ABSTRACT
Despite considerable interest in medical and pharmaceutical fields, there remains a notable absence of functional textiles that concurrently exhibit antibacterial and antioxidant properties. Herein, a new composite fabric constructed using nanostructured bacterial cellulose (BC) covalently-linked with cerium oxide nanoparticles (BC@CeO2NPs) is introduced. The synthesis of CeO2NPs on the BC is performed via a microwave-assisted, in situ chemical deposition technique, resulting in the formation of mixed valence Ce3+/Ce4+ CeO2NPs. This approach ensures the durability of the composite fabric subjected to multiple washing cycles. The Reactive oxygen species (ROS) scavenging activity of CeO2NPs and their rapid and efficient eradication of >99% model microbes, such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus remain unaltered in the composite. To demonstrate the feasibility of incorporating the fabric in marketable products, antimicrobial face masks are fabricated with filter layers made of BC@CeO2NPs cross-linked with propylene or cotton fibers. These masks exhibit complete inhibition of bacterial growth in the three bacterial strains, improved breathability compared to respirator masks and enhanced filtration efficiency compared to single-use surgical face masks. This study provides valuable insights into the development of functional BC@CeO2NPs biotextiles in which design can be extended to the fabrication of medical dressings and cosmetic products with combined antibiotic, antioxidant and anti-inflammatory activities.
Subject(s)
Anti-Bacterial Agents , Antioxidants , Cellulose , Cerium , Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus , Cellulose/chemistry , Cerium/chemistry , Cerium/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Antioxidants/chemistry , Antioxidants/pharmacology , Escherichia coli/drug effects , Staphylococcus aureus/drug effects , Pseudomonas aeruginosa/drug effects , Masks , Textiles , Humans , Reactive Oxygen Species/metabolism , Nanoparticles/chemistry , Microbial Sensitivity TestsABSTRACT
Advanced oxidation processes using TiO2-based nanomaterials are sustainable technologies that hold great promise for the degradation of many types of pollutants including pharmaceutical residues. A wide variety of heterostructures coupling TiO2 with visible-light active nanomaterials have been explored to shift its photocatalytic properties to harness sun irradiation but a systematic comparison between them is lacking in the current literature. Furthermore, the high number of proposed nanostructures with different size, morphology, and surface area, and the often complex synthesis processes hamper the transition of these materials into commercial and effective solutions for environmental remediation. Herein, we have designed a facile and cost-effective method to synthesize two heterostructured photocatalysts representative of two main families of novel structures proposed, hybrids of TiO2 with metal (Au) and semiconductor (CeO2) nanomaterials. The photocatalysts have been extensively characterized to ensure a good comparability in terms of co-catalyst doping characteristics, morphology and surface area. The photocatalytic degradation of ciprofloxacin and sulfamethoxazole as target pollutants, two antibiotics of high concern polluting water sources, has been evaluated and CeO2/TiO2 exhibited the highest activity, achieving complete antibiotic degradation at very low photocatalyst concentrations. Our study provides new insights into the development of inexpensive heterostructured photocatalysts and suggests that the non-stoichiometry and characteristic d and f electronic orbital configuration of CeO2 have a significantly improved role in the enhancement of the photocatalytic reaction.
ABSTRACT
Cerium oxide nanozymes (CeO2NZs) are attracting vast attention due to their antioxidant and catalytic properties and mimic the activities of multiple endogenous enzymes. However, as is the case for nanomedicines in general, the success in showing their unique medical applications has not been matched by an understanding of their pharmacokinetics, which is delaying their implementation in clinical settings. Furthermore, the data of their modifications in body fluids and the impact on their activity are scarce. Herein, two types of widely used CeO2NZs, electrostatically stabilized and coated with a mesoporous silica shell, were exposed to simulated saliva and lung, gastric and intestinal fluids, and cell culture media. Their physicochemical modifications and bioactivity were tracked over time up to 15 days combining the data of different characterization techniques and biological assays. The results show that the biocompatibility and antioxidant activity are retained in all cases despite the different evolution behaviors in different fluids, including agglomeration. This work provides an experimental basis from a pharmacokinetic perspective that supports the therapeutic effectiveness of CeO2NZs observed in vivo for the treatment of many conditions related to chronic inflammation and cancer, and suggests that they can be safely administered through different portals of entry including intravenous injection, oral ingestion or inhalation.
