Inhibition of endocytic uptake of severe acute respiratory syndrome coronavirus 2 and endo-lysosomal acidification by diphenoxylate.

Cell culture-based screening of a chemical library identified diphenoxylate as an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The observed 50% effective concentrations ranged between 1.4 and 4.9 µM against the original wild-type strain and its variants. Time-of-addition experiments indicated that diphenoxylate is an entry blocker targeting a host factor involved in viral infection. Fluorescence microscopic analysis visualized that diphenoxylate prevented SARS-CoV-2 particles from penetrating the cell membrane and also impaired endo-lysosomal acidification. Diphenoxylate exhibited a synergistic inhibitory effect on SARS-CoV-2 infection in human lung epithelial Calu-3 cells when combined with a transmembrane serine protease 2 (TMPRSS2) inhibitor, nafamostat. This synergy suggested that efficient antiviral activity is achieved by blocking both TMPRSS2-mediated early and endosome-mediated late SARS-CoV-2 entry pathways. The antiviral efficacy of diphenoxylate against SARS-CoV-2 was reproducible in a human tonsil organoids system. In a transgenic mouse model expressing the obligate SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, intranasal administration of diphenoxylate (10 mg/kg/day) significantly reduced the viral RNA copy number in the lungs by 70% on day 3. This study underscores that diphenoxylate represents a promising core scaffold, warranting further exploration for chemical modifications aimed at developing a new class of clinically effective antiviral drugs against SARS-CoV-2.

Low-Temperature Nanosecond Laser Process of HZO-IGZO FeFETs toward Monolithic 3D System on Chip Integration.

Ferroelectric field-effect transistors (FeFETs) are increasingly important for in-memory computing and monolithic 3D (M3D) integration in system-on-chip (SoC) applications. However, the high-temperature processing required by most ferroelectric memories can lead to thermal damage to the underlying device layers, which poses significant physical limitations for 3D integration processes. To solve this problem, the study proposes using a nanosecond pulsed laser for selective annealing of hafnia-based FeFETs, enabling precise control of heat penetration depth within thin films. Sufficient thermal energy is delivered to the IGZO oxide channel and HZO ferroelectric gate oxide without causing thermal damage to the bottom layer, which has a low transition temperature (<250 °C). Using optimized laser conditions, a fast response time (<1 µs) and excellent stability (cycle > 106, retention > 106 s) are achieved in the ferroelectric HZO film. The resulting FeFET exhibited a wide memory window (>1.7 V) with a high on/off ratio (>105). In addition, moderate ferroelectric properties (2·Pr of 14.7 µC cm-2) and pattern recognition rate-based linearity (potentiation: 1.13, depression: 1.6) are obtained. These results demonstrate compatibility in HZO FeFETs by specific laser annealing control and thin-film layer design for various structures (3D integrated, flexible) with neuromorphic applications.

Piezoelectric catalytic driven advanced oxidation process using two-dimensional metal dichalcogenides for wastewater pollutants remediation.

The public and society have increasingly recognized numerous grave environmental issues, including water pollution, attributed to the rapid expansion of industrialization and agriculture. Renewable energy-driven catalytic advanced oxidation processes (AOPs) represent a green, sustainable, and environmentally friendly approach to meet the demands of environmental remediation. In this context, 2D transition metal dichalcogenides (TMDCs) piezoelectric materials, with their non-centrosymmetric crystal structure, exhibit unique features. They create dipole polarization, inducing a built-in electric field that generates polarized holes and electrons and triggers redox reactions, thereby facilitating the generation of reactive oxygen species for wastewater pollutant remediation. A broad spectrum of 2D TMDCs piezoelectric materials have been explored in self-integrated Fenton-like processes and persulfate activation processes. These materials offer a more simplistic and practical method than traditional approaches. Consequently, this review highlights recent advancements in 2D TMDCs piezoelectric catalysts and their roles in wastewater pollutant remediation through piezocatalytic-driven AOPs, such as Fenton-like processes and sulfate radicals-based oxidation processes.

Redesign of Anode Catalyst for Sustainable Survival of Fuel Cells.

Polymer electrolyte membrane fuel cells (PEMFCs) suffer from severe performance degradation when operating under harsh conditions such as fuel starvation, shut-down/start-up, and open circuit voltage. A fundamental solution to these technical issues requires an integrated approach rather than condition-specific solutions. In this study, an anode catalyst based on Pt nanoparticles encapsulated in a multifunctional carbon layer (MCL), acting as a molecular sieve layer and protective layer is designed. The MCL enabled selective hydrogen oxidation reaction on the surface of the Pt nanoparticles while preventing their dissolution and agglomeration. Thus, the structural deterioration of a membrane electrode assembly can be effectively suppressed under various harsh operating conditions. The results demonstrated that redesigning the anode catalyst structure can serve as a promising strategy to maximize the service life of the current PEMFC system.

Implantable Self-Reporting Stents for Detecting In-Stent Restenosis and Cardiac Functional Dynamics.

Despite the increasing number of stents implanted each year worldwide, patients remain at high risk for developing in-stent restenosis. Various self-reporting stents have been developed to address this challenge, but their practical utility has been limited by low sensitivity and limited data collection. Herein, we propose a next-generation self-reporting stent that can monitor blood pressure and blood flow inside the blood arteries. This proposed self-reporting stent utilizes a larger inductor coil encapsulated on the entire surface of the stent strut, resulting in a 2-fold increase in the sensing resolution and coupling distance between the sensor and external antenna. The dual-pressure sensors enable the detection of blood flow in situ. The feasibility of the proposed self-reporting stent is successfully demonstrated through in vivo analysis in rats, verifying its biocompatibility and multifunctional utilities. This multifunctional self-reporting stent has the potential to greatly improve cardiovascular care by providing real-time monitoring and unprecedented insight into the functional dynamics of the heart.

Correction: Quantitative assessment of cardiomyocyte mechanobiology through high-throughput cantilever-based functional well plate systems.

Correction for 'Quantitative assessment of cardiomyocyte mechanobiology through high-throughput cantilever-based functional well plate systems' by Jongyun Kim et al., Analyst, 2023, 148, 5133-5143, https://doi.org/10.1039/D3AN01286G.

Quantitative assessment of cardiomyocyte mechanobiology through high-throughput cantilever-based functional well plate systems.

Proper regulation of the in vitro cell culture environment is essential for disease modelling and drug toxicity screening. The main limitation of well plates used for cell culture is that they cannot accurately maintain energy sources and compounds needed during cell growth. Herein, to understand the importance of perfusion in cardiomyocyte culture, changes in contractile force and heart rate during cardiomyocyte growth are systematically investigated, and the results are compared with those of a perfusion-free system. The proposed perfusion system consists of a Peltier refrigerator, a peristaltic pump, and a functional well plate. A functional well plate with 12 wells is made through injection moulding, with two tubes integrated in the cover for each well to continuously circulate the culture medium. The contractile force of cardiomyocytes growing on the cantilever surface is analysed through changes in cantilever displacement. The maturation of cardiomyocytes is evaluated through fluorescence staining and western blot; cardiomyocytes cultured in the perfusion system show greater maturity than those cultured in a manually replaced culture medium. The pH of the culture medium manually replaced at intervals of 3 days decreases to 6.8, resulting in an abnormal heartbeat, while cardiomyocytes cultured in the perfusion system maintained at pH 7.4 show improved contractility and a uniform heart rate. Two well-known ion channel blockers, verapamil and quinidine, are used to measure changes in the contractile force of cardiomyocytes from the two systems. Cardiomyocytes in the perfusion system show greater stability during drug toxicity screening, proving that the perfusion system provides a better environment for cell growth.

Discovery and Feasibility Study of Medical Fluorophore 33 as a Novel Theranostic Agent.

