Gene-Environment Interaction in the Era of Precision Medicine.

Innovative analytical frameworks are required to capture the complex gene-environment interactions. We investigate the insufficiency of commonly used models for disease genome analysis and suggest considering genetic interactions in complex diseases. For non-genetic factors, we study the emerging wearable technologies that have enabled quantification of physiological and environmental factors at an unprecedented breadth and depth. We propose a Bayesian framework to hierarchically model personalized gene-environmental interaction to enable precision health and medicine.

Decoding the Genomics of Abdominal Aortic Aneurysm.

A key aspect of genomic medicine is to make individualized clinical decisions from personal genomes. We developed a machine-learning framework to integrate personal genomes and electronic health record (EHR) data and used this framework to study abdominal aortic aneurysm (AAA), a prevalent irreversible cardiovascular disease with unclear etiology. Performing whole-genome sequencing on AAA patients and controls, we demonstrated its predictive precision solely from personal genomes. By modeling personal genomes with EHRs, this framework quantitatively assessed the effectiveness of adjusting personal lifestyles given personal genome baselines, demonstrating its utility as a personal health management tool. We showed that this new framework agnostically identified genetic components involved in AAA, which were subsequently validated in human aortic tissues and in murine models. Our study presents a new framework for disease genome analysis, which can be used for both health management and understanding the biological architecture of complex diseases. VIDEO ABSTRACT.

Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue.

Invariant natural killer T cells (iNKT cells) are lipid-sensing innate T cells that are restricted by the antigen-presenting molecule CD1d and express the transcription factor PLZF. iNKT cells accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, as well as their targets in adipose tissue, are unknown. Here we found that iNKT cells in adipose tissue had a unique transcriptional program and produced interleukin 2 (IL-2) and IL-10. Unlike other iNKT cells, they lacked PLZF but expressed the transcription factor E4BP4, which controlled their IL-10 production. The adipose iNKT cells were a tissue-resident population that induced an anti-inflammatory phenotype in macrophages and, through the production of IL-2, controlled the number, proliferation and suppressor function of regulatory T cells (Treg cells) in adipose tissue. Thus, iNKT cells in adipose tissue are unique regulators of immunological homeostasis in this tissue.

A tale of two copies: Evolutionary trajectories of moth pheromone receptors.

Pheromone communication is an essential component of reproductive isolation in animals. As such, evolution of pheromone signaling can be linked to speciation. For example, the evolution of sex pheromones is thought to have played a major role in the diversification of moths. In the crop pests Spodoptera littoralis and S. litura, the major component of the sex pheromone blend is (Z,E)-9,11-tetradecadienyl acetate, which is lacking in other Spodoptera species. It indicates that a major shift occurred in their common ancestor. It has been shown recently in S. littoralis that this compound is detected with high specificity by an atypical pheromone receptor, named SlitOR5. Here, we studied its evolutionary history through functional characterization of receptors from different Spodoptera species. SlitOR5 orthologs in S. exigua and S. frugiperda exhibited a broad tuning to several pheromone compounds. We evidenced a duplication of OR5 in a common ancestor of S. littoralis and S. litura and found that in these two species, one duplicate is also broadly tuned while the other is specific to (Z,E)-9,11-tetradecadienyl acetate. By using ancestral gene resurrection, we confirmed that this narrow tuning evolved only in one of the two copies issued from the OR5 duplication. Finally, we identified eight amino acid positions in the binding pocket of these receptors whose evolution has been responsible for narrowing the response spectrum to a single ligand. The evolution of OR5 is a clear case of subfunctionalization that could have had a determinant impact in the speciation process in Spodoptera species.

Precision environmental health monitoring by longitudinal exposome and multi-omics profiling.

Conventional environmental health studies have primarily focused on limited environmental stressors at the population level, which lacks the power to dissect the complexity and heterogeneity of individualized environmental exposures. Here, as a pilot case study, we integrated deep-profiled longitudinal personal exposome and internal multi-omics to systematically investigate how the exposome shapes a single individual's phenome. We annotated thousands of chemical and biological components in the personal exposome cloud and found they were significantly correlated with thousands of internal biomolecules, which was further cross-validated using corresponding clinical data. Our results showed that agrochemicals and fungi predominated in the highly diverse and dynamic personal exposome, and the biomolecules and pathways related to the individual's immune system, kidney, and liver were highly associated with the personal external exposome. Overall, this data-driven longitudinal monitoring study shows the potential dynamic interactions between the personal exposome and internal multi-omics, as well as the impact of the exposome on precision health by producing abundant testable hypotheses.

