfunction causes a complex multi-organ disease but, to date, most of the morbidity and mortality in people with cystic fibrosis is due to muco-obstructive lung disease. Cystic fibrosis care has long been limited to treating symptoms using nutritional support, airway clearance techniques and antibiotics to suppress airway infection. The widespread implementation of newborn screening for cystic fibrosis and the introduction of a highly effective triple combination CFTR modulator therapy that has unprecedented clinical benefits in up to 90% of genetically eligible people with cystic fibrosis has fundamentally changed the therapeutic landscape and improved prognosis. However, people with cystic fibrosis who are not eligible based on their CFTR genotype or who live in countries where they do not have access to this breakthrough therapy remain with a high unmet medical need.

Lung transplant list withdrawal in a liver transplant patient thanks to elexacaftor-tezacaftor-ivacaftor: a case report

BackgroundElexacaftor-tezacaftor-ivacaftor (ETI) is a transmembrane conductance regulator modulator that significantly improves lung function in patients affected by cystic fibrosis (CF). This triple drug is currently not indicated in liver transplant patients, as clinical trials including subjects with previous solid organ transplantation are lacking.Case presentationWe report on a liver transplant girl with CF-related advanced pulmonary disease meeting clinical criteria for lung transplant, who started the triple modulator because she could not get on the lung transplant waiting list due to psycho-social motivations. Since initiation of ETI therapy, she has experienced a significant improvement in respiratory function and quality of life, without adverse effects.ConclusionsThis case shows that ETI therapy can represent a lifesaving drug for individuals without alternatives, even in liver transplant patients. The clinical benefits of the modulator overcome risks, which may be limited with a close drug monitoring of immunosuppressants serum levels and functional liver tests.

P324 Changes to the dietetic landscape in a UK adult cystic fibrosis centre following the introduction of triple CFTR modulator therapy and continuous glucose monitoring to screen for CF diabetes

P324 Changes to the dietetic landscape in a UK adult cystic fibrosis centre following the introduction of triple CFTR modulator therapy and continuous glucose monitoring to screen for CF diabetes

P286 Triple CFTR modulator combination improves glucose tolerance in adolescents with cystic fibrosis. Data from the French observational paediatric study MODUL-CF

P286 Triple CFTR modulator combination improves glucose tolerance in adolescents with cystic fibrosis. Data from the French observational paediatric study MODUL-CF

P076 The effectiveness of triple modulator therapy with elexacaftor/tezacaftor/ivacaftor on pulmonary function in cystic fibrosis patients with advanced lung disease

P076 The effectiveness of triple modulator therapy with elexacaftor/tezacaftor/ivacaftor on pulmonary function in cystic fibrosis patients with advanced lung disease

Optical soliton solutions of complex Ginzburg–Landau equation with triple power law and modulation instability

This paper examines the complex Ginzburg Landau equation, which describes pulse propagation inside a fiber with the triple power law of self-phase modulation. Since the effect of parameter selection has become very important in relevant model studies recently, self-phase modulation has been added to the complex Ginzburg Landau equation, which has been studied in the literature, and it is aimed at investigating the analytical solutions of the presented equation. Adding the triple power law of the self-phase modulation parameter to the model, in addition to existing studies in the literature, emphasizes the innovative aspect and importance of the study. The first aim is to reveal bright and singular solitons using the new Kudryashov method. The new Kudryashov method is a technique that is frequently used in the literature, is effective for generating analytical solutions, provides ease of operation, and can be applied to a wide class of nonlinear partial differential equations. The second goal is to show that the obtained solutions have modulation stability. By using modulation instability analysis, the gain spectrum is formed for different parameter values. Graphic presentations support the findings. Moreover, bright and singular soliton portraits are demonstrated with 3D and 2D graphs. The novelty of the study lies in the fact that the relevant model has not been studied before with an effective method such as the new Kudryashov method, and the modulation instability has been studied for the first time.

Predicting weight gain in patients with cystic fibrosis on triple combination modulator.

Cystic fibrosis (CF) is caused by CF transmembrane conductance regulator (CFTR) gene mutations producing dysfunctional CFTR proteins leading to progressive clinical disease. Elexacaftor-tezacaftor-ivacaftor (ETI) remarkably improves lung disease but is associated with substantial weight gain. We performed a single-center longitudinal study predicting 6-month weight gain after ETI initiation. We used linear mixed effects modeling (LME) to determine association of ETI treatment with changing body mass index (BMI). Using linear regression, we examined BMI prediction models with distinct combinations of main effects to identify a model useful for patient counseling. We used up to eight commonly observed clinical characteristics as input variables (age, sex, percent predicted FEV1 [FEV1%], F508del homozygous state, pancreatic sufficiency, HgbA1c, prior modulator use and prior year number of pulmonary exacerbations). We evaluated 154 patients (19-73 years old, 54% female, FEV1% = 19-121, 0-6 prior year pulmonary exacerbations). LME demonstrated an association between ETI use and weight increases. Exhaustive testing suggested a parsimonious linear regression model well-fitted to data that is potentially useful for counseling. The two variable model shows that on average, BMI decreases by 0.045 (95% Confidence Interval [CI] = -0.069 to -0.021, p < 0.001) for every year of age and increases by 0.322 (CI = 0.142 to 0.502, p = 0.001) for each additional prior year exacerbation at the time of ETI initiation. Young patients with many prior year pulmonary exacerbations likely have the largest 6 month weight gain after starting ETI.

Dual and triple modulator therapy for chronic rhinosinusitis in cystic fibrosis patients.

The introduction of CFTR modulators has changed the landscape in the treatment of cystic fibrosis (CF) and early case series have shown improvements in sinonasal outcomes in this patient population. A real-word data study was performed to evaluate the impact of dual therapy with tezacaftor/ivacaftor (TEZ/IVA) and triple therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on CF-related chronic rhinosinusitis (CRS), by comparing subjective and objective outcome measures at baseline, 12 months after treatment with TEZ/IVA and six months after treatment with ELX/TEZ/IVA. In total, 43 CF patients, with a mean age of 32 years, were included. After triple therapy, significant improvements in overall visual analogue scale, SNOT-22, Lund Kennedy, nasal polyps, and Lund-Mackay scores were observed, whereas no beneficial effect could be seen in patients treated with dual therapy. Bacterial upper airway colonization did not differ pre- and postmodulator therapy in the present study. The number of responders to dual and triple therapy is 23.8% and 63.2% of the patients, respectively. Triple therapy with ELX/TEZ/IVA is superior to dual therapy with TEZ/IVA in the treatment of CF-CRS, as significantly reduced sinonasal complaints, nasal endoscopy and CT scores were observed after triple therapy, whereas this was not the case for dual therapy.

Enhancing Electrode Performance through Triple Distribution Modulation of Active Material, Conductive Agent, and Porosity.

The increasing demand for large-scale energy storage propels the development of lithium-ion batteries with high energy and high power density. Low tortuosity electrodes with aligned straight channels have proved to be effective in building such batteries. However, manufacturing such low tortuosity electrodes in large scale remains extremely challenging. In contrast, high-performance electrodes with customized gradients of materials and porosity are possible to be made by industrial roll-to-roll coating process. Yet, the desired design of gradients combining materials and porosity is unclear for high-performance gradient electrodes. Here, triple gradient LiFePO4 electrodes (TGE) are fabricated featuring distribution modulation of active material, conductive agent, and porosity by combining suction filtration with the phase inversion method. The effects and mechanism of active material, conductive agent, and porosity distribution on electrode performance are analyzed by experiments. It is found that the electrode with a gradual increase of active material content from current collector to separator coupled with the distribution of conductive agent and porosity in the opposite direction, demonstrates the best rate capability, the fastest electrochemical reaction kinetics, and the highest utilization of active material. This work provides valuable insights into the design of gradient electrodes with high performance and high potential in application.