Fluorescent dyes have garnered significant attention as theranostic platforms owing to their inherent characteristics. In this study, we present the discovery of Medical Fluorophore 33 (MF33), a novel and potent theranostic agent with a phenaleno-isoquinolinium salt structure that can serve as a cancer therapeutic strategy. The synthesis of MF33 is readily achievable through a simple Rh(III)-catalyzed reaction. Moreover, MF33 displayed strong fluorescence signals, excellent microsomal stability, and high biocompatibility in vivo. It induces significant apoptosis in cancer cells via the p53/p21/caspase-3 signaling pathway, leading to selective cytotoxicity in various cancer cells. In vivo fluorescence imaging with MF33 enabled the visualization of sentinel lymph nodes in living mice. Notably, repeated intraperitoneal administration of MF33 resulted in antitumor activity in mice with colorectal cancer. Collectively, our findings suggest that phenaleno-isoquinolinium salt-based MF33 is a viable theranostic agent for biomedical imaging and cancer treatment.

Kidney sparing surgery in upper tract urothelial carcinoma: paradigm change in surgical treatment for ureter cancer.

PURPOSE: To extend the indications of kidney-sparing surgery (KSS) for ureter cancer by comparing the oncological outcomes between patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU) or KSS. METHODS: We retrospectively reviewed 708 patients with UTUC who underwent RNU (N = 646) or KSS (N = 62) between 2011 and 2019 to analyze the oncologic outcomes and prognostic factors. Subgroup analyses were performed for patients with unifocal ureteral urothelial carcinoma (UC). RESULTS: No significant difference was observed in the overall survival (OS) or cancer-specific survival (CSS) between RNU and KSS (distal ureterectomy with reimplantation (N = 33), ureterectomy with ileal ureter (N = 14), ureteroscopic tumor resection (N = 10), and ureterectomy with ureteroureterostomy (N = 5)). Among 269 (38.0%) patients with unifocal ureteral UC, 219 and 50 patients underwent RNU and KSS, respectively. OS and CSS were not significantly different between these two groups. Pathologic stage was a significant risk factor in multivariate analysis (hazard ratio = 2.621; p = 0.000). Among 646 RNU patients, 219 (33.9%) had unifocal ureteral UC, 40 (18.3%) with low-grade tumors. Among these, 13 (5.9%) patients with unifocal, low-grade and small (< 2 cm) tumors received nephroureterectomy. CONCLUSION: Kidney-sparing surgery should be regarded as an important alternative to RNU for patients with unifocal ureteral UC thought to have noninvasive disease to preserve renal function and reduce overtreatment.

Effect of decreased renal function on poor oncological outcome after radical cystectomy.

PURPOSE: To evaluate the impact of preoperative renal impairment on the oncological outcomes of patients with urothelial carcinoma who underwent radical cystectomy. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients with urothelial carcinoma who underwent radical cystectomy from 2004 to 2017. All patients who underwent preoperative 99mTc-diethylenetriaminepentaacetic acid renal scintigraphy (DTPA) were identified. We divided the patients into two groups according to their glomerular filtration rates (GFRs): GFR group 1, GFR≥90 mL/min/1.73 m²; GFR group 2, 60≤GFR<90 mL/min/1.73 m². We included 89 patients in GFR group 1 and 246 patients in GFR group 2 and compared the clinicopathological characteristics and oncological outcomes between the two groups. RESULTS: The mean time required for recurrence was 125.5±8.0 months in GFR group 1 and 85.7±7.4 months in GFR group 2 (p=0.030). The mean cancer-specific survival was 131.7±7.8 months in GFR group 1 and 95.5±6.9 months in GFR group 2 (p=0.051). The mean overall survival was 123.3±8.1 months in GFR group 1 and 79.5±6.6 months in GFR group 2 (p=0.004). CONCLUSIONS: Preoperative GFR values in the range of 60≤GFR<90 mL/min/1.73 m² are independent prognostic factors for poor recurrence-free survival, cancer-specific survival, and overall survival in patients after radical cystectomy compared with GFR values of ≥90 mL/min/1.73 m².

Understanding cell fate acquisition in stem-cell-derived pancreatic islets using single-cell multiome-inferred regulomes.

Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem-cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, serotonin-producing pre-ß cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro ß cell maturation and identify sex hormones as drivers of ß cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem-cell-derived islets and a framework for manipulating cell identities and maturity.

Carboxylate-functionalized dragon fruit peel powder as an effective adsorbent for the removal of Rhodamine B (cationic dye) from aqueous solution: adsorption behavior and mechanism.

