Superhuman artificial intelligence can improve human decision-making by increasing novelty.

How will superhuman artificial intelligence (AI) affect human decision-making? And what will be the mechanisms behind this effect? We address these questions in a domain where AI already exceeds human performance, analyzing more than 5.8 million move decisions made by professional Go players over the past 71 y (1950 to 2021). To address the first question, we use a superhuman AI program to estimate the quality of human decisions across time, generating 58 billion counterfactual game patterns and comparing the win rates of actual human decisions with those of counterfactual AI decisions. We find that humans began to make significantly better decisions following the advent of superhuman AI. We then examine human players' strategies across time and find that novel decisions (i.e., previously unobserved moves) occurred more frequently and became associated with higher decision quality after the advent of superhuman AI. Our findings suggest that the development of superhuman AI programs may have prompted human players to break away from traditional strategies and induced them to explore novel moves, which in turn may have improved their decision-making.

CRISPR-Cas12a-Based Nucleic Acid Amplification-Free DNA Biosensor via Au Nanoparticle-Assisted Metal-Enhanced Fluorescence and Colorimetric Analysis.

Cell-free DNA (cfDNA) has attracted significant attention due to its high potential to diagnose diseases, such as cancer. Still, its detection by amplification method has limitations because of false-positive signals and difficulty in designing target-specific primers. CRISPR-Cas-based fluorescent biosensors have been developed but also need the amplification step for the detection. In this study, for the first time CRISPR-Cas12a based nucleic acid amplification-free fluorescent biosensor was developed to detect cfDNA by a metal-enhanced fluorescence (MEF) using DNA-functionalized Au nanoparticle (AuNP). Upon activating the CRISPR-Cas12a complex by the target cfDNA and subsequent single-strand DNA (ssDNA) degradation between AuNP and fluorophore, MEF occurred with color changes from purple to red-purple. Using this system, breast cancer gene-1 (BRCA-1) can be detected with very high sensitivity in 30 min. This rapid and highly selective sensor can be applied to measure other nucleic acid biomarkers such as viral DNA in field-deployable and point-of-care testing (POCT) platform.

Hidden osteonecrosis of the femoral head after healed femoral neck fractures: magnetic resonance imaging study of 58 consecutive patients.

INTRODUCTION: Several studies investigated the posttraumatic osteonecrosis of the femoral head (ONFH) after femoral neck fracture (FNF). However, no study has investigated the hidden ONFH after FNF, which is missed by simple radiographs, using magnetic resonance imaging (MRI). MATERIALS AND METHODS: This retrospective study involved 58 consecutive patients who underwent implant removal surgery after internal fixation due to FNF. MRI was used to investigate the incidence of hidden ONFHs, which were not initially revealed on plain radiographs. The comparisons between hidden ONFH and other groups were performed for patent demographics and clinical variables including ONFH location, lesion size, the progression rate of ONFH collapse, and end-stage arthroplasty conversion rate. RESULTS: Of the 58 patients, 38 exhibited no evidence of ONFH on plain radiograph screening. However, 13 of the 38 patients were confirmed of hidden ONFH via MRI. The collapse progressed in four of the 13 patients, and one of them underwent total hip arthroplasty surgery. No significant differences were found between the hidden and definite ONFH groups in demographics and clinical variables. However, a significant difference exists between the hidden ONFH and the normally healed FNF groups in terms of the Garden type (P < 0.001). CONCLUSIONS: A large number of cases with hidden ONFH were confirmed using MRI following healed FNF, and most of them were initially displaced FNF. Thus, the treatment method between internal fixation and hip arthroplasty should be carefully selected, particularly with displaced FNF.

Metergoline inhibits the neuronal Nav1.2 voltage-dependent Na(+) channels expressed in Xenopus oocytes.

AIM: Metergoline is an ergot-derived psychoactive drug that acts as a ligand for serotonin and dopamine receptors. The aim of this study was to investigate the regulatory effects of metergoline on the neuronal Nav1.2 voltage-dependent Na(+) channels in vitro. METHODS: Xenopus oocytes were injected with cRNAs encoding rat brain Nav1.2 α and ß1 subunits. Voltage-activated Na(+) currents were recorded using two-electrode voltage clamp technique. Drugs were applied though perfusion. RESULTS: Both metergoline and lidocaine reversibly and concentration-dependently inhibited the peak of Na(+) currents with IC50 values of 3.6 ± 4.2 and 916.9 ± 98.8 µmol/L, respectively. Metergoline (3 µmol/L) caused a 6.8 ± 1.2 mV depolarizing shift of the steady-state activation curve of the Na(+) currents, and did not alter the inactivation curve. In contrast, lidocaine (3 µmol/L) caused a 12.7 ± 1.2 mV hyperpolarizing shift of the inactivation curve of the Na(+) currents without changing the steady-state activation curve. Both metergoline and lidocaine produced tonic and use-dependent inhibition on the peak of Na(+) currents. CONCLUSION: Metergoline exerts potent inhibition on the activity of neuronal Nav1.2 channels, which may contribute to its actions on the central nervous system.

Carbon-based nanocomposites for biomedical applications.

Carbon nanomaterials have attracted significant attention in the biomedical field, including for biosensing, drug delivery, and tissue engineering applications. Based on their inherent properties such as their unique structure and high conductivity, carbon nanomaterials can overcome the current limitations in biomedical research such as poor stability of biomolecules, low sensitivity and selectivity of biosensors, and difficulty in precise drug delivery. In addition, recently, several novel nanomaterials have been integrated with carbon nanomaterials to develop carbon-based nanocomposites for application in biomedical research. In this review, we discuss recent studies on carbon-based nanocomposites and their biomedical applications. First, we discuss the representative carbon nanomaterials and nanocomposites composed of carbon and other novel nanomaterials. Next, applications of carbon nanomaterials and nanocomposites in the biomedical field are discussed according to topics in the biomedical field. We have discussed the recent studies on biosensors, drug delivery, and tissue engineering. In conclusion, we believe that this review provides the potential and applicability of carbon nanomaterials and their nanocomposites and suggests future directions of the application of carbon-based nanocomposites in biomedical applications.

Drug Evaluation of Parkinson's Disease Patient-Derived Midbrain Organoids Using Mesoporous Au Nanodot-Patterned 3D Concave Electrode.

Brain organoids are being recognized as valuable tools for drug evaluation in neurodegenerative diseases due to their similarity to the human brain's structure and function. However, a critical challenge is the lack of selective and sensitive electrochemical sensing platforms to detect the response of brain organoids, particularly changes in the neurotransmitter concentration upon drug treatment. This study introduces a 3D concave electrode patterned with a mesoporous Au nanodot for the detection of electrochemical signals of dopamine in response to drugs in brain organoids for the first time. The mesoporous Au nanodot-patterned film was fabricated using laser interference lithography and electrochemical deposition. Then, the film was attached to a polymer-based 3D concave mold to obtain a 3D concave electrode. Midbrain organoids generated from Parkinson's disease (PD) patient-derived iPSCs with gene mutations (named as PD midbrain organoid) or normal midbrain organoids were positioned on the developed 3D concave electrode. The 3D concave electrode showed a 1.4 times higher electrochemical signal of dopamine compared to the bare gold electrode. And the dopamine secreted from normal midbrain organoids or PD midbrain organoids on the 3D concave electrode could be detected electrochemically. After the treatment of PD midbrain organoids with levodopa, the drug for PD, the increase in dopamine level was detected due to the activation of dopaminergic neurons by the drug. The results suggest the potential of the proposed 3D concave electrode combined with brain organoids as a useful tool for assessing drug efficacy. This sensing system can be applied to a variety of organoids for a comprehensive drug evaluation.

Human Motor System-Based Biohybrid Robot-On-a-Chip for Drug Evaluation of Neurodegenerative Disease.

Biohybrid robots have been developed for biomedical applications and industrial robotics. However, the biohybrid robots have limitations to be applied in neurodegenerative disease research due to the absence of a central nervous system. In addition, the organoids-on-a-chip has not yet been able to replicate the physiological function of muscle movement in the human motor system, which is essential for evaluating the accuracy of the drugs used for treating neurodegenerative diseases. Here, a human motor system-based biohybrid robot-on-a-chip composed of a brain organoid, multi-motor neuron spheroids, and muscle bundle on solid substrateis proposed to evaluate the drug effect on neurodegenerative diseases for the first time. The electrophysiological signals from the cerebral organoid induced the muscle bundle movement through motor neuron spheroids. To evaluate the drug effect on Parkinson's disease (PD), a patient-derived midbrain organoid is generated and incorporated into a biohybrid robot-on-a-chip. The drug effect on PD is successfully evaluated by measuring muscle bundle movement. The muscle bundle movement of PD patient-derived midbrain organoid-based biohybrid robot-on-a-chip is increased from 4.5 ± 0.99 µm to 18.67 ± 2.25 µm in response to levodopa. The proposed human motor system-based biohybrid robot-on-a-chip can serve as a standard biohybrid robot model for drug evaluation.

The standardized herbal formula, PM014, ameliorated cigarette smoke-induced lung inflammation in a murine model of chronic obstructive pulmonary disease.

BACKGROUND: In this study, we evaluated the anti-inflammatory effect of PM014 on cigarette smoke induced lung disease in the murine animal model of chronic obstructive pulmonary disease (COPD). METHODS: Mice were exposed to cigarette smoke (CS) for 2 weeks to induce COPD-like lung inflammation. Two hours prior to cigarette smoke exposure, the treatment group was administered PM014 via an oral injection. To investigate the effects of PM014, we assessed PM014 functions in vivo, including immune cell infiltration, cytokine profiles in bronchoalveolar lavage (BAL) fluid and histopathological changes in the lung. The efficacy of PM014 was compared with that of the recently developed anti-COPD drug, roflumilast. RESULTS: PM014 substantially inhibited immune cell infiltration (neutrophils, macrophages, and lymphocytes) into the airway. In addition, IL-6, TNF-α and MCP-1 were decreased in the BAL fluid of PM014-treated mice compared to cigarette smoke stimulated mice. These changes were more prominent than roflumilast treated mice. The expression of PAS-positive cells in the bronchial layer was also significantly reduced in both PM014 and roflumilast treated mice. CONCLUSIONS: These data suggest that PM014 exerts strong therapeutic effects against CS induced, COPD-like lung inflammation. Therefore, this herbal medicine may represent a novel therapeutic agent for lung inflammation in general, as well as a specific agent for COPD treatment.

Nanomaterial-based biohybrid hydrogel in bioelectronics.

Despite the broadly applicable potential in the bioelectronics, organic/inorganic material-based bioelectronics have some limitations such as hard stiffness and low biocompatibility. To overcome these limitations, hydrogels capable of bridging the interface and connecting biological materials and electronics have been investigated for development of hydrogel bioelectronics. Although hydrogel bioelectronics have shown unique properties including flexibility and biocompatibility, there are still limitations in developing novel hydrogel bioelectronics using only hydrogels such as their low electrical conductivity and structural stability. As an alternative solution to address these issues, studies on the development of biohybrid hydrogels that incorporating nanomaterials into the hydrogels have been conducted for bioelectronic applications. Nanomaterials complement the shortcomings of hydrogels for bioelectronic applications, and provide new functionality in biohybrid hydrogel bioelectronics. In this review, we provide the recent studies on biohybrid hydrogels and their bioelectronic applications. Firstly, representative nanomaterials and hydrogels constituting biohybrid hydrogels are provided, and next, applications of biohybrid hydrogels in bioelectronics categorized in flexible/wearable bioelectronic devices, tissue engineering, and biorobotics are discussed with recent studies. In conclusion, we strongly believe that this review provides the latest knowledge and strategies on hydrogel bioelectronics through the combination of nanomaterials and hydrogels, and direction of future hydrogel bioelectronics.

A Nano-Biohybrid-Based Bio-Solar Cell to Regulate the Electrical Signal Transmission to Living Cells for Biomedical Application.

Bio-solar cells are studied as sustainable and biocompatible energy sources with significant potential for biomedical applications. However, they are composed of light-harvesting biomolecules with narrow absorption wavelengths and weak transient photocurrent generation. In this study, a nano-biohybrid-based bio-solar cell composed of bacteriorhodopsin, chlorophyllin, and Ni/TiO2 nanoparticles is developed to overcome the current limitations and verify the possibility of biomedical applications. Bacteriorhodopsin and chlorophyllin are introduced as light-harvesting biomolecules to broaden the absorption wavelength. As a photocatalyst, Ni/TiO2 nanoparticles are introduced to generate a photocurrent and amplify the photocurrent generated by the biomolecules. The developed bio-solar cell absorbs a broad range of visible wavelengths and generates an amplified stationary photocurrent density (152.6 nA cm-2 ) with a long lifetime (up to 1 month). Besides, the electrophysiological signals of muscle cells at neuromuscular junctions are precisely regulated by motor neurons excited by the photocurrent of the bio-solar cell, indicating that the bio-solar cell can control living cells by signal transmission through other types of living cells. The proposed nano-biohybrid-based bio-solar cell can be used as a sustainable and biocompatible energy source for the development of wearable and implantable biodevices and bioelectronic medicines for humans.

