An atom-and step-economical method for the synthesis of indenoisoquinolines as a scaffold of topoisomerase I inhibitors was developed using rhodium-catalysed cyclocondensation of N-monosubstituted benzamides with 2-diazoindenedione, where the unexpected indenoisochromenes were obtained in high yields with high selectivity through rhodium-catalysed cyclocondensation of N-tert-butylbenzamides with 2-diazoindenediones (2). These results indicated that the kinds of substituents on a nitrogen atom of the starting benzamides controlled which product-indenoisoquinolines or indenoisochromenes-could be obtained selectively by the tuning of rhodium catalyst systems under optimal reaction conditions. Namely, indeno[1,2-c]isoquinolin-5,11-diones (3 and 5) were formed directly from 1,3-dicarbonyl intermediates by intramolecular nucleophilic attack of an amide nitrogen atom on a carbonyl group in 1,3-dicarbonyl intermediates, followed by dehydration, whereas indeno[1,2-c]isochromene-5,11-diones (7) were obtained from enol tautomers of 1,3-dicarbonyl intermediates by intramolecular nucleophilic attack of a hydroxyl group on an amide carbonyl group together with liberation of an amine.

Recently, much attention has been focused on developing theranostic probes that could make it possible to achieve diagnosis and therapy at the same time. As for theranostics of cancers, cisplatin (cis‒diamminedichloro-platinum(II), CDDP) is a potent anticancer drug; however, cisplatin has some serious drawbacks, including poor water solubility as well as low lipophilicity. Here, we report the synthesis and in vivo evaluation of cisplatin-incorporating gelatin-coated gadolinium oxide (Gd2O3) nanoparticles, gelatin-CDDP-Gd2O3 NPs, which are a highly efficient theranostic probe for cancer treatment. The controlled release of CDDP from gelatin-CDDP-Gd2O3 NPs was realized by the enzymatic degradation of surface-gelatin of NPs with matrix metalloproteinases, MMP-2 and MMP-9, which are highly expressed in cancer cells. Then, gelatin-CDDP-Gd2O3 NPs served as a dual contrast agent for magnetic resonance and photoacoustic imaging to give important information on tumor regression under treatment.

Allergic rhinitis (AR), driven by immune imbalance and excessive IgE production, manifests with symptoms that significantly impair the patient's quality of life. Current therapies mainly provide symptomatic relief without correcting the underlying immune dysregulation. Bryostatin-1 (bryo-1) is a promising candidate for the causal treatment of AR. It potently inhibits IgE-mediated allergic responses while enhancing nasal mucosal defense through the selective induction of IgA antibodies upon intranasal administration. However, the intranasal delivery of bryo-1 faces challenges, including high cost, chemical instability, and limited permeability across the nasal mucosal barrier. In this study, bryo-1 was incorporated with liposomes with varying surface charges. These LNPs exhibited stronger interactions with antigen-presenting cells and enhanced cellular uptake and delivery efficiency of bryo-1 in vitro. Notably, anionic LNPs achieved superior bryo-1 delivery to B cells, selectively promoting IgA class switching while suppressing IgE expression. In an AR mouse model, even the low-dose (0.5 ng) intranasal administration of bryo-1-loaded anionic LNPs elevated antigen-specific IgA levels in salivary secretions. These findings indicate that anionic LNPs enhance delivery efficiency, representing a promising platform for intranasal bryo-1 delivery to modulate mucosal immunity and treat AR.

Immunotherapy efficacy is often hindered by the immunosuppressive “cold tumor” microenvironment, dominated by M2 macrophages. We developed pullulan–mannose–IR820 (PMI) nanogels as targeted photoacoustic (PA) contrast agents and performed a comparative study with mannan (MI) and fucoidan (FI) nanogels to establish structural design guidelines for M2 targeting. All the variants formed stable nanogels ( < 100 nm) driven by IR-820 self-association, providing robust PA signals. Despite the high intrinsic sugar content of natural polysaccharides, PMI nanogels exhibited significantly greater internalization by M2 macrophages. This superior efficiency was not due to electrostatic interactions, as all the variants possessed comparable negative ζ-potentials. Competitive inhibition assays revealed a moderate decrease in uptake ( ~ 10–15%) for all the nanogels, indicating that while nonspecific pathways are dominant in overall cell association, mannose receptors are partly involved. Remarkably, despite having a significantly lower mannose content than native mannan did, the inhibition rate of the PMI nanogel was comparable, suggesting that its unique pendant configuration offers superior spatial accessibility for efficient receptor interaction. Consequently, the PMI nanogels achieved the highest PA contrast in M2 macrophage imaging. These findings highlight that spatial ligand presentation, rather than absolute density, is a critical determinant in the design of next-generation drug delivery systems for targeting the immunosuppressive tumor microenvironment. Three types of self-assembled nanogels were synthesized by conjugating the near-infrared dye IR-820 with polysaccharides (pullulan, mannan, and fucoidan) as M2 macrophage-targeting photoacoustic imaging agents. Among these, the pullulan-modified (PMI) nanogel exhibited the most effective interaction with M2 macrophages, as demonstrated through comparative cellular uptake evaluations.