In this study, we used a simple and low-toxicity chemical treatment to make a carboxylate-functionalized dragon fruit peel powder (CF-DFPP) from dragon fruit peel to improve its capacity for adsorbing Rhodamine B (RhB) from an aqueous medium. Field Emission-Scanning Electron Microscopy/Energy-Dispersive X-ray (FE-SEM/EDX), point of zero charges (pHPZC), Brunauer-Emmett-Teller (BET), and Fourier Transform Infrared (FT-IR) analyses were performed to characterize the adsorbent materials. The adsorption performance and mechanism for the removal of RhB were examined. The kinetic, isotherm and thermodynamic parameters were employed to evaluate the adsorption mechanism. Compared to other models, the Langmuir isotherm and PSO kinetic models better defined the experimental data. CF-DFPP adsorbent exhibited a maximum adsorption efficiency of 228.7 mg/g at 298 K for RhB adsorption. Thermodynamic analysis revealed that the adsorption of RhB by CF-DFPP was spontaneous (ΔGo < 0) and exothermic (ΔHo < 0) nature of the process. Different eluting agents were used in desorption tests, and NaOH was revealed to have greater desorption efficiency (96.8%). Furthermore, regeneration examinations revealed that the biosorbent could effectively retain RhB, even after six adsorption/desorption cycles. These findings demonstrated that the CF-DFPP might be a novel material for removing RhB from an aqueous medium.

Oxygen Plasma-Mediated Microstructured Hydrocarbon Membrane for Improving Interface Adhesion and Mass Transport in Polymer Electrolyte Fuel Cells.

Developing a method for fabricating high-efficient and low-cost fuel cells is imperative for commercializing polymer electrolyte membrane (PEM) fuel cells (FCs). This study introduces a mechanical and chemical modification technique using the oxygen plasma irradiation process for hydrocarbon-based (HC) PEM. The oxygen functional groups were introduced on the HC-PEM surface through the plasma process in the controlled area, and microsized structures were formed. The modified membrane was incorporated with plasma-treated electrodes, improving the adhesive force between the HC-PEM and the electrode. The decal transfer was enabled at low temperatures and pressures, and the interfacial resistance in the membrane-electrode assembly (MEA) was reduced. Furthermore, the micropillar structured electrode configuration significantly reduced the oxygen transport resistance in the MEA. Various diagnostic techniques were conducted to find out the effects of the membrane surface modification, interface adhesion, and mass transport, such as physical characterizations, mechanical stress tests, and diverse electrochemical measurements.

Reinforced Nafion Membrane with Ultrathin MWCNTs/Ceria Layers for Durable Proton-Exchange Membrane Fuel Cells.

For further commercializing proton-exchange membrane fuel cells, it is crucial to attain long-term durability while achieving high performance. In this study, a strategy for modifying commercial Nafion membranes by introducing ultrathin multiwalled carbon nanotubes (MWCNTs)/CeO2 layers on both sides of the membrane was developed to construct a mechanically and chemically reinforced membrane electrode assembly. The dispersion properties of the MWCNTs were greatly improved through chemical modification with acid treatment, and the mixed solution of MWCNTs/CeO2 was uniformly prepared through a high-energy ball-milling process. By employing a spray-coating technique, the ultrathin MWCNTs/CeO2 layers were introduced onto the membrane surfaces without any agglomeration problem because the solvent rapidly evaporated during the layer-by-layer stacking process. These ultrathin and highly dispersed MWCNTs/CeO2 layers effectively reinforced the mechanical properties and chemical durability of the membrane while minimizing the performance drop despite their non-ion-conducting properties. The characteristics of the MWCNTs/CeO2 layers and the reinforced Nafion membrane were investigated using various in situ and ex situ measurement techniques; in addition, electrochemical measurements for fuel cells were conducted.

Stress induced self-rollable smart-stent-based U-health platform for in-stent restenosis monitoring.