Subject(s)
Body Fluids , Saliva , Antioxidants/pharmacology , Biological Assay , CatalysisABSTRACT
Micro-organic pollutants, particularly organic dyes and personal care products (PPCPs), are widely present in wastewater, and thus pose a serious risk to human health. The capture and solar-light photodegradation of micro-organic pollutants are highly challenging tasks, which require the design and synthesis of microporous materials with specific structures. As we know, organic dyes and PPCPs can be absorbed via π-π* stacking. In this paper, an iron-based metal-organic framework (Fe-UiO-68-terNap) containing semirigid conjugated aromatic ligands is prepared for the capture and solar-light photodegradation of multiple water contaminants. UiO-68-terNap was synthesized based on ternaphthalene with π-π* stacking, which would increase the adsorption capacities of organic micropollutants in wastewater. Additionally, the formation of Fe-O-Zr enhances the charge-separation ability resulting in the successful degradation of micropollutants in 240 min. The novel material has been elucidated by single-crystal X-ray diffraction and Fe K-edge XANES, which provide key insights at a molecular level for the design of novel materials for the capture and photodegradation of organic micropollutants.
ABSTRACT
The integration of progressive technologies such as nanomedicine with the use of natural products from traditional medicine (TM) provides a unique opportunity for the longed-for harmonization between traditional and modern medicine. Although several actions have been initiated decades ago, a disparity of reasons including some misunderstandings between each other limits the possibilities of a truly complementation. Herein, we analyze some common challenges between nanomedicine and traditional Chinese medicine (TCM). These challenges, if solved in a consensual way, can give a boost to such harmonization. Nanomedicine is a recently born technology, while TCM has been used by the Chinese people for thousands of years. However, for these disciplines, the regulation and standardization of many of the protocols, especially related to the toxicity and safety, regulatory aspects, and manufacturing procedures, are under discussion. Besides, both TCM and nanomedicine still need to achieve a wider social acceptance. Herein, we first briefly discuss the strengths and weaknesses of TCM. This analysis serves to focus afterward on the aspects where TCM and nanomedicine can mutually help to bridge the existing gaps between TCM and Western modern medicine. As discussed, many of these challenges can be applied to TM in general. Finally, recent successful cases in scientific literature that merge TCM and nanomedicine are reviewed as examples of the benefits of this harmonization.
Subject(s)
Biological Products , Drugs, Chinese Herbal , Humans , Medicine, Chinese Traditional , Drugs, Chinese Herbal/therapeutic use , NanomedicineABSTRACT
Developing sensitive and miniaturized biosensors for the detection of microRNAs (miRNAs) is highly desirable due to their association with early cancer diagnosis and prognosis. Here, a new microfluidic-based biosensor, combined with multifunctional nanosurface and DSN-assisted target recycle amplification strategy, is designed for the detection of miRNA-21. The design of nanosurface includes gold nanoparticles on porous anodic aluminum oxide (AAO) for surface enhanced Raman scattering (SERS) substrate, AuMBA@Ag core-shell nanoparticles for SERS nanotags and single-stranded DNA (ssDNA) in between for miRNA capture and nanotags immobilization. When the target miRNA is present near the nanosurface, it will be captured by ssDNA via hybridization reaction. Then, triggered by the DSN-assisted target recycle process, the freshly formed DNA/miRNA heteroduplexes are cleaved by DSN enzyme into DNA fragments and single-strand miRNA. The SERS nanotags are also dissociated from the nanosurface, leading to decrease of SERS signal. The cleaved target miRNA can be captured and SERS nanotags are released again in the next cycle, resulting in amplification of detection signal. To improve the accuracy of this biosensor, the functionalized AAO membrane is subdivided into two groups - AAO/Au array linked with encoded core-shell SERS nanotags acting as a reactor and primary detector and AAO/Au@Ag array serving as a collector and secondary detector for the dissociative SERS nanotags from the reactor. The decrease of SERS signal in primary detector and increase of signal in secondary detector ensures the accuracy and it is called dual-SERS detection strategy. The detection of miRNA-21 can be achieved with only 30 µL sample and 10 µL enzyme and a wide linear range of 10 fMâ¼10 nM is obtained. In addition, the microfluidic dual-SERS detection strategy can greatly reduce the possibility of false positive or false negative in single detection mode and it can be applied to the simultaneous detection of multiple miRNAs via integrating different probes.