Microarray analysis of the gene expression profile of HMC-1 mast cells following Schizonepeta tenuifolia Briquet treatment.

It has long been believed that mast cells play a crucial role in the development of many physiological changes during immediate allergic responses. This study was conducted to evaluate the anti-inflammation mechanism of Schizonepeta tenuifolia (ST) extract and ST purified chemicals on the PMA plus A23187-induced stimulation of HMC-1 human mast cells. ST, rosmarinic acid, pulegone, and 2α,3α,24-thrihydrooxylen-12en-28oic acid treatment of HMC-1 cells led to significant suppression of pro-inflammatory cytokines (IL-6, IL-8, and TNF-α) in a dose dependent manner. In addition, the results of the microarray and real-time RT-PCR analyses revealed that ST regulates several pathways, including the cytokine-cytokine receptor interaction (CCRI), MAPK, and the Toll-like receptor (TLR) signaling pathways. ST may be useful for the treatment of inflammation disease via anti-inflammation activity that occurs through inhibition of the CCRI, MAPK, and TLR signaling pathways.

Methyl gallate exhibits potent antitumor activities by inhibiting tumor infiltration of CD4+CD25+ regulatory T cells.

CD4(+)CD25(+) regulatory T (Treg) cells play crucial roles in the host response to tumors. Increasing evidence supports the existence of elevated numbers of Treg cells in solid tumors and hematologic malignancies. In this study, the effects of methyl gallate on Treg cells were examined. Methyl gallate inhibited Treg cell-suppressive effects on effector CD4(+) T cells and Treg migration toward tumor environment. The expression of Treg surface markers including CTLA-4, CCR4, CXCR4, and glucocorticoid-induced TNFR was significantly suppressed upon methyl gallate treatment. Furthermore, forkhead box P3 (Foxp3) expression was also significantly decreased by methyl gallate, suggesting that the suppressive effects of methyl gallate on Treg were medicated by decrease of Treg-specific transcription factor Foxp3. In tumor-bearing hosts, methyl gallate treatment substantially reduced tumor growth and prolonged the survival rate. In contrast, nu/nu mice did not show decreased tumor progression in response to methyl gallate. In addition, in tumor-bearing Treg-depleted mice, tumor growth and the survival rates were not changed by methyl gallate treatment, strongly suggesting that the main therapeutic target of methyl gallate in tumor suppression was related to modulation of the CD4(+)CD25(+) Treg cell functions. In the spleen of tumor-bearing mice, methyl gallate treatment induced a significant decrease in the CD4(+)CD25(+)Foxp3(high) Treg cell population. Especially, the number of tumor-infiltrating CD25(+)Foxp3(high) Treg cells was significantly lower in methyl gallate-treated mice. These results suggest that methyl gallate can be used to reverse immune suppression and as a potentially useful adjunct for enhancing the efficacy of immune-based cancer therapy.

Electroacupuncture Attenuates Ovalbumin-Induced Allergic Asthma via Modulating CD4(+)CD25(+) Regulatory T Cells.

A mouse pulmonary hypersensitivity experimental model that mimics human asthma was developed, and electroacupuncture (EA) treatment was shown to reduce allergic inflammatory processes. In addition, we also assessed whether the beneficial effects of EA on allergic asthma could be correlated with CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg). Cellular profiles and histopathologic analysis demonstrated that peribronchial and perivascular inflammatory cell infiltrates were significantly decreased in the EA-treated groups when compared to the OVA and anti-CD25 Ab-injected (Treg depletion) groups. Furthermore, total BAL cells were reduced in the EA groups when compared to other groups. Interestingly, the population of CD4(+)CD25(+)Foxp3(+)Tregs in pneumonocytes increased in EA-treated group when compared to OVA and Treg depletion groups. These results imply that EA stimulation at ST 36 may affect CD4(+)CD25(+)Foxp3(+) Treg in an OVA-induced experimental model and may enhance Treg function by suppressing other T cells and limiting the immune response.

