Institute for Basic Science

GLUT2 (SLC2A2), a vital glucose transporter in liver, pancreas, and kidney tissues, regulates blood glucose levels and energy metabolism. Beyond its metabolic role, SLC2A2 contributes to cell differentiation and metabolic adaptation during embryogenesis and tissue regeneration. Despite its significance, the role of SLC2A2 in liver differentiation and hepatocellular carcinoma (HCC) remains underexplored. This study investigated SLC2A2’s role in liver differentiation using in silico, in vitro, and in vivo approaches. Analysis of GEO datasets (GSE132606, GSE25417, GSE67848) and TCGA HCC data revealed that while SLC2A2 expression decreases with HCC progression, stemness-associated genes, including SOX2 and POU5F1, are upregulated. Zebrafish embryos injected with SLC2A2-targeting morpholino exhibited reduced expression of the liver differentiation marker fabp10a without significantly altering the hepatoblast marker hhex. In HepG2 cells, SLC2A2 knockdown increased stemness and IGF1R pathway markers, indicating a shift toward less differentiated states. These findings suggest that SLC2A2 supports liver differentiation by regulating glucose metabolism and suppressing pathways associated with stemness and malignancy. Targeting SLC2A2 may serve as a promising therapeutic strategy for liver-related diseases, particularly HCC, by addressing its dual role in differentiation and tumor progression. Further mechanistic studies are warranted to fully elucidate these processes.

BACKGROUND Delayed emergence from anesthesia presents clinical challenges, including prolonged stays in the postanesthesia care unit (PACU). The neurobiological mechanisms underlying delayed emergence, particularly in remimazolam-induced anesthesia, remain poorly understood. This study aimed to explore patterns of brain electrical activity of delayed emergence in remimazolam-induced anesthesia by comparing dynamic changes in electroencephalogram (EEG) activity under various anesthesia states of remimazolam and propofol, focusing on the prefrontal region. METHODS Forty-eight patients (age >18) who underwent laparoscopic cholecystectomy randomly received remimazolam- or propofol-induced general anesthesia. Power spectrogram analysis and functional connectivity measures, phase lag entropy (PLE) and phase lag index (PLI), were used to the prefrontal EEG data collected at baseline, unconsciousness, and emergence. Correlation between EEG measures and Patient State Index (PSI) at PACU, as well as time to Aldrete 9 , were compared. RESULTS During emergence from anesthesia, EEG power revealed that the remimazolam group had higher powers than the propofol group in theta band during eyes-open (EO) (mean of 2.933 [standard deviation of 5.762] vs − 2.342 [4.869]; P -value of 0.018 with independent 2-sample t test), and in the alpha band during eyes-closed (EC) (5.821 [7.35] vs − 2.399 [4.53]; P < .001) and EO (4.84 [6.411] vs − 3.613 [4.556]; P < .001). Conversely, the functional connectivity result showed lower PLE in the alpha band during EC (0.619 [0.0338] vs 0.684 [0.0392]; P < .0001) and EO (0.651 [0.0358] vs 0.692 [0.0428]; P = .015), and in the beta band during EC (0.682 [0.0308] vs 0.712 [0.0236]; P = .016) and EO (0.695 [0.0236] vs 0.725 [0.0195]; P < .001). In line with this, the remimazolam group had lower PSI values at PACU during EC (65.10 [14.67] vs 82.40 [6.678]; P < .0001) and EO (72.35 [12.55] vs 83.53 [6.632]; P = .006) and were slower to reach Aldrete score of 9 (median difference of 17.5; interquartile range of [0.0–21.0]; P < .001). Delayed consciousness recovery ( time to Aldrete 9 ) under remimazolam was significantly correlated with PLE (Pearson’s correlation = −.78, P < .0001) and PLI (Pearson’s correlation =.69, P = .028) in the alpha band during deep anesthesia. CONCLUSIONS Dynamic changes in prefrontal EEG during recovery and the correlation analyses show the potential of EEG in reflecting distinct consciousness recovery profiles between 2 drugs—slower recovery under remimazolam anesthesia. This suggests an association of EEG parameters with a unique behavioral profile of remimazolam, especially reflecting progressive changes in cerebral activity during recovery.