Subject(s)
Biosensing Techniques , Metal Nanoparticles , MicroRNAs , Biosensing Techniques/methods , DNA , Gold , Limit of Detection , MicroRNAs/genetics , Microfluidics , Spectrum Analysis, Raman/methodsABSTRACT
Circulating levels of 2-hydroxybutyrate (2HB) are highly related to glycemic status in different metabolomic studies. According to recent evidence, 2HB is an early biomarker of the future development of dysglycemia and type 2 diabetes mellitus and may be causally related to the progression of normal subjects to impaired fasting glucose or insulin resistance. In the present study, we developed and validated a simple, specific and sensitive gas chromatography-mass spectrometry (GC-MS) method specifically intended to quantify serum levels of 2HB. Liquid-liquid extraction with ethyl acetate was followed by 2 min of microwave-assisted derivatization. The method presented acceptable accuracy, precision and recovery, and the limit of quantification was 5 µM. Levels of 2HB were found to be stable in serum after three freeze-thaw cycles, and at ambient temperature and at a temperature of 4 °C for up to 24 h. Extracts derivatized under microwave irradiation were stable for up to 96 h. No differences were found in 2HB concentrations measured in serum or plasma EDTA samples. In summary, the method is useful for a rapid, precise and accurate quantification of 2HB in serum samples assessed for the evaluation of dysglycemia and diabetes mellitus.
Subject(s)
Diabetes Mellitus, Type 2 , Microwaves , Biomarkers , Diabetes Mellitus, Type 2/diagnosis , Gas Chromatography-Mass Spectrometry/methods , Humans , HydroxybutyratesABSTRACT
The immobilization of enzymes has received much attention. Metal-organic framework (MOF) as the adsorbent for enzyme encapsulation provides an effective strategy. However, the encapsulation efficacy is not dependent solely on the specific surface area. Though leading into appropriate substrate with negative charge would enhance the encapsulation efficacy. Polyoxometalates (POMs) as the electron sponge would donate electrons without any structural change. In this study, Keggin-type phosphotungstic acid (PW12) was encapsulated in Zirconium metal-organic framework (PW12@UiO-67) as a heterogeneous adsorbent for the encapsulation of enzyme. Our following data proved that this composite cluster could enhance the adsorption of enzyme and the stability of MP-11 was then significantly improved after immobilization.
Subject(s)
Metal-Organic Frameworks , Anions , Enzymes, Immobilized/chemistry , Metal-Organic Frameworks/chemistry , Oligopeptides , PolyelectrolytesABSTRACT
Acute ischemic stroke has become the major cause of mortality and disability worldwide. Following ischemic stroke, the reperfusion injury is mainly mediated by the burst of reactive oxygen and nitrogen species (RONS). Therefore, blocking the excessive production or removing RONS holds great promise as a potential therapeutic strategy. Herein, we developed a Co-doped Fe3O4 nanozyme that is capable of scavenging H2O2, O2â¢-, â¢NO, and ONOO- in vitro and in vivo and provides neuroprotection against ischemic stroke. In vitro experiments showed that pre-incubation with the Co-Fe3O4 nanozyme could prevent neurotoxicity and neuroinflammation induced by H2O2 or lipopolysaccharide, respectively, in HT22 cells. After intravenous administration, the Co-Fe3O4 nanozyme showed no signs of toxicity in peripheral organs of C57BL/6J mice, even after prolonged delivery for 4 weeks. In permanent photothrombotic stroke model and transient middle cerebral artery occlusion stroke model, the Co-Fe3O4 nanozyme specifically accumulated in the infarct rim at 72 h post-stroke and was endocytosed by neurons, astrocytes, microglia, and endothelial cells. Importantly, the Co-Fe3O4 nanozyme delivery reduced the infarct volume in both stroke models. The observation that the Co-Fe3O4 nanozyme was efficacious in two well-characterized ischemic stroke models provides strong evidence that it represents a powerful tool for targeting oxidative and nitrosative stress in the ischemic brain.