An odorant receptor mediates the avoidance of Plutella xylostella against parasitoid.

BACKGROUND: Ecosystems are brimming with myriad compounds, including some at very low concentrations that are indispensable for insect survival and reproduction. Screening strategies for identifying active compounds are typically based on bioassay-guided approaches. RESULTS: Here, we selected two candidate odorant receptors from a major pest of cruciferous plants-the diamondback moth Plutella xylostella-as targets to screen for active semiochemicals. One of these ORs, PxylOR16, exhibited a specific, sensitive response to heptanal, with both larvae and adult P. xylostella displaying heptanal avoidance behavior. Gene knockout studies based on CRISPR/Cas9 experimentally confirmed that PxylOR16 mediates this avoidance. Intriguingly, rather than being involved in P. xylostella-host plant interaction, we discovered that P. xylostella recognizes heptanal from the cuticular volatiles of the parasitoid wasp Cotesia vestalis, possibly to avoid parasitization. CONCLUSIONS: Our study thus showcases how the deorphanization of odorant receptors can drive discoveries about their complex functions in mediating insect survival. We also demonstrate that the use of odorant receptors as a screening platform could be efficient in identifying new behavioral regulators for application in pest management.

Transcriptomic and physiological analysis of atractylodes chinensis in response to drought stress reveals the putative genes related to sesquiterpenoid biosynthesis.

BACKGROUND: Atractylodes chinensis (DC) Koidz., a dicotyledonous and hypogeal germination species, is an important medicinal plant because its rhizome is enriched in sesquiterpenes. The development and production of A. chinensis are negatively affected by drought stress, especially at the seedling stage. Understanding the molecular mechanism of A. chinensis drought stress response plays an important role in ensuring medicinal plant production and quality. In this study, A. chinensis seedlings were subjected to drought stress treatment for 0 (control), 3 (D3), and 9 days (D9). For the control, the sample was watered every two days and collected on the second morning after watering. The integration of physiological and transcriptomic analyses was carried out to investigate the effects of drought stress on A. chinensis seedlings and to reveal the molecular mechanism of its drought stress response. RESULTS: The malondialdehyde, proline, soluble sugar, and crude protein contents and antioxidative enzyme (superoxide dismutase, peroxidase, and catalase) activity were significantly increased under drought stress compared with the control. Transcriptomic analysis indicated a total of 215,665 unigenes with an average length of 759.09 bp and an N50 of 1140 bp. A total of 29,449 differentially expressed genes (DEGs) were detected between the control and D3, and 14,538 DEGs were detected between the control and D9. Under drought stress, terpenoid backbone biosynthesis had the highest number of unigenes in the metabolism of terpenoids and polyketides. To identify candidate genes involved in the sesquiterpenoid and triterpenoid biosynthetic pathways, we observed 22 unigene-encoding enzymes in the terpenoid backbone biosynthetic pathway and 15 unigene-encoding enzymes in the sesquiterpenoid and triterpenoid biosynthetic pathways under drought stress. CONCLUSION: Our study provides transcriptome profiles and candidate genes involved in sesquiterpenoid and triterpenoid biosynthesis in A. chinensis in response to drought stress. Our results improve our understanding of how drought stress might affect sesquiterpenoid and triterpenoid biosynthetic pathways in A. chinensis.

A Highly Sensitive and Selective Fluorescent Sensor for Folic Acid Detection Based on D-penicillamine Stabilized Ag/Cu Alloy Nanoclusters.