We study the generalized Ramsey–Turán function $\mathrm {RT}(n,K_s,K_t,o(n))$, which is the maximum possible number of copies of $K_s$ in an n-vertex $K_t$-free graph with independence number o(n). The case when s=2 was settled by Erdős, Sós, Bollobás, Hajnal, and Szemerédi in the 1980s. We combinatorially resolve the general case for all $s\ge 3$, showing that the (asymptotic) extremal graphs for this problem have simple (bounded) structures. In particular, it implies that the extremal structures follow a periodic pattern when t is much larger than s. Our results disprove a conjecture of Balogh, Liu, and Sharifzadeh and show that a relaxed version does hold.

The radical-mediated C–H functionalization of pyridines, catalyzed by visible light, has emerged as a powerful and versatile strategy in organic chemistry. This approach enables direct and selective modification of the pyridine framework, significantly expanding the toolkit available for organic synthesis. In recent years, N-functionalized pyridinium salts have gained considerable attention in this field, serving dual roles as both radical precursors and pyridine surrogates. N-functionalized pyridinium salts offer several key advantages over traditional pyridine reactants. They enhance reactivity and selectivity in synthetically valuable transformations; perform excellently under mild, acid-free conditions; and provide superior regiocontrol for nontraditional Minisci-type reactions. These properties have made them increasingly valuable in modern organic synthesis, particularly in the context of late-stage functionalization and complex molecule synthesis. Recent advancements in this area have been substantial and diverse. Researchers have developed a wide array of synthetic applications using pyridinium salts under visible-light conditions, ranging from C–H functionalization to heterocycle formation. Notably, N-substituted pyridinium salts have been ingeniously utilized as bifunctional reagents for alkene difunctionalization, opening new avenues for molecular complexity generation. Innovative approaches involving light-absorbing electron donor-acceptor (EDA) complexes between pyridinium salts and electron-rich donors have been introduced, enabling new reactivity patterns in photocatalyst-free conditions. This strategy not only simplifies reaction setups but also expands the scope of accessible transformations. Furthermore, the establishment of enantioselective reactions using pyridinium salts represents a significant breakthrough, further broadening their synthetic utility and addressing long-standing challenges in asymmetric synthesis. These developments collectively demonstrate the versatility and potential of N-functionalized pyridinium salts in advancing the frontiers of organic synthesis. This comprehensive chapter provides an in-depth overview of these developments, meticulously organized based on the N-substituent of pyridinium salts and their distinct reactivity patterns. It delves into recent advancements in N-functionalized pyridinium salt chemistry, discussing a wide range of organic reactions utilizing these compounds under visible-light conditions. The authors explore crucial structure-reactivity relationships based on N-substituents as well as innovative activation modes and their mechanistic implications, providing insights that are vital for reaction design and optimization.

Background Stroke results in substantial long-term disability, necessitating effective recovery interventions. This study explored the effects of multi-channel transcranial direct current stimulation (tDCS) on hemodynamic responses and upper limb motor function in stroke patients, targeting the ipsilesional primary motor cortex (M1) and anterior intraparietal sulcus (aIPS). Methods A double-blind, randomized, sham-controlled trial was conducted with 24 stroke patients (18 men; mean age, 57.3×14.2 years), who underwent 10 sessions of real or sham multi-channel tDCS combined with upper limb exercises. Functional near-infrared spectroscopy (fNIRS) measured resting-state cerebral hemodynamic responses for 5 min before and after each session. Motor function was evaluated using the Fugl–Meyer assessment for upper extremity (FMA-UE), box and block test (BBT), and other motor function tests before and after the interventions. Results The real multi-channel tDCS group exhibited increases in regional accumulation of oxyhemoglobin (HbO Acc ) and stronger seeded connectivity networks within the motor cortex poststimulation. In contrast, the sham group exhibited disassociation from these areas. The group × time interaction was significant for the Box and Block Test (BBT), indicating greater improvements in gross manual dexterity in the real-tDCS group compared to the sham group. While poststimulation changes in HbOAcc were examined in relation to FMA-UE scores, no strong linear relationship was observed in the real-tDCS group. Conclusions Multi-channel tDCS targeting the ipsilesional M1 and aIPS, combined with upper limb exercises, showed potential effects on cerebral hemodynamics and motor function in stroke patients. These findings suggest that multi-channel tDCS may have a role in motor rehabilitation, but further research is needed to validate its efficacy and clinical applicability. ClinicalTrials.gov This study was registered at ClinicalTrials.gov (NCT05275114).