Subject(s)
Free Radical Scavengers/therapeutic use , Ischemic Stroke/drug therapy , Magnetite Nanoparticles/therapeutic use , Neuroprotective Agents/therapeutic use , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Animals , Catalysis , Cell Line , Cobalt/chemistry , Cobalt/toxicity , Free Radical Scavengers/chemistry , Free Radical Scavengers/toxicity , Lipopolysaccharides , Magnetite Nanoparticles/chemistry , Magnetite Nanoparticles/toxicity , Male , Mice, Inbred C57BL , Neuroinflammatory Diseases/chemically induced , Neuroinflammatory Diseases/drug therapy , Neuroprotection/drug effects , Neuroprotective Agents/chemistry , Neuroprotective Agents/toxicity , Oxidation-Reduction , Reactive Nitrogen Species/chemistry , Reactive Oxygen Species/chemistryABSTRACT
Integrating multiple materials with different functionalities in a single nanostructure enables advances in many scientific and technological applications. However, such highly sophisticated nanomaterials usually require complex synthesis processes that complicate their preparation in a sustainable and industrially feasible manner. Herein, we designed a simple general method to grow a mesoporous silica shell onto any combination of hydrophilic nanoparticle cores. The synthetic strategy, based on the adjustment of the key parameters of the sol-gel process for the silica shell formation, allows for the embedment of single, double, and triple inorganic nanoparticles within the same shell, as well as the size-control of the obtained nanocomposites. No additional interfacial adhesive layer is required on the nanoparticle surfaces for the embedding process. Adopting this approach, electrostatically stabilized, small-sized (from 4 to 15 nm) CeO2, Fe3O4, Gd2O3, NaYF4, Au, and Ag cores were used to test the methodology. The mean diameter of the resulting nanocomposites could be as low as 55 nm, with high monodispersity. These are very feasible sizes for biological intervention, and we further observed increased nanoparticle stability in physiological environments. As a demonstration of their increased activity as a result of this, the antioxidant activity of CeO2 cores was enhanced when in core-shell form. Remarkably, the method is conducted entirely at room temperature, atmospheric conditions, and in aqueous solvent with the use of ethanol as co-solvent. These facile and even "green" synthesis conditions favor scalability and easy preparation of multicomponent nanocomposite libraries with standard laboratory glassware and simple benchtop chemistry, through this sustainable and cost-effective fabrication process.
Subject(s)
Nanocomposites , Nanoparticles , Silicon DioxideABSTRACT
The metabolic ratios lactate/pyruvate and ß-hydroxybutyrate/acetoacetate are considered valuable tools to evaluate the in vivo redox cellular state by estimating the free NAD+/NADH in cytoplasm and mitochondria, respectively. The aim of the current study was to validate a gas-chromatography mass spectrometry method for simultaneous determination of the four metabolites in plasma and liver tissue. The procedure included an o-phenylenediamine microwave-assisted derivatization, followed by liquid-liquid extraction with ethyl acetate and silylation with bis(trimethylsilyl)trifluoroacetamide:trimethylchlorosilane 99:1. The calibration curves presented acceptable linearity, with a limit of quantification of 0.001 mM for pyruvate, ß-hydroxybutyrate and acetoacetate and of 0.01 mM for lactate. The intra-day and inter-day accuracy and precision were within the European Medicines Agency's Guideline specifications. No significant differences were observed in the slope coefficient of three-point standard metabolite-spiked curves in plasma or liver and water, and acceptable recoveries were obtained in the metabolite-spiked samples. Applicability of the method was tested in precision-cut liver rat slices and also in HepG2 cells incubated under different experimental conditions challenging the redox state. In conclusion, the validated method presented good sensitivity, specificity and reproducibility in the quantification of lactate/pyruvate and ß-hydroxybutyrate/acetate metabolites and may be useful in the evaluation of in vivo redox states.