Actuation-Augmented Biohybrid Robot by Hyaluronic Acid-Modified Au Nanoparticles in Muscle Bundles to Evaluate Drug Effects.

Biohybrid robots, which comprise soft materials with biological components, have the potential to sense, respond, and adapt to changing environmental loads dynamically. Instead of humans and other living things, biohybrid robots can be used in various fields such as drug screening and toxicity assessment. In the actuation part, however, since a muscle cell-based biohybrid robot is limited in that the driving force is weak, it is difficult to evaluate drug and toxicological effects by distinguishing changes in the biohybrid robot's motion. To overcome this limitation, we introduced hyaluronic acid-modified gold nanoparticles (HA-AuNPs) into a muscle bundle-based biohybrid robot that moves forward in response to electrical stimulation. To enhance the actuation of muscle bundles, HA-AuNPs were embedded into the muscle bundles. The motion of the fabricated biohybrid robot was improved due to the enhanced differentiation and the improved electrical conductivity of muscle bundles by HA-AuNPs. In addition, the fabricated biohybrid robot exhibited huge changes in motion with respect to the addition of positive and negative inotropic drugs. The proposed biohybrid robot has the potential for neuromuscular disease drug screening by incorporating nervous tissues such as motor neuron organoids and brain organoids.

Recent progress in nanomaterial-based bioelectronic devices for biocomputing system.

Bioelectronic devices have received the massive attention because of their huge potential to develop the core electronic components for biocomputing system. Up to now, numerous bioelectronic devices have been reported such as biomemory and biologic gate by employment of biomolecules including metalloproteins and nucleic acids. However, the intrinsic limitations of biomolecules such as instability and low signal production hinder the development of novel bioelectronic devices capable of performing various novel computing functions. As a way to overcome these limitations, nanomaterials have the great potential and wide applicability to grant and extend the electronic functions, and improve the inherent properties from biomolecules. Accordingly, lots of nanomaterials including the conductive metal, graphene, and transition metal dichalcogenide nanomaterials are being used to develop the remarkable functional bioelectronic devices like the multi-bit biomemory and resistive random-access biomemory. This review discusses the nanomaterial-based superb bioelectronic devices including the biomemory, biologic gates, and bioprocessors. In conclusion, this review will provide the interdisciplinary information about utilization of various novel nanomaterials applicable for biocomputing system.

RNA interference (RNAi)-based plasmonic nanomaterials for cancer diagnosis and therapy.

RNA interference (RNAi) is being extensively investigated as a potential therapeutic strategy for cancer treatment. However, RNAi-based therapeutics have not yet been used to treat cancer because of their instability and the difficulty of microRNA (miRNA) delivery. Plasmonic nanoparticle-based RNAi nanotherapeutics have been developed for accurate and sensitive diagnosis and a strong therapeutic effect on cancers by leveraging their ease-of-use and specific properties such as photothermal conversion. In this review, recent strategies and advances in plasmonic nanoparticle-based miRNA delivery are briefly presented to facilitate the detection and treatment of several cancers. The challenges and potential opportunities afforded by the RNAi-based theragnosis field are discussed. We expect that the RNAi-integrated plasmonic nanotherapeutics discussed in this review can provide insights for the early diagnosis and effective treatment of cancer.

Biomolecular Electron Controller Composed of Nanobiohybrid with Electrically Released Complex for Spatiotemporal Control of Neuronal Differentiation.

In vitro spatiotemporal control of cell differentiation is a critical issue in several biomedical fields such as stem cell therapy and regenerative medicine, as it enables the generation of heterogeneous tissue structures similar to those of their native counterparts. However, the simultaneous control of both spatial and temporal cell differentiation poses important challenges, and therefore no previous studies have achieved this goal. Here, the authors develop a cell differentiation biomolecular electron controller ("Biomoletron") composed of recombinant proteins, DNA, Au nanoparticles, peptides, and an electrically released complex with retinoic acid (RA) to spatiotemporally control SH-SY5Y cell differentiation. RA is only released from the Biomoletron when the complex is electrically stimulated, thus demonstrating the temporal control of SH-SY5Y cell differentiation. Furthermore, by introducing a patterned Au substrate that allows controlling the area where the Biomoletron is immobilized, spatiotemporal differentiation of the SH-SY5Y cell is successfully achieved. Therefore, the proposed Biomoletron-mediated differentiation method provides a promising strategy for spatiotemporal cell differentiation control with applications in regenerative medicine and cell therapy.