Electrochemical functionalization of graphene facilitates simple and various modifications of graphene properties. However, the scope of the available functional groups and the electrochemical behavior of graphene is not fully understood. The electrochemical reactivity of single crystal and monolayer graphene‐on‐Cu(111) with various phenyl and alkyl iodides is investigated, and discovered different onset potentials, identifying the extent of the reaction with Raman spectroscopy and X‐ray photoelectron spectroscopy (XPS). Differential pulse voltammetry (DPV) and density functional theory (DFT) calculations are employed to elucidate the onset potential differences between the phenyl iodides with different substituents. A comprehensive understanding of graphene's electrochemical reactivity is presented.

Inspired by the prominent redox and optical properties of natural flavins, synthetic flavins have found broad applications in organic, photochemical, and biochemical research. Tailoring these properties of flavins, however, remains a challenge. In this work, we present three pentacyclic flavins (C-PF, O-PF, and S-PF) that leverage a strategic molecular design to modify the flavin’s electronic structure. Notably, the oxygen- and sulfur-linked pentacyclic flavins (O-PF and S-PF) exhibit deep-red and NIR emission, respectively, driven by enhanced π-conjugation, substituent effects, and charge separation upon excitation. These heteroatom-incorporated pentacyclic flavins exhibit unusual quasi-reversible oxidation, expanding both optical and redox limits of synthetic flavins. Comprehensive spectroscopic, structural, and computational analyses reveal how heteroatom incorporation within this five-ring-fused system unlocks redox and optical properties of flavin-derived chromophores.

Fear extinction training in rodents decreases fear responses, providing a model for the development of post-traumatic stress disorder therapeutics. Fear memory recall reactivates the consolidated fear memory trace across multiple brain regions, and several studies have suggested that these recall-activated neurons are re-engaged during extinction. However, the molecular mechanisms linking this reactivation to extinction remain largely elusive. Here, we investigated the role of N-Methyl- d -Aspartate receptors (NMDARs) in remote memory recall–activated neurons within the basolateral amygdala and the medial prefrontal cortex during extinction training in mice. We found that Grin1 knockdown in these specific ensembles impaired extinction of remote fear memory, but did not reduce their reactivation during retrieval of the extinguished memory. These data suggest that while reactivation of these neuronal populations persists, their NMDARs are crucial for driving the synaptic plasticity needed to extinguish remote fear memories.

Zinc–air batteries (ZABs) are promising electrochemical energy storages, but inefficient oxygen reduction reaction (ORR) during discharging and oxygen evolution reaction (OER) during charging at their cathodes impede achieving high energy density and stable cycling. We report a serrated leaf‐like nitrogen‐doped copper sulfide (N‐CuS) cathode with conductive N 2p‐S 3p hybridized orbitals, oxygen‐transporting mesopores, and about fivefold larger surface area than Cu. A ZAB with the N‐CuS cathode exhibits a 788 mAh g⁻¹ capacity (96% of theoretical) and a hitherto highest energy density of 916.0 Wh kg⁻¹, surpassing one with the state‐of‐the‐art Pt/C+RuO₂ cathode (712.43 mAh g⁻¹ and 874 Wh kg⁻¹). Density functional theory calculations elucidate that O═O bond dissociation is 0.97 eV more favorable on N‐CuS than CuS. Subsequently, protonation of surface‐adsorbed *O to *OH occurs via dissociate (0.55 V), non‐spit associate (1.05 V), and split associate (1.05 V) pathways, with *OH then desorbing as OH‐. Under anaerobic conditions, copper oxide transitions from CuO to Cu2O (1.05 V) and eventually to Cu (0.75 V) releasing oxygen to sustain ORR. Additionally, a ZAB with the N‐CuS cathode achieves about threefold longer cyclability than one with the Pt/C+IrO₂ cathode, and about six‐fold longer cyclability than one with the Pt/C+RuO₂ cathode.