In this work, a highly sensitive and selective method for detecting folic acid (FA) was developed using D-penicillamine (DPA) stabilized Ag/Cu alloy nanoclusters (DPA@Ag/Cu NCs). The yellow emission of DPA@Ag/Cu NCs was found to be quenched upon the addition of FA to the system. The fluorescence intensity quenching value demonstrated a linear relationship with FA concentrations ranging from 0.01 to 1200 µM, with a limit of detection (LOD) of 5.3 nM. Furthermore, the detection mechanism was investigated through various characterization analyses, including high resolution transmission electron microscopy, fluorescence spectra, ultraviolet-visible absorption spectra, and fluorescence lifetime. The results indicated that the fluorescence quenching induced by FA was a result of electron transfer from FA to the ligands of DPA@Ag/Cu NCs. The selectivity of the FA sensor was also evaluated, showing that common amino acids and inorganic ions had minimal impact on the detection of FA. Moreover, the standard addition method was successfully applied to detect FA in human serum, chewable tablets and FA tablets with promising results. The use of DPA@Ag/Cu NCs demonstrates significant potential for detecting FA in complex biological samples.

Deep learning-based pseudo-mass spectrometry imaging analysis for precision medicine.

Liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics provides systematic profiling of metabolic. Yet, its applications in precision medicine (disease diagnosis) have been limited by several challenges, including metabolite identification, information loss and low reproducibility. Here, we present the deep-learning-based Pseudo-Mass Spectrometry Imaging (deepPseudoMSI) project (https://www.deeppseudomsi.org/), which converts LC-MS raw data to pseudo-MS images and then processes them by deep learning for precision medicine, such as disease diagnosis. Extensive tests based on real data demonstrated the superiority of deepPseudoMSI over traditional approaches and the capacity of our method to achieve an accurate individualized diagnosis. Our framework lays the foundation for future metabolic-based precision medicine.

Circadian rhythm disruption upregulating Per1 in mandibular condylar chondrocytes mediating temporomandibular joint osteoarthritis via GSK3ß/ß-CATENIN pathway.

BACKGROUND: Temporomandibular joint osteoarthritis (TMJOA) has a high incidence rate, but its pathogenesis remains unclear. Circadian rhythm is an important oscillation in the human body and influences various biological activities. However, it is still unclear whether circadian rhythm affects the onset and development of TMJOA. METHODS: We disrupted the normal rhythm of rats and examined the expression of core clock genes in the mandibular condylar cartilage of the jaw and histological changes in condyles. After isolating rat mandibular condylar chondrocytes, we upregulated or downregulated the clock gene Per1, examined the expression of cartilage matrix-degrading enzymes, tested the activation of the GSK3ß/ß-CATENIN pathway and verified it using agonists and inhibitors. Finally, after downregulating the expression of Per1 in the mandibular condylar cartilage of rats with jet lag, we examined the expression of cartilage matrix-degrading enzymes and histological changes in condyles. RESULTS: Jet lag led to TMJOA-like lesions in the rat mandibular condyles, and the expression of the clock gene Per1 and cartilage matrix-degrading enzymes increased in the condylar cartilage of rats. When Per1 was downregulated or upregulated in mandibular condylar chondrocytes, the GSK3ß/ß-CATENIN pathway was inhibited or activated, and the expression of cartilage matrix-degrading enzymes decreased or increased, which can be rescued by activator and inhibitor of the GSK3ß/ß-CATENIN pathway. Moreover, after down-regulation of Per1 in mandibular condylar cartilage in vivo, significant alleviation of cartilage degradation, cartilage loss, subchondral bone loss induced by jet lag, and inhibition of the GSK3ß/ß-CATENIN signaling pathway were observed. Circadian rhythm disruption can lead to TMJOA. The clock gene Per1 can promote the occurrence of TMJOA by activating the GSK3ß/ß-CATENIN pathway and promoting the expression of cartilage matrix-degrading enzymes. The clock gene Per1 is a target for the prevention and treatment of TMJOA.

Hyperglycemia Induces Tear Reduction and Dry Eye in Diabetic Mice through the Norepinephrine-α1 Adrenergic Receptor-Mitochondrial Impairment Axis of Lacrimal Gland.