To date, several smart stents have been proposed to continuously detect biological cues, which is essential for tracking patients' critical vital signs and therapy. However, the proposed smart stent fabrication techniques rely on conventional laser micro-cutting or 3D printing technologies. The sensors are then integrated into the stent structure using an adhesive, conductive epoxy, or laser micro-welding process. The sensor packaging method using additional fabrication processes can cause electrical noise, and there is a possibility of sensor detachment from the sent structure after implantation, which may pose a significant risk to patients. Herein, we are demonstrating for the first time a single-step fabrication method to develop a smart stent with an integrated sensor for detecting in-stent restenosis and assessing the functional dynamics of the heart. The smart stent is fabricated using a microelectromechanical system (MEMS)-based micromachining technology. The proposed smart stent can detect biological cues without additional power and wirelessly transmit the signal to the network analyzer. The cytocompatibility of the smart stent is confirmed through a cytotoxicity test by monitoring the cell growth, proliferation, and viability of the cultured cardiomyocytes. The capacitance of the smart stent exhibits an excellent linear relationship with the applied pressure. The exceptional sensitivity of the pressure sensor enabled the proposed smart stent to detect biological cues during in vivo analysis. The preliminary findings confirmed the proposed smart stent's higher level of structural integrity, durability and repeatability. Finally, the practical feasibility of the smart stent is demonstrated by monitoring diastole and systole at various beat rates using a phantom. The results of the phantom study showed a similar pattern to the human model, indicating the potential use of the proposed multifunctional smart stent for real-time applications.

The effect of cancer on traditional, complementary and alternative medicine utilization in Korea: a fixed effect analysis using Korea Health Panel data.

BACKGROUND: Cancer-related incidence and mortality rates are rapidly increasing worldwide. However, no studies have examined the effect of cancer as a single factor on the use of traditional, complementary, and alternative medicine (T&CAM). We aimed to determine the effect of cancer occurrence on T&CAM utilization using Korea Health Panel (KHP) data. METHODS: We analyzed longitudinal data (49,380 observations) derived from 12,975 Korean adult participants with complete KHP data from 2011 to 2014 and 2016, and divided them into two groups based on cancer diagnosis. A panel multinomial logit model was used to assess whether the participants used T&CAM or conventional medicine or both in outpatient settings. Additionally, a negative binomial regression model was used to examine the effect of cancer on the number of outpatient visits for T&CAM. RESULTS: In total, 25.54% of the study participants in the cancer group used T&CAM, which was higher than that in the non-cancer group (18.37%, p < 0.0001). A panel multinomial logistic regression analysis using KHP data showed that cancer occurrence was significantly more likely to be associated with 'Using both Korean medicine and conventional medicine' (Coef. = 0.80, p = 0.017) and 'Not using Korean medicine but using conventional medicine' (Coef. = 0.85, p = 0.008) than 'Not using Korean medicine and conventional medicine.' A panel negative binomial regression showed a significant effect of cancer on increasing the number of T&CAM outpatient visits (Coef. = 0.11, p = 0.040). CONCLUSIONS: Our findings showed that cancer occurrence within an individual led to the simultaneous use of conventional medicine and T&CAM. In addition, the occurrence of cancer significantly increased the number of T&CAM outpatient visits among participants already using T&CAM. It was also found that T&CAM has been utilized more often by the most vulnerable people, such as medical beneficiaries and those with a low level of education.

A Study on the Development of a Model for Providing Traditional Korean Medicine and Welfare Services for Community Care.

Objectives: This study aims to develop a community care model in traditional Korean medicine (TKM) by developing a community care participation model for the health of the elderly and deriving tasks to implement it. Methods: This study implemented a group interview with experts. A fact-finding survey was conducted targeting 16 local governments that are implementing a leading project to identify the status of TKM service provision and welfare service linkage in all regions. An expert group interview (FGI) targeted public and private sector experts for each job role, the former represented by those in charge of the central government's health care policy and administrative delivery system, and the latter by professors majoring in social welfare, professors majoring in health, and local TKM societies. After forming the expert groups, three expert group interviews were conducted. Results: Through collective interviews with experts, a model for providing TKM and welfare services in community integrated care was derived by dividing it into local and central government levels. The strategies and tasks for promoting TKM-oriented health welfare services were derived from 3 strategies, 8 tasks, and 20 detailed tasks. Conclusion: The core direction of the TKM health care model is the region-centered provision of TKM and welfare services. To this end, policy support for the use and linkage of health care service resources is required at the central government level, and linkage and provision of health welfare services centered on TKM are necessary through linkage and convergence between service subjects and between government health care projects.