Subject(s)
3-Hydroxybutyric Acid/metabolism , Acetoacetates/metabolism , Gas Chromatography-Mass Spectrometry , Lactates/metabolism , Pyruvates/metabolism , 3-Hydroxybutyric Acid/analysis , 3-Hydroxybutyric Acid/blood , Acetoacetates/analysis , Acetoacetates/blood , Animals , Female , Gas Chromatography-Mass Spectrometry/methods , Hep G2 Cells , Humans , Lactates/analysis , Lactates/blood , Limit of Detection , Liver/chemistry , Liver/metabolism , Oxidation-Reduction , Pyruvates/analysis , Pyruvates/blood , Rats, WistarABSTRACT
Obesity is one of the most important public health problems that is associated with an array of metabolic disorders linked to cardiovascular disease, stroke, type 2 diabetes, and cancer. A sustained therapeutic approach to stop the escalating prevalence of obesity and its associated metabolic comorbidities remains elusive. Herein, we developed a novel nanocomposite based on mesoporous silica coated cerium oxide (CeO2) nanozymes that reduce the circulating levels of fatty acids and remarkably improve the metabolic phenotype in a model of obese Zucker rats five weeks after its administration. Lipidomic and gene expression analyses showed an amelioration of the hyperlipidemia and of the hepatic and adipose metabolic dysregulations, which was associated with a down-regulation of the hepatic PI3K/mTOR/AKT pathway and a reduction of the M1 proinflammatory cytokine TNF-α. In addition, the coating of the CeO2 maximized its cell antioxidant protective effects and minimized non-hepatic biodistribution. The one-pot synthesis method for the nanocomposite fabrication is implemented entirely in aqueous solution, room temperature and open atmosphere conditions, favoring scalability and offering a safe and translatable lipid-lowering and antioxidant nanomedicine to treat metabolic comorbidities associated with obesity. This approach may be further applied to address other metabolic disorders related to hyperlipidemia, low-grade inflammation and oxidative stress.
Subject(s)
Antioxidants , Diabetes Mellitus, Type 2 , Animals , Lipids , Metabolome , Obesity/drug therapy , Rats , Rats, Zucker , Silicon Dioxide , Tissue DistributionABSTRACT
Acoustic manipulation of submicron particles in a controlled manner has been challenging to date because of the increased contribution of acoustic streaming, which leads to fluid mixing and homogenization. This article describes the patterning of submicron particles and the migration of their patterned locations from pressure nodes to antinodes in a non-ionic surfactant (Tween 20) aqueous solution in a conventional standing surface acoustic wave field with a wavelength of 150 µm. Phase separation of the aqueous surfactant solution occurs when they are exposed to acoustic waves, probably due to the "clouding behavior" of non-ionic surfactant. The generated surfactant precipitates are pushed to the pressure antinodes due to the negative acoustic contrast factor relative to water. Compared with the mixing appearance in pure water media, the patterning behavior of submicron particles with a diameter of 300 nm dominated by acoustic radiation force is readily apparent in an aqueous solution with 2% volumetric concentration of Tween 20 surfactant, thanks to the suppression effect of acoustic streaming in inhomogeneous fluids. These submicron particles are first pushed to acoustic pressure nodes and then are migrated to antinodes where the surfactant precipitates stay. More attractively, the migration of acoustically patterned locations is not only limited to submicron particles, but also occurs to micrometer-sized particles in solutions with higher surfactant concentrations. These findings open up a novel avenue for controllable acoustic manipulation.
ABSTRACT
Antioxidant nanoparticles have recently gained tremendous attention for their enormous potential in biomedicine. However, discrepant reports of either medical benefits or toxicity, and lack of reproducibility of many studies, generate uncertainties delaying their effective implementation. Herein, the case of cerium oxide is considered, a well-known catalyst in the petrochemistry industry and one of the first antioxidant nanoparticles proposed for medicine. Like other nanoparticles, it is now described as a promising therapeutic alternative, now as threatening to health. Sources of these discrepancies and how this analysis helps to overcome contradictions found for other nanoparticles are summarized and discussed. For the context of this analysis, what has been reported in the liver is reviewed, where many diseases are related to oxidative stress. Since well-dispersed nanoparticles passively accumulate in liver, it represents a major testing field for the study of new nanomedicines and their clinical translation. Even more, many contradictory works have reported in liver either cerium-oxide-associated toxicity or protection against oxidative stress and inflammation. Based on this, finally, the intention is to propose solutions to design improved nanoparticles that will work more precisely in medicine and safely in society.
Subject(s)
Cerium , Nanoparticles , Cerium/toxicity , Nanoparticles/toxicity , Oxidative Stress , Reproducibility of Results , Tissue DistributionABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic accumulation of lipids. Antisteatotic effects of cerium oxide nanoparticles (CeO2NPs) have recently been shown in animal models of liver disease. However, it is unclear whether the activity of CeO2NPs is related solely to the decrease in oxidative stress or, in addition, they directly decrease liver fatty acid accumulation. To address this question, in this work, we used an in vitro model of hepatocellular steatosis, exposing HepG2 cells to oleic and palmitic acid. Cell uptake of CeO2NPs and their effect on oxidative stress and viability of hepatic cells cultured with H2O2 were also evaluated. Results show that CeO2NPs were uptaken by HepG2 cells and reduced oxidative stress and improved cell viability. Treatment with oleic and palmitic acid increased lipogenesis and the content of different fatty acids. CeO2NPs reduced palmitic and stearic acid and most fatty acids consisting of more than 18 carbon atoms. These effects were associated with significant changes in elongase and desaturase activity. In conclusion, CeO2NPs directly protected HepG2 cells from cell injury in oxidative stress conditions and reduced fatty acid content in steatotic conditions by inducing specific changes in fatty acid metabolism, thus showing potential in the treatment of NAFLD.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Cerium/chemistry , Fatty Acids/metabolism , Liver Neoplasms/metabolism , Metal Nanoparticles/chemistry , Metal Nanoparticles/therapeutic use , Reactive Oxygen Species/metabolism , Cell Survival/drug effects , Fatty Acid Desaturases/metabolism , Fatty Acid Elongases/metabolism , Hep G2 Cells , Humans , Hydrogen Peroxide/pharmacology , Oxidative Stress/drug effects , Palmitic Acid/metabolism , Spectrometry, Fluorescence , Stearic Acids/metabolismABSTRACT
The topic of calcite and aragonite polymorphism attracts enormous interest from fields including biomineralization and paleogeochemistry. While aragonite is only slightly less thermodynamically stable than calcite under ambient conditions, it typically only forms as a minor product in additive-free solutions at room temperature. However, aragonite is an abundant biomineral, and certain organisms can selectively generate calcite and aragonite. This fascinating behavior has been the focus of decades of research, where this has been driven by a search for specific organic macromolecules that can generate these polymorphs. However, despite these efforts, we still have a poor understanding of how organisms achieve such selectivity. In this work, we consider an alternative possibility and explore whether the confined volumes in which all biomineralization occurs could also influence polymorph. Calcium carbonate was precipitated within the cylindrical pores of track-etched membranes, where these enabled us to systematically investigate the relationship between the membrane pore diameter and polymorph formation. Aragonite was obtained in increasing quantities as the pore size was reduced, such that oriented single crystals of aragonite were the sole product from additive-free solutions in 25-nm pores and significant quantities of aragonite formed in pores as large as 200 nm in the presence of low concentrations of magnesium and sulfate ions. This effect can be attributed to the effect of the pore size on the ion distribution, which becomes of increasing importance in small pores. These intriguing results suggest that organisms may exploit confinement effects to gain control over crystal polymorph.
ABSTRACT
Segmented flow microfluidic devices offer an attractive means of studying crystallization processes. However, while they are widely employed for protein crystallization, there are few examples of their use for sparingly soluble compounds due to problems with rapid device fouling and irreproducibility over longer run-times. This article presents a microfluidic device which overcomes these issues, as this is constructed around a novel design of "picoinjector" that facilitates direct injection into flowing droplets. Exploiting a Venturi junction to reduce the pressure within the droplet, it is shown that passive injection of solution from a side-capillary can be achieved in the absence of an applied electric field. The operation of this device is demonstrated for calcium carbonate, where highly reproducible results are obtained over long run-times at high supersaturations. This compares with conventional devices that use a Y-junction to achieve solution loading, where in-channel precipitation of calcium carbonate occurs even at low supersaturations. This work not only opens the door to the use of microfluidics to study the crystallization of low solubility compounds, but the simple design of a passive picoinjector will find wide utility in areas including multistep reactions and investigation of reaction dynamics.