Dry eye syndrome is a common complication in diabetic patients with a prevalence of up to 54.3%. However, the pathogenic mechanisms underlying hyperglycemia-induced tear reduction and dry eye remain less understood. The present study indicated that both norepinephrine (NE) and tyrosine hydroxylase levels were elevated in the lacrimal gland of diabetic mice, accompanied by increased Fos proto-oncogene (c-FOS)+ cells in the superior cervical ganglion. However, the elimination of NE accumulation by surgical and chemical sympathectomy significantly ameliorated the reduction in tear production, suppressed abnormal inflammation of the lacrimal gland, and improved the severity of dry eye symptoms in diabetic mice. Among various adrenergic receptors (ARs), the α1 subtype played a predominant role in the regulation of tear production, as treatments of α1AR antagonists improved tear secretion in diabetic mice compared with ßAR antagonist propranolol. Moreover, the α1AR antagonist alfuzosin treatment also alleviated functional impairments of the meibomian gland and goblet cells in diabetic mice. Mechanically, the α1AR antagonist rescued the mitochondrial bioenergetic deficit, increased the mitochondrial DNA copy numbers, and elevated the glutathione levels of the diabetic lacrimal gland. Overall, these results deciphered a previously unrecognized involvement of the NE-α1AR-mitochondrial bioenergetics axis in the regulation of tear production in the lacrimal gland, which may provide a potential strategy to counteract diabetic dry eye by interfering with the α1AR activity.

Design and Asymmetric Control of Orientational Chirality by Using the Combination of C(sp2)-C(sp) Levers and Achiral N-Protecting Group.

New chiral targets of orientational chirality have been designed and asymmetrically synthesized by taking advantage of N-sulfinyl imine-directed nucleophilic addition/oxidation, Suzuki-Miyaura, and Sonogashira cross-coupling reactions. Orientation of single isomers has been selectively controlled by using aryl/alkynyl levers [C(sp2)-C(sp) axis] and tBuSO2- protecting group on nitrogen as proven by X-ray diffraction analysis. The key structural characteristic of resulting orientational products is shown by remote through-space blocking manner. Seventeen examples of multi-step synthesis were obtained with modest to good chemical yields and complete orientational selectivity.

Electrosynthesis of Ammonia from Nitrate Using a Self-Activated Carbon Fiber Paper.

While electrochemically upcycling nitrate wastes to valuable ammonia is considered a very promising pathway for tackling the environmental and energy challenges underlying the nitrogen cycle, the effective catalysts involved are mainly limited to metal-based materials. Here, we report that commercial carbon fiber paper, which is a classical current collector and is typically assumed to be electrochemically inert, can be significantly activated during the reaction. As a result, it shows a high NH3 Faradaic efficiency of 87.39% at an industrial-level current density of 300 mA cm-2 for over 90 h of continuous operation, with a NH3 production rate of as high as 1.22 mmol cm-2 h-1. Through experimental and theoretical analysis, the in situ-formed oxygen functional groups are demonstrated to be responsible for the NO3RR performance. Among them, the C-O-C group is finally identified as the active center, which lowers the thermodynamic energy barrier and simultaneously improves the hydrogenation kinetics. Moreover, high-purity NH4Cl and NH3·H2O were obtained by coupling the NO3RR with an air-stripping approach, providing an effective way for converting nitrate waste into high-value-added NH3 products.

Semisynthesis and biological evaluation of novel honokiol thioethers against colon cancer cells HCT116 via inhibiting the transcription and expression of YAP protein.

Honokiol, derived from Magnolia officinalis (a traditional Chinese medicine), has been reported to have anticancer activity. Here, a series of novel honokiol thioethers bearing a 1,3,4-oxadiazole moiety were prepared and evaluated for their anticancer activities against three types of digestive system tumor cells. Biological evaluation showed that honokiol derivative 3k exhibited the best antiproliferative activity against HCT116 cells with an IC50 value of 6.1 µmol/L, superior to the reference drug 5-fluorouracil (IC50: 9.63 ± 0.27 µmol/L). The structure-activity relationships (SARs) indicated that the introduction of -(4-NO2)Ph, 3-pyridyl, -(2-F)Ph, -(4-F)Ph, -(3-F)Ph, -(4-Cl)Ph, and -(3-Cl)Ph groups was favorable for enhancing the anticancer activity of the title honokiol thioethers. Further study revealed that honokiol thioether 3k can well inhibit the proliferation of colon cancer cells HCT116, arresting the cells in G1 phase and inducing cell death. Moreover, a preliminary mechanism study indicated that 3k directly inhibits the transcription and expression of YAP protein without activating the Hippo signaling pathway. Thus, honokiol thioether 3k could be deeply developed for the development of honokiol-based anticancer candidates.