The engineering of theranostic nanoparticles, which integrate diagnostics and therapy in a single administration, enables targeted drug delivery and disease visualization. In cancer theranostics, gadolinium-based nanoparticles are valuable tools for noninvasive magnetic resonance imaging (MRI) and provide high-resolution images of the tumor. When MRI is combined with other imaging modalities, complementary therapeutic information is obtained for more accurate identification of tumor characteristics and precise guidance of anticancer drug delivery. Among the many possible modalities combined with MRI, photoacoustic imaging (PAI) is a candidate that enables sensitive in vivo detection of tumors. We have already succeeded in synthesizing biocompatible gelatin-coated gadolinium oxide nanoparticles with a controlled size by adjusting the timing of gelatin addition, which were a highly efficient contrast agent for MR and PA dual imaging. Herein, we conjugated a clinically used anticancer drug (doxorubicin, DOX) to size-defined and biocompatible gadolinium oxide nanoparticles which are novel theranostic probes. Succinylated gelatin enabled the electrostatic conjugation of DOX with gadolinium oxide nanoparticles, and the release of DOX was controlled through the enzymatic degradation of gelatin by matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9), which are highly expressed in cancer cells. The released DOX efficiently inhibited the growth of HeLa cells in vitro and the growth of the inoculated tumor tissues in vivo. The dual-modality MRI and PAI capabilities provide anatomical information that assists in the localization and targeting of theranostic probes.

This letter describes the chemodivergent synthesis of isocoumarins and isoquinolones using identical starting materials. A rhodium(III) catalyst induces C(sp2)-H bond activation, carbene migratory insertion, and intramolecular annulation under mild reaction conditions. The selectivity of isocoumarins versus isoquinolones is tuned by controlling the additives. Specifically, acetic acid promotes lactonization, affording isocoumarins, whereas the cationic Cp*Rh(III) (Cp* = eta 5-pentamethylcyclopentadienyl) facilitates lactamization, affording isoquinolones. Overall, the developed protocol enables chemodivergent synthesis of isocoumarins and isoquinolones with high (regio)selectivity, excellent functional group tolerance, and high yields.

Immunotherapy can reduce treatment-related side effects but shows limited efficacy in “cold tumors,” whose immunosuppressive tumor immune microenvironment is characterized by abundant M2 macrophages and poor T cell infiltration. Because biopsy-based qualitative assessment of the tumor microenvironment is invasive and conventional imaging lacks functional information, this study aimed to develop an M2 macrophage-targeted theranostic agent enabling non-invasive photoacoustic (PA) imaging and pH-triggered cytotoxicity. A pullulan-based nanogel conjugated with mannose and near-infrared dye (IR-820) was further functionalized with the pH-responsive doxorubicin (DOX) prodrug, Aldoxorubicin, to develop Pullulan-mannose-IR820-Aldoxorubicin (PMID) nanogel. PMID was successfully synthesized, and the resulting self-assembled nanogels (<100 nm) exhibited a highly negative ζ-potential, near-infrared absorption peaks at 780 and 850 nm, and PA contrast comparable to IR-820 at 850 nm excitation. Dialysis studies demonstrated suppressed drug release at neutral pH (~20%) but accelerated release under acidic conditions, reaching ~80% within 48 h at pH 5.5, consistent with hydrazone hydrolysis and supporting tumor/lysosome-activated delivery. In RAW264.7 macrophages, PMID nanogel showed preferential uptake by M2-poralized versus M1-polarized macrophages, outperforming non-mannosylated PID nanogel and IR-820, and produced the strongest PA signal in M2 macrophage pellets. PMID nanogel also induced the highest concentration-dependent cytotoxicity in M2 macrophages, and microscopy indicated lysosomal accumulation of the nanogel with partial nuclear localization of released DOX. These findings support the use of PMID nanogel as M2 macrophage-targeted PA contrast agents and pH-responsive drug carriers with the potential to deplete immunosuppressive macrophages, modulate cold tumor microenvironments, and improve precision cancer theranostics.

Cancer immunotherapy provides high anti-tumor effects with minimal side effects by harnessing the patient's immune systems. However, immunosuppressive tumors, called cold tumors, are unresponsive to immunotherapy, mainly owing to the high density of surrounding M2 macrophages, the exclusion of T cells, and the low expression of PD-L1 molecules. Thus, early identification of cold tumors through differences in the immunological environments of tumors would be promising to determine the optimal cancer treatment for each patient. Here, we developed a contrast agent targeting M2 macrophages to identify cold tumors by photoacoustic imaging. The polysaccharide-based contrast agent (denoted PMI) was synthesized by conjugating pullulan with mannose (M2 macrophage-targeting moiety) and IR-820 (near-infrared dye). In an aqueous solution, PMI formed a nanogel with a diameter of less than 100 nm via hydrophobic interactions involving IR-820 molecules. Owing to the IR-820 molecules, PMI nanogel absorbed near-infrared light, providing contrast for fluorescence and photoacoustic imaging. Moreover, M2 polarized RAW264.7 macrophage cells interacted with PMI nanogel but did not interact with IR-820 molecules and nanogels without mannose modification, indicating specific ligand-receptor interactions between mannose and CD206, a mannose receptor on M2 macrophages. Finally, PMI nanogel injected into colon26 tumor-bearing mice provided contrast for photoacoustic imaging of cold tumors. Therefore, PMI nanogel successfully targeted M2 macrophages to provide high contrast for photoacoustic imaging of cold tumors, demonstrating its potential as a platform for imaging and therapy of cold tumors.

We analyse the relationship between population influx and the effective reproduction number in the 23 wards of Tokyo during the COVID-19 pandemic to estimate hotspots of infection. We identify some patterns of population influx via factor analysis and estimate specific areas as infection-related hotspots by focusing on influx patterns that are highly correlated with the effective reproduction number. As a result, several influx patterns are assumed to be directly related to the subsequent spread of the infection. This analytical method has the potential to detect unknown hotspots related to pandemics in the future.

In this study, we analysed the novel coronavirus disease (COVID-19) cases data to investigate the regional infection trends in Japan. There had been seven outbreaks by October 2022 in Japan. In each outbreak, the number of COVID-19 cases has increased at different rates in different regions. The prefectural infection ratio is defined using COVID-19 cases data. We calculate the prefectural infection ratio and study the characteristic of each pandemic wave. The prefectural order of infection progression is estimated in each past wave of the COVID-19 pandemic. This study shows that the infection spread from the Kanto region in the fourth pandemic wave and the infection spread simultaneously from four regions in the sixth wave. It is also found that the infection situation trend in Okinawa differs from that in the other regions.

Background SINE-VNTR-Alu (SVA) retrotransposons move from one genomic location to another in a 'copy-and-paste' manner. They continue to move actively and cause monogenic diseases through various mechanisms. Currently, disease-causing SVA retrotransposons are classified into human-specific young SVA_E or SVA_F subfamilies. In this study, we identified an evolutionarily old SVA_D retrotransposon as a novel cause of occipital horn syndrome (OHS). OHS is an X-linked, copper metabolism disorder caused by dysfunction of the copper transporter, ATP7A. Methods We investigated a 16-year-old boy with OHS whose pathogenic variant could not be detected via routine molecular genetic analyses. Results A 2.8 kb insertion was detected deep within the intron of the patient's ATP7A gene. This insertion caused aberrant mRNA splicing activated by a new donor splice site located within it. Long-read circular consensus sequencing enabled us to accurately read the entire insertion sequence, which contained highly repetitive and GC-rich segments. Consequently, the insertion was identified as an SVA_D retrotransposon. Antisense oligonucleotides (AOs) targeting the new splice site restored the expression of normal transcripts and functional ATP7A proteins. AO treatment alleviated excessive accumulation of copper in patient fibroblasts in a dose-dependent manner. Pedigree analysis revealed that the retrotransposon had moved into the OHS-causing position two generations ago. Conclusion This is the first report of a human monogenic disease caused by the SVA_D retrotransposon. The fact that the evolutionarily old SVA_D is still actively transposed, leading to increased copy numbers may make a notable impact on rare genetic disease research.