Topology and Control Optimization of Bidirectional DC/DC Converter for Electric Vehicles

With the rapid development of intelligent electric vehicles, the number of electrical equipment increases, and the interconnection and energy transmission between on-board DC buses has become urgent. This paper proposes a partial isolated bidirectional converter based on dual active bridge converter. By partial switch sharing, the converter has a simplified structure and can supply energy to DC loads of different voltage levels. The system adopts a hybrid control strategy of pulse width modulation and triple phase shift modulation, and introduces a fundamental phase shift to reduce coupling between variables. The operation process is analyzed, and the models of transmitted power, current stress and soft-switching range under two typical operation modes, corresponding to the full load and light load, are established respectively. Under wide gain and different power distribution conditions, the multi-objective optimization is realized. Finally, the correctness of theoretical analysis is verified by experiments.

Nano‐Mediated PDT as a Multifunctional Immunomodulatory Agent in the Intricate Milieu of Melanoma

AbstractThe complexity of the tumor microenvironment (TME) and nutrient competition represent the main causes of therapy resistance in cancers, including malignant melanoma (MM). Photodynamic therapy (PDT), through a cascade of events including its ability to induce significant immune responses, causes tumor eradication. However, the high pigmentation level of melanoma, lack of adequate accumulation of photosensitizers (PSs) in the target tissue as well as their nonspecific toxicity represent three main obstacles to obtaining satisfactory responses in melanoma. To prevail over these challenges, this study employs a depigmentation strategy followed by a nano‐mediated topical application of PDT using a chlorophyllin derivative as PS, focusing on the evaluation of the immunomodulatory and metabolic regulatory axes of PDT in melanoma. Photo‐immunomodulation is assessed in a melanoma mouse model using a nanocarrier system of the PS. Markers of the immunosuppressive microenvironment and T cell exhaustion, as independent immune hallmarks, are quantified. The histopathology of the spleen and skin/tumor is evaluated. The amino acid profile is quantified from normal skin or tumor biopsies using UHPLC‐MS/MS. Around 80% of the 300 nm transethosomal ferrous chlorophyllin (fC‐TEs) are retained in the tumor over 24 h upon topical application. Arbutin 2% gel not only decreased the melanin content of tumors but also regulated the expression of interleukin 12 (IL‐12), IL‐10, transforming growth factor beta (TGF‐β), and tumor necrosis factor‐alpha (TNF‐α). Additionally, the nano‐mediated PDT strategy decreased the expression of programmed cell death protein 1 (PD‐1) and its ligand 1 (PD‐L1) and reduces the activity of arginase 1 (Arg1) through an upregulation of miRNA155. A mild recruitment of megakaryocytes (MKs) is observed in the spleen of the PDT group. This special localization of MKs depicts effector immune properties. Lastly, the combination of PDT and arbutin restores the normal tissue levels of arginine (Arg), and glutamine (Gln) and lavished those of tryptophan (Trp). Nano‐mediated PDT represents a novel immunotherapeutic approach in melanoma by a triple modulation of the immune suppressive TME, immune checkpoint signaling, and reprogrammed tumor metabolism.

The gut microbiota in adults with cystic fibrosis compared to colorectal cancer

BackgroundGut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples. We also assessed changes in CRC-associated taxa before and after triple CF transmembrane conductance regulator (CFTR) modulator therapy. MethodsBacterial DNA amplification comprising V4 16S rRNA analysis was conducted on 84 baseline and 53 matched follow-up stool samples from adults with CF. These data were compared to an existing cohort of 430 CRC and 491 control gFOBT samples from the NHS Bowel Cancer Screening Programme. Data were also compared to 26 previously identified CRC-associated taxa from a published meta-analysis. ResultsFaecal CF samples had a lower alpha diversity and clustered distinctly from both CRC and control samples, with no clear clinical variables explaining the variation. Compared to controls, CF samples had an increased relative abundance in 6 of the 20 enriched CRC-associated taxa and depletion of 2 of the 6 taxa which have been reported as reduced in CRC. Commencing triple modulator therapy had subtle influence on the relative abundance of CRC-associated microbiota (n = 23 paired CF samples). ConclusionsCF stool samples were clearly dysbiotic, clustering distinctly from both CRC and control samples. Several bacterial shifts in CF samples resembled those observed in CRC. Studies assessing the impact of dietary or other interventions and the longer-term use of CFTR modulators on reducing this potentially pro-oncogenic milieu are needed.