Enhancement of ANN-based wind power forecasting by modification of surface roughness parameterization over complex terrain.

Wind energy plays an important role in the sustainable energy transition towards a low-carbon society. Proper assessment of wind energy resources and accurate wind energy prediction are essential prerequisites for balancing electricity supply and demand. However, these remain challenging, especially for onshore wind farms over complex terrains, owing to the interplay between surface heterogeneities and intermittent turbulent flows in the planetary boundary layer. This study aimed to improve wind characteristic assessment and medium-term wind power forecasts over complex hilly terrain using a numerical weather prediction (NWP) model. The NWP model reproduced the wind speed distribution, duration, and spatio-temporal variabilities of the observed hub-height wind speed at 24 wind turbines in onshore wind farms when incorporating more realistic surface roughness effects, such as the subgrid-scale topography, roughness sublayer, and canopy height. This study also emphasizes the good features for machine learning that represent heterogeneities in the surface roughness elements in the atmospheric model. We showed that medium-term forecasting using the NWP model output and a simple artificial neural network (ANN) improved day-ahead wind power forecasts by 14% in terms of annual normalized mean absolute error. Our results suggest that better parameterizations of surface friction in atmospheric models are important for wind power forecasting and resource assessment using NWP models, especially when combined with machine learning techniques, and shed light on onshore wind power forecasting and wind energy assessment in mountainous regions.

Precipitation data in Seoul, Korea during 1778-1907.

Precipitation plays a crucial role in the global energy and water cycle and has important implications for food, water, and energy security. To enhance our understanding of the water cycle, it is invaluable to have a comprehensive historical record of precipitation. However, obtaining such records, especially for the period before the Industrial Revolution, can be challenging. During the Joseon Dynasty, Korea established a network for measuring rainfall and recorded this information in historical documents known as Seungjeongwon Ilgi and Ilseongnok. Recently, these documents have been digitized, providing us with daily precipitation data for Seoul spanning 130 years, from 1778 to 1907. By combining and analyzing these two documents, we were able to address inconsistencies found in previous studies and improve the quality of the data. Notably, this dataset is free of any missing values, making it the longest daily precipitation record in the world before the Industrial Revolution. Its availability to the public holds great potential for climate research in East Asia during the late Little Ice Age.

Metabolic Modulation of Kynurenine Based on Kynureninase-Loaded Nanoparticle Depot Overcomes Tumor Immune Evasion in Cancer Immunotherapy.

Evading recognition of immune cells is a well-known strategy of tumors used for their survival. One of the immune evasion mechanisms is the synthesis of kynurenine (KYN), a metabolite of tryptophan, which suppresses the effector T cells. Therefore, lowering the KYN concentration can be an efficient antitumor therapy by restoring the activity of immune cells. Recently, kynureninase (KYNase), which is an enzyme transforming KYN into anthranilate, was demonstrated to show the potential to decrease KYN concentration and inhibit tumor growth. However, due to the limited bioavailability and instability of proteins in vivo, it has been challenging to maintain the KYNase concentration sufficiently high in the tumor microenvironment (TME). Here, we developed a nanoparticle system loaded with KYNase, which formed a Biodegradable and Implantable Nanoparticle Depot named 'BIND' following subcutaneous injection. The BIND sustainably supplied KYNase around the TME while located around the tumor, until it eventually degraded and disappeared. As a result, the BIND system enhanced the proliferation and cytokine production of effector T cells in the TME, followed by tumor growth inhibition and increased mean survival. Finally, we showed that the BIND carrying KYNase significantly synergized with PD-1 blockade in three mouse models of colon cancer, breast cancer, and melanoma.

Enhanced Local Delivery of Engineered IL-2 mRNA by Porous Silica Nanoparticles to Promote Effective Antitumor Immunity.