Background. Many anti-cancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (Compound A) and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one (Compound B), showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds in comparison with four popular anti-cancer drugs. Methods: Tumor-specificity (TSM, TSE, TSN) was evaluated as the ratio of mean CC50 for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. Results: Compounds A and B showed one order of magnitude higher TSM than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two orders of magnitude lower TSE than Compounds A and B. Compounds A and B showed higher TSM, TSE, and TSN values than doxorubicin, 5-FU, and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that Compounds A and B may inhibit the signaling pathway of estrogen-related receptors.

Restrictions on outdoor activities are required to suppress the COVID-19 pandemic. To monitor social risks and control the pandemic through sustainable restrictions, we focus on the relationship between the number of people going out and the effective reproduction number. The novelty of this study is that we have considered influx population instead of staying-population, as the data represent congestion. This enables us to apply our analysis method to all meshes because the influx population may always represent the congestion of specific areas, which include the residential areas as well. In this study, we report the correlation between the influx population in downtown areas and business districts in Tokyo during the pandemic considering the effective reproduction number and associated time delay. Moreover, we validate our method and the influx population data by confirming the consistency of the results with those of the previous research and epidemiological studies. As a result, it is confirmed that the social risk with regard to the spread of COVID-19 infection when people travel to downtown areas and business districts is high, and the risk when people visit only residential areas is low.

Thirty-five pyridone derivatives were synthesized, with derivatization conducted on polycyclic pyridone scaffolds, including cis- or trans-oxydecalin and other cyclic structures, by domino-Knoevenagel-electrocyclic reactions. The anti-fungal activities of the synthesized compounds were tested against Candida albicans. Ten compounds inhibited hyphal formation without inhibiting growth. Pyridones with anti-hyphal formation activity (4c, 6d, 12a and 12c) were tested for their ability to inhibit biofilm formation. Compound 6d showed both anti-hyphal and biofilm inhibition activity.

Phosphonated mesoporous silica nanoparticles bearing ruthenium complexes in their pores were prepared as biocompatible molecular probes to visualize oxygen status in cells and tissues.

Three-dimensional (3D) representation of a tumor with respect to its size, shape, location, and boundaries is still a challenge in photoacoustic (PA) imaging using artificial contrast agents as probes. We carried out PA imaging of tumors in mice using 800RS-PMPC, which was obtained by coupling of 800RS, a near-infrared cyanine dye, with PMPC, a highly selective tumor-targeting methacrylate polymer having phosphorylcholine side chains, as a probe. The conjugate 800RS-PMPC forms compact nanoparticles (dDLS = 14.3 nm), retains the biocompatibility of the parent polymer (PMPC) and exhibits unprecedented PA performance. When applied to mice bearing a 6 × 3 × 3 mm3 tumor buried 6 mm beneath the skin, the probe 800RS-PMPC selectively accumulates in the tumor and emits PA signals that are strong enough to be unambiguously distinguished from noise signals of endogenous blood/hemoglobin. The PA image thus obtained under high-threshold conditions allows 3D characterization of the tumor in terms of its size, shape, location, and boundaries.

Tumor- selective accumulation of gold nanorods ( GNR) has been demonstrated for visualization of tumor hypoxia by photoacoustic imaging. We prepared GNRs with hypoxia- targeting nitroimidazole units ( G- NI) on their surface. Biological experiments revealed that G- NI produced a strong photoacoustic signal in hypoxic tumor cells and tissues.

Exogenous nucleic acids showed low efficiency regarding cellular uptake and low stability in biological conditions; therefore, a number of techniques have been developed to improve their basic properties. One of the best solutions is the application of nanosized particles consisting of oligonucleotides that penetrate the cell membrane without any additives and exhibit high stability in cells. In this report, we employed a simple approach to address the basic properties of nanoparticles of oligonucleotides in biological systems. We prepared BODIPY-labeled oligonucleotides that carried an exclusive modification at the strand end. BODIPY shows high hydrophobicity and fluorescent emission; therefore, the oligonucleotides formed nanosized aggregates in aqueous solution and their behaviors in cells or tissues were easily tracked. Detailed experiments revealed that aggregate formation was indispensable for the high cellular uptake of the oligonucleotides via scavenger-receptor-mediated endocytosis. In addition, the aggregates provided an efficient gene regulation in living cells and tumor tissues transplanted into mice.