We discuss a universal relation that we call the $x-y$ swap relation, which plays a prominent role in the theory of topological recursion, Hurwitz theory, and free probability theory. We describe in a very precise and detailed way the interaction of the $x-y$ swap relation and KP integrability. As an application, we prove a recent conjecture that relates some particular instances of topological recursion to the Mironov–Morozov–Semenoff matrix integrals.

Background The conscious state is maintained through intact communication between brain regions. However, studies on global and regional connectivity changes in unconscious state have been inconsistent. These inconsistencies could arise from unclear definition of unconsciousness, spatial and temporal limitations of neuroimaging modalities, and estimating only single connectivity measure. Here, we investigated global and regional changes in amplitude and phase based functional connectivity in propofol-induced unconsciousness, which is widely recognized as unconsciousness. Methods We calculated amplitude and phase based functional connectivity using amplitude envelope correlation (AEC), weighted phase lag index (wPLI), and magnitude squared coherence (MSC) from intracranial electroencephalography data of 73 patients. Global changes in connectivity, complexity, and network efficiency were estimated. Regional connectivity changes between Brodmann areas, between 7 cortical lobes, and between resting state networks were assessed across all frequency bands. Additionally, we employed machine learning analysis to identify specific regions in classifying conscious and unconscious states. Results In the unconscious state, global connectivity increased across all frequency bands, while global complexity and efficiency decreased, accompanied by increased delta and decreased high gamma power spectral density. Regional connectivity increased between entire cortical regions across all frequency bands. Machine learning analysis revealed that posterior connectivity was the most influential in classifying consciousness. Amplitude-based connectivity predominantly increased in the delta and theta bands, while phase-based connectivity predominantly increased from the beta to high gamma bands. Conclusions Propofol anesthesia suppresses cortical activity and induces oscillatory changes characterized by increased delta power and decreased high gamma power. These changes are accompanied by increased functional connectivity and reduced network complexity and efficiency. These changes limit the brain's ability to generate a diverse repertoire of activity, ultimately leading to unconsciousness. Posterior connectivity, which showed high accuracy in predicting conscious states, would be crucial for sustaining consciousness.

Plant molecular farming (PMF), or “pharming,” leverages plant cells or whole plants as expression systems to produce recombinant proteins for pharmaceuticals and other applications. This approach has emerged as a viable alternative to traditional platforms like Escherichia coli and mammalian cell lines, offering distinct advantages such as low production costs, high protein stability, and human-like post-translational modifications. However, the reliance on terrestrial plants as bioreactors poses challenges, including competition with food crops for agricultural resources and the risk of contaminating the food supply. As a result, identifying new host platforms for efficient recombinant protein production is a critical priority for advancing PMF. In this review, we highlight duckweeds-small, fast-growing aquatic monocots in the family Lemnaceae -as a promising alternative. Duckweeds offer advantages such as rapid growth, high biomass yield, and a rich metabolic profile, making them an attractive platform for recombinant protein production. We summarize recent developments in the use of duckweeds for PMF, including advancements in tissue culture, transformation techniques, and the expanding availability of genetic resources. Finally, we discuss remaining challenges and propose future directions for establishing duckweeds as a robust host platform in synthetic biology.