Localized expression of immunomodulatory molecules can stimulate immune responses against tumors in the tumor microenvironment while avoiding toxicities associated with systemic administration. In this study, we developed a polyethylenimine-modified porous silica nanoparticle (PPSN)-based delivery platform carrying cytokine mRNA for local immunotherapy in vivo. Our delivery platform was significantly more efficient than FDA-approved lipid nanoparticles for localized mRNA translation. We observed no off-target translation of mRNA in any organs and no evidence of systemic toxicity. Intratumoral injection of cytokine mRNA-loaded PPSNs led to high-level expression of protein within the tumor and stimulated immunogenic cancer cell death. Additionally, combining cytokine mRNA with an immune checkpoint inhibitor enhanced anticancer responses in several murine cancer models and enabled the inhibition of distant metastatic tumors. Our results demonstrate the potential of PPSNs-mediated mRNA delivery as a specific, effective, and safe platform for mRNA-based therapeutics in cancer immunotherapy.

Highly Efficient Messenger RNA Transfection of Hard-to-Transfect Cells using Carbon Nanodots.

Although messenger RNA (mRNA)-based therapeutics opened up new avenues for treating various diseases, intracellular delivery of mRNA is still challenging, especially to hard-to-transfect cells. For successful mRNA therapy, the development of a delivery vehicle that can effectively transport mRNA into cells is essential. In this study, we synthesized carbon nanodots (CNDs) as an efficient mRNA delivery vehicle via a one-step microwave-assisted method. CNDs easily formed complexes with mRNA molecules by electrostatic interactions, and the gene delivery performance of CNDs was highly effective in hard-to-transfect cells. Considering their outstanding transfection ability, CNDs are expected to be further applied for mRNA-based cellular engineering.

Development of a Cancer Nanovaccine to Induce Antigen-specific Immune Responses Based on Large-Sized Porous Silica Nanoparticles.

Cancer vaccine is one of the immunotherapeutic strategies aiming to effectively deliver cancer antigens to professional antigen-presenting cells such as dendritic cells (DCs), macrophages, and B cells to elicit a cancer-specific immune response. Despite the advantages of the cancer vaccine that can be applied to various cancer types, the clinical approach is limited due to the non-specific or adverse immune responses, stability, and safety issues. In this study, we report an injectable nanovaccine platform based on large-sized (∼350 nm) porous silica nanoparticles (PSNs). We found that large-sized PSNs, called PS3, facilitated the formation of an antigen supply depot at the site of injection so that a single injection of PSN-based nanovaccine elicited sufficient tumor-specific cell-mediated and humoral immune response. As a result, antigen-loaded PS3 induced successful tumor regression in prophylactic and therapeutic vaccination.

Graphene oxide-based fluorescent biosensors and their biomedical applications in diagnosis and drug discovery.

Graphene oxide (GO), an oxidized derivative of graphene, has received much attention for developing novel fluorescent bioanalytic platforms due to its remarkable optical properties and biocompatibility. The reliable performance and robustness of GO-based biosensors have enabled various applications in the biomedical field including diagnosis and drug discovery. Here, recent advances in the development of GO-based fluorescent biosensors are overviewed, particularly nucleic acid detection and enzyme activity assay. In addition, practical applications in biomarker detection and high-throughput screening are also examined. Lastly, basic design principles and remaining challenges of these types of biosensors are discussed for further progress.

Identification of a Direct-Acting Antiviral Agent Targeting RNA Helicase via a Graphene Oxide Nanobiosensor.

Dengue virus (DENV), an arbovirus transmitted by mosquitoes, causes infectious diseases such as dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Despite the dangers posed by DENV, there are no approved antiviral drugs for treatment of DENV infection. Considering the potential for a global dengue outbreak, rapid development of antiviral agents against DENV infections is crucial as a preemptive measure; thus, the selection of apparent drug targets, such as the viral enzymes involved in the viral life cycle, is recommended. Helicase, a potential drug target in DENV, is a crucial viral enzyme that unwinds double-stranded viral RNA, releasing single-stranded RNA genomes during viral replication. Therefore, an inhibitor of helicase activity could serve as a direct-acting antiviral agent. Here, we introduce an RNA helicase assay based on graphene oxide, which enables fluorescence-based analysis of RNA substrate-specific helicase enzyme activity. This assay demonstrated high reliability and ability for high-throughput screening, identifying a new helicase inhibitor candidate, micafungin (MCFG), from an FDA-approved drug library. As a direct-acting antiviral agent targeting RNA helicase, MCFG inhibits DENV proliferation in cells and an animal model. Notably, in vivo, MCFG treatment reduced viremia, inflammatory cytokine levels, and viral loads in several tissues and improved survival rates by up to 40% in a lethal mouse model. Therefore, we suggest MCFG as a potential direct-acting antiviral drug candidate.

A graphene oxide-based fluorescent nanosensor to identify antiviral agents via a drug repurposing screen.

Currently, there are no approved therapeutics for Dengue virus (DENV) infection, even though it can cause fatal complications. Understanding DENV infection and its propagation process in host cells is necessary to develop specific antiviral therapeutics. Here, we developed a graphene oxide-based fluorescent system (Graphene Oxide-based Viral RNA Analysis system, GOViRA) that enables sensitive and quantitative real-time monitoring of the intracellular viral RNA level in living cells. The GOViRA system consists of a fluorescent dye-labeled peptide nucleic acid (PNA) with a complementary sequence to the DENV genome and a dextran-coated reduced graphene oxide nanocolloid (DRGON). When the dye labeled PNA is adsorbed onto DRGON, the fluorescence of the dye is effectively quenched. The quenched fluorescence signal is recovered when the dye labeled PNA forms interaction with intracellular viral RNA in DENV infected host cells. We demonstrated the successful use of the GOViRA platform for high-throughput screening to discover novel antiviral compounds. Through a cell-based high-throughput screening of FDA-approved small-molecule drugs, we identified ulipristal, a selective progesterone receptor modulator (SPRM), as a potent inhibitor against DENV infection. The anti-DENV activity of ulipristal was confirmed both in vitro and in vivo. Moreover, we suggest that the mode of action of ulipristal is mediated by inhibiting viral entry into the host cells.

Non-viral, direct neuronal reprogramming from human fibroblast using a polymer-functionalized nanodot.

Among various strategies to treat neurodegenerative disorders, cell replacement therapies have drawn much attention recently. Such a trend led to the increase in demand for the rare and specialized cells, followed by the outburst development of various cell reprogramming strategies. However, several limitations on these conventional methods remain to be solved, including the genetic instability of the viral vectors and the high cytotoxicity or poor performance of the non-viral carriers. Therefore, non-viral methods need to be developed to ensure safe and efficient cell reprogramming. Here, we introduce a polymer-modified nano-reagent (Polymer-functionalized Nanodot, PolyN) for the safe and efficient, non-viral direct cell reprogramming. PolyN facilitated the highly efficient contemporary overexpression of the transgene compared to the conventional reagent. With our nano-reagent, we demonstrated the SOX2-mediated cell reprogramming and successfully generated the neuron-like cell from the human fibroblast.

Discovery of direct-acting antiviral agents with a graphene-based fluorescent nanosensor.

Direct-acting agents against viral components are considered as the most promising candidates for the successful antiviral therapeutics. To date, no direct-acting drugs exist for the treatment against dengue virus (DV) infection, which can develop into life-threatening diseases. RNA-dependent RNA polymerase (RdRp), an RNA virus-specific enzyme highly conserved among various viral families, has been known as the broad-range antiviral drug target. Here, we developed an RNA-based graphene biosensor system [RNA nano-graphene oxide system (RANGO)] to enable the fluorescence-based quantitative analysis of the RdRp enzyme activity. We used the RANGO system to a high-throughput chemical screening to identify novel direct-acting antiviral drug candidates targeting DV RdRp from the FDA-approved small-molecule library. RANGO accelerated the massive selection of drug candidates. We found that one of the selected hit compounds, montelukast, showed antiviral activity in vitro and in vivo by directly inhibiting replication of DV and thus relieved related symptoms.