Point Cloud Registration Method Based on Geometric Constraint and Transformation Evaluation.

Existing point-to-point registration methods often suffer from inaccuracies caused by erroneous matches and noisy correspondences, leading to significant decreases in registration accuracy and efficiency. To address these challenges, this paper presents a new coarse registration method based on a geometric constraint and a matrix evaluation. Compared to traditional registration methods that require a minimum of three correspondences to complete the registration, the proposed method only requires two correspondences to generate a transformation matrix. Additionally, by using geometric constraints to select out high-quality correspondences and evaluating the matrix, we greatly increase the likelihood of finding the optimal result. In the proposed method, we first employ a combination of descriptors and keypoint detection techniques to generate initial correspondences. Next, we utilize the nearest neighbor similarity ratio (NNSR) to select high-quality correspondences. Subsequently, we evaluate the quality of these correspondences using rigidity constraints and salient points' distance constraints, favoring higher-scoring correspondences. For each selected correspondence pair, we compute the rotation and translation matrix based on their centroids and local reference frames. With the transformation matrices of the source and target point clouds known, we deduce the transformation matrix of the source point cloud in reverse. To identify the best-transformed point cloud, we propose an evaluation method based on the overlap ratio and inliers points. Through parameter experiments, we investigate the performance of the proposed method under various parameter settings. By conducting comparative experiments, we verified that the proposed method's geometric constraints, evaluation methods, and transformation matrix computation consistently outperformed other methods in terms of root mean square error (RMSE) values. Additionally, we validated that our chosen combination for generating initial correspondences outperforms other descriptor and keypoint detection combinations in terms of the registration result accuracy. Furthermore, we compared our method with several feature-matching registration methods, and the results demonstrate the superior accuracy of our approach. Ultimately, by testing the proposed method on various types of point cloud datasets, we convincingly established its effectiveness. Based on the evaluation and selection of correspondences and the registration result's quality, our proposed method offers a solution with fewer iterations and higher accuracy.

Optimization Design of CMUT Sensors with Broadband and High Sensitivity Characteristics Based on the Genetic Algorithm.

In this study, we propose a method for optimizing the design of CMUT sensors using genetic algorithms. Existing CMUT sensors face frequency response and sensitivity limitations, necessitating optimization to enhance their sensing performance. Traditional optimization methods are often intricate and time-consuming and may fail to yield the optimal solution. Genetic algorithms, which simulate the biological evolution process, offer advantages in global optimization and efficiency, making them widely utilized in the optimization design of Microelectromechanical Systems (MEMS) devices. Based on the theoretical framework and finite element model of CMUT sensors, we propose a CMUT array element optimization design method based on genetic algorithms. The optimization and validation results demonstrate that we have successfully designed a broadband CMUT array element consisting of four microelements with a 1-2 MHz frequency range. Compared with a randomly arranged array element, the optimized array shows a 63.9% increase in bandwidth and a 7.5% increase in average sensitivity within the passband. Moreover, the sensitivity variance within the passband is reduced by 50.2%. Our proposed method effectively optimizes the design of high sensitivity CMUT sensors with the desired bandwidth, thereby offering significant reference value for the optimization design of CMUT sensors.

Effect of recycled phosphogypsum and calcium aluminate cement on the strength behavior optimization of cement-treated dredged soil: A co-utilization of solid wastes.

Dredged soil and phosphogypsum (PG) are waste materials that must be treated to reduce their negative environmental effects. Guided by the concept of waste treatment, this study proposed the use of PG as a supplementary cementitious material to stabilize waste-dredged soil, and calcium aluminate cement (CAC) was selected to further improve the strength of the cement-treated dredged soil. Several laboratory tests were conducted to investigate the pH, unconfined compressive strength (UCS), and failure strain of the cement-treated soils in different proportions. Microstructural and mineralogical tests were performed to reveal the mechanisms underlying the strength improvement of PG and CAC. The results showed that both PG and CAC enhanced the strength of cement-treated dredged soil. PG provided SO2- 4 to promote the formation of ettringite (aluminum ferrite trisulfate (AFt)), whereas CAC neutralized the acidity of PG and provided reactants to the reaction system, leading to an increase in the pH and strength with an increase in the relative CAC content. Meanwhile, an exponential relationship was obtained between pH and qu. Mineralogical changes demonstrated that the major hydration products of cementitious materials, such as calcium silicate (aluminate) hydrate (C-(A)-S-H), AFt, and calcium aluminate hydrate (C-A-H), enhanced the strength by filling pores between particles and bridging soil particles. However, excess CAC content may not be favorable for the later strength formation, the relative CAC content is recommended to be in the range of 40%-60%. Compared to using sand, the construction of a square kilometer of reclamation consumed 3.5 million tons of PG, and saved 1.54 billion USD by using dredged soil as raw material. Hence, the use of PG to treat dredged soils will have great environmental sustainability, economic benefits, and engineering value.

Optimizing soil tetrabromobisphenol A remediation through iron-based activation of persulfate: A comparative analysis of homogeneous and heterogeneous systems.

Tetrabromobisphenol A (TBBPA) that widely exists in soil and poses a potential threat to ecological environment urgently needs economically efficient remediation techniques. This study utilized both homogeneous Fe2⁺ solution and heterogeneous iron-based nanomaterials (chemically synthesized nano zero-valence iron (nZVI) and green-synthesized iron nanoparticles (G-Fe NPs)) to activate persulfate (PS) and assess their efficacy in degrading TBBPA in soil. The results demonstrate the superior performance of heterogeneous catalytic systems (WG-Fe NPs/PS (82.07%) and WnZVI/PS (78.32%)) over homogeneous catalytic system (WFe2+/PS (71.69%)), In addition, G-Fe NPs and nZVI effectively controlled the slow release of Fe2+. The optimization analysis using response surface methodology (RSM) reveal the remarkable significance of the experimental model based on the box-behnken design. RSM show that G-Fe NPs/PS exhibited optimal process parameters and predicted the maximum soil TBBPA degradation efficiency reaching 98.77%. The results of density functional theory calculations suggest that C-Br are the primary targets for electrophilic substitution reactions. Based on the f0 value and △G, the degradation pathway of TBBPA is inferred to involve a sequential debromination process, followed by the cleavage of intermediate carbon-carbon bonds and subsequent oxidation reactions. Hence, G-Fe NPs/PS not only facilitate waste resource utilization but also hold significant application potential.

Remediation effect of walnut shell biochar on Cu and Pb co-contaminated soils in different utilization types.

Biochar, with its dual roles of soil remediation and carbon sequestration, is gradually demonstrating great potential for sustainability in agricultural and ecological aspects. In this study, a porous biochar derived from walnut shell wastes was prepared via a facile pyrolysis coupling with in-situ alkali etching method. An incubation study was conducted to investigate its performance in stabilizing copper (Cu) and lead (Pb) co-contaminated soils under different utilization types. The biochar effectively decreased the bioavailable Cu (8.5-91.68%) and Pb (5.03-88.54%), while increasing the pH, CEC, and SOM contents in both soils. Additionally, the results of sequential extraction confirmed that biochar promoted the transformation of the labile fraction of Cu and Pb to stable fractions. The mechanisms of Cu and Pb stabilization were found to be greatly dependent on the soil types. For tea plantation yellow soil, the main approach for stabilization was the complexation of heavy metals with abundant organic functional groups and deprotonation structure. Surface electrostatic adsorption and cation exchange contributed to the immobilization of Cu and Pb in vegetable-cultivated purple soil. This research provides valuable information for the stabilization of Cu and Pb co-contaminated soils for different utilization types using environmentally-friendly biochar.

C(sp)-C(sp) Lever-Based Targets of Orientational Chirality: Design and Asymmetric Synthesis.

In this study, the design and asymmetric synthesis of a series of chiral targets of orientational chirality were conducted by taking advantage of N-sulfinylimine-assisted nucleophilic addition and modified Sonogashira catalytic coupling systems. Orientational isomers were controlled completely using alkynyl/alkynyl levers [C(sp)-C(sp) axis] with absolute configuration assignment determined by X-ray structural analysis. The key structural element of the resulting orientational chirality is uniquely characterized by remote through-space blocking. Forty examples of multi-step synthesis were performed, with modest to good yields and excellent orientational selectivity. Several chiral orientational amino targets are attached with scaffolds of natural and medicinal products, showing potential pharmaceutical and medical applications in the future.