The therapeutic efficacy of a nanomedicine or a natural biomaterial can vary in different disorders due to their complex pathophysiology. A nanomedicine that is capable of not only targeting specific pathological cues through functional ligands but also optimizing the therapeutic efficacy of its components throughout the intricate pathways involved in complex disorders is highly desired. Here, ceria‐nanoparticle‐entangled reticulation for angiogenic and therapeutic embrocation (CERATE), composed of hyaluronic acid, levofloxacin, and the as‐synthesized ceria nanoparticles is developed. CERATE is formulated in situ as a rigid nanoparticle‐based network that integrates its components intimately using highly diluted concentrations, thereby augmenting the therapeutic efficiency of its individual components. The physical states of CERATE can be altered freely while retaining its integrity, by adjusting the water proportion to accommodate diverse clinical needs. This physically robust CERATE can withstand enzymatical degradation, display antibacterial activity, scavenge reactive oxygen species, and improve the migration and proliferation of fibroblasts by activating the proangiogenic factors. CERATE accelerates the repair of diabetic wounds by promoting both the angiogenesis and the synthesis of collagen. The results demonstrate the effectiveness of a multifactorial approach involving the recruitment of minimally modified biofunctional ligands and nanomaterials altogether with synergistic efficacy in treating complex disorders.

Immunity by vaccination can protect human against heterologous viruses. However, protective abilities of artificial vaccines are still weaker than natural infections. Here we develop a kinetically engineered vaccine (KE-VAC) that mimics the multidimensional immunomodulation in natural infections via dynamic activation of antigen presenting cells with masked TLR7/8 agonist and sustained supplies of antigens and adjuvants to lymph nodes, leading to follicular helper T and germinal centre B cell activation in vaccinated mice. KE-VAC demonstrates superior efficacy than traditional alum and mRNA vaccines, achieving a 100% survival rate with increased neutralizing antibodies titers and polyfunctional CD8⁺ T cells, recognizing heterologous SARS-CoV-2 variants, and inducing broad and long-term protection against multiple strains of influenza viruses. Prime/boost vaccination with KE-VAC also protect aged ferrets from severe fever with thrombocytopenia syndrome virus infection, with no virus detected in any organs at day 6 p.i. The efficacy of KE-VAC across various pathogens thus highlights its potential as an effective vaccine against emerging infectious risks.

The emergence of a pseudogap is a hallmark of anomalous electronic states formed through substantial manybody interaction but the mechanism of the pseudogap formation and its role in related emerging quantum states such as unconventional superconductivity remain largely elusive. Here, the emergence of an unusual pseudogap in a representative van der Waals chiral charge density wave (CDW) materials with strong electron correlation, 1T‐TaS2 is reported, through isoelectronic substitute of S. The evolution of electronic band dispersions of 1T‐TaS2 − xSex (0 ⩽ x ⩽ 2) is systematically investigated using angle‐resolved photoemission spectroscopy (ARPES). The results show that the Se substitution induces a quantum transition from an insulating to a pseudogap metallic phase with the CDW order preserved. Moreover, the asymmetry of the pseudogap spectral function is found, which reflects the chiral nature of CDW structure. The present observation is contrasted with the previous suggestions of a Mott transition driven by band width control or charge transfer. Instead, the pseudogap phase is attributed to a disordered Mott insulator in line with the recent observation of substantial lateral electronic disorder. These findings provide a unique electronic system with chiral pseudogap, where the complex interplay between CDW, chirality, disorder, and electronic correlation may lead to unconventional emergent physics.

Antiferromagnetic spin fluctuations are the most promising candidate as the pairing glue of high critical temperature (Tc) superconductivity in cuprates. However, many-body states and intertwined orders have made it difficult to determine how electrons couple with fluctuating spins to form Cooper pairs. Recent experimental and theoretical studies have suggested spin fluctuation-driven quasiparticle band folding, but the relationship between the resultant Fermi pockets and superconductivity remains unclear. Here, using angle-resolved photoemission spectroscopy and numerical simulations, we show a proportional relationship between Tc and the quasiparticle weight of the incipient hole pocket near the nodal point in electron-doped Pr1−xLaCexCuO4±δ. Through complementary muon spin spectroscopy measurements, we uncover that the hole pocket forms only in the regime of the fluctuating antiferromagnetic ground state around a presumed quantum critical point. Our observations highlight the significance of the electron-spin fluctuation interaction in enhancing the hole pocket and consequently driving superconductivity.