Developing Microbial Co-Culture System for Enhanced Polyhydroxyalkanoates (PHA) Production Using Acid Pretreated Lignocellulosic Biomass.

In the growing polymer industry, the interest of researchers is captivated by bioplastics production with biodegradable and biocompatible properties. This study examines the polyhydroxyalkanoates (PHA) production performance of individual Lysinibacillus sp. RGS and Ralstonia eutropha ATCC 17699 and their co-culture by utilizing sugarcane bagasse (SCB) hydrolysates. Initially, acidic (H2SO4) and acidified sodium chlorite pretreatment was employed for the hydrolysis of SCB. The effects of chemical pretreatment on the SCB biomass assembly and its chemical constituents were studied by employing numerous analytical methods. Acidic pretreatment under optimal conditions showed effective delignification (60%) of the SCB biomass, leading to a maximum hydrolysis yield of 74.9 ± 1.65% and a saccharification yield of 569.0 ± 5.65 mg/g of SCB after enzymatic hydrolysis. The resulting SCB enzymatic hydrolysates were harnessed for PHA synthesis using individual microbial culture and their defined co-culture. Co-culture strategy was found to be effective in sugar assimilation, bacterial growth, and PHA production kinetic parameters relative to the individual strains. Furthermore, the effects of increasing acid pretreated SCB hydrolysates (20, 30, and 40 g/L) on cell density and PHA synthesis were studied. The effects of different cost-effective nutrient supplements and volatile fatty acids (VFAs) with acid pretreated SCB hydrolysates on cell growth and PHA production were studied. By employing optimal conditions and supplementation of corn steep liquor (CSL) and spent coffee waste extracted oil (SCGO), the co-culture produced maximum cell growth (DCW: 11.68 and 11.0 g/L), PHA accumulation (76% and 76%), and PHA titer (8.87 and 8.36 g/L), respectively. The findings collectively suggest that the development of a microbial co-culture strategy is a promising route for the efficient production of high-value bioplastics using different agricultural waste biomass.

Lignin-Mediated Silver Nanoparticle Synthesis for Photocatalytic Degradation of Reactive Yellow 4G and In Vitro Assessment of Antioxidant, Antidiabetic, and Antibacterial Activities.

This study explored the potential of abundantly available sodium lignosulfonate (LS) as a reducer and fabricating agent in preparing silver nanoparticles (LS-Ag NPs). The operational conditions were optimized to make the synthesis process simpler, rapid, and eco-friendly. The prepared LS-Ag NPs were analyzed via UV-Vis spectroscopy, X-ray diffraction spectroscopy, Fourier transform infrared spectroscopy, and high-resolution transmission electron microscopy. Results demonstrated that LS-Ag NPs were of crystalline structure, capped with LS constituents, and spherical in shape with a size of approximately 20 nm. Under optimized conditions, LS-Ag NPs exhibited significant photocatalytic activity in Reactive Yellow 4G degradation. The effects of photocatalyst (LS-Ag NPs) dosage, dye concentration, and its reusability for dye degradation were studied to make the process practically applicable in textile wastewater treatment. Additionally, the synthesized LS-Ag NPs displayed significant free radical scavenging against 2-diphenyl-1-picrylhydrazyl (DPPH) with an IC50 value of (50.2 ± 0.70 µg/mL) and also exhibited antidiabetic activity in terms of inhibition in the activity of carbohydrate-degrading marker enzyme α-glucosidase with an IC50 value of (58.1 ± 0.65 µg/mL). LS-Ag NPs showed substantial antibacterial potential against pathogenic strains, namely E. coli and S. aureus. In conclusion, LS-Ag NPs can be a reliable and eco-friendly material for their possible application in the treatment of dye-containing wastewater and have a great perspective in the biomedical and pharmaceutical sectors.