Bionanohybrid composed of metalloprotein/DNA/MoS2/peptides to control the intracellular redox states of living cells and its applicability as a cell-based biomemory device.

The development of cell-based bioelectronic devices largely depends on the direct control of intracellular redox states. However, most related studies have focused on the accurate measurement of electrical signals from living cells, whereas direct intracellular state control remains largely unexplored. Here, we developed a biocompatible transmembranal bionanohybrid structure composed of a recombinant metalloprotein, DNA, molybdenum disulfide nanoparticles (MoS2), and peptides to control intracellular redox states, which can be used as a cell-based biomemory device. Using the capacitance of MoS2 located inside the cell, the bionanohybrid controled the intracellular redox states of living cells by recording and extracting intracellular charges, which inturn was achieved by activating (writing) and deactivating (erasing) the cells. As a proof of concept, cell-based biomemory functions including writing, reading, and erasing were successfully demonstrated and confirmed via electrochemical methods and patch-clamp analyses, resulting in the development of the first in vitro cell-based biomemory device. This newly developed bionanohybrid provides a novel approach to control cellular redox states for cell-based bioelectronic applications, and can be applicable in a wide range of biological fields including bioelectronic medicine and intracellular redox status regulation.

Electroactive nano-Biohybrid actuator composed of gold nanoparticle-embedded muscle bundle on molybdenum disulfide nanosheet-modified electrode for motion enhancement of biohybrid robot.

There have been several trials to develop the bioactuator using skeletal muscle cells for controllable biobybird robot. However, due to the weak contraction force of muscle cells, the muscle cells could not be used for practical applications such as biorobotic hand for carrying objects, and actuator of biohybrid robot for toxicity test and drug screening. Based on reported hyaluronic acid-modified gold nanoparticles (HA@GNPs)-embedded muscle bundle on PDMS substrate, in this study for augmented actuation, we developed the electroactive nano-biohybrid actuator composed of the HA@GNP-embedded muscle bundle and molybdenum disulfide nanosheet (MoS2 NS)-modified electrode to enhance the motion performance. The MoS2 NS-modified Au-coated polyimide (PI) electrode to be worked in mild pH condition for viable muscle cell was utilized as supporting- and motion enhancing- substrate since it was electrochemically active, which caused the movement of flexible PI electrode. The motion performance of this electroactive nano-biohybrid actuator by electrical stimulation was increased about 3.18 times compared with that of only HA@GNPs embedded-muscle bundle on bare PI substrate. The proposed electroactive nano-biohybrid actuator can be applied to the biorobotic hand and biohybrid robot.

3D Neural Network Composed of Neurospheroid and Bionanohybrid on Microelectrode Array to Realize the Spatial Input Signal Recognition in Neurospheroid.

There have been several studies for demonstration of 2D neural network using living cells or organic/inorganic molecules, but to date, there is no report of development of a 3D neural network in vitro. Based on developed bionanohybrid composed of protein, DNA, molybdenum disulfide nanoparticles, and peptides for controlling electrophysiological states of living cells, here, the in vitro 3D neural network composed of the bionanohybrid, 3D neurospheroid and the microelectrode array (MEA) is developed. After production of the 3D neurospheroid derived from human neural stem cells, the bionanohybrid developed on the MEA successfully semi-penetrates the neurites of the 3D neurospheroid and forms the 3D neural network. The developed 3D neural network successfully exhibited the electrophysiological output signals of the 3D neurospheroid by transmitting the input signal applied by the bionanohybrid. Moreover, by using the selectively immobilized bionanohybrid on the MEA, the spatial input signal recognition in the neurospheroid of 3D neural network is realized for the first time. This newly developed in vitro 3D neural network provides a promising strategy to be applied in brain-on-a-chip, brain disease-related drug efficacy evaluation, bioelectronics, and bioelectronic medicine.