Search

The intricate relationship between immune dysregulation and neurodevelopmental disorders (NDDs) has been observed across the stages of both prenatal and postnatal development. In this Review, we provide a comprehensive overview of various maternal immune conditions, ranging from infections to chronic inflammatory conditions, that impact the neurodevelopment of the fetus during pregnancy. Furthermore, we examine the presence of immunological phenotypes, such as immune-related markers and coexisting immunological disorders, in individuals with NDDs. By delving into these findings, we shed light on the potential underlying mechanisms responsible for the high occurrence of immune dysregulation alongside NDDs. We also discuss current mouse models of NDDs and their contributions to our understanding of the immune mechanisms underlying these diseases. Additionally, we discuss how neuroimmune interactions contribute to shaping the manifestation of neurological phenotypes in individuals with NDDs while also exploring potential avenues for mitigating these effects., (© 2024. Springer Nature America, Inc.)

In this qualitative study, we explored the challenges that transgender and gender non-confirming (TGNC) individuals face in South Korea. For this, we conducted in-depth interviews with 14 South Korean TGNC younger adults attending colleges or graduate schools and analyzed their data through consensus qualitative research. Analyses revealed that issues related to interpersonal relationships and medical transiting were major challenges perceived by participants. Four categories emerged in the domain of challenges in interpersonal relationships, including issues associated with family, romantic partner, coming out and outing, and transphobia and cisnormativity. In addition, two categories (i.e., medical difficulties and physical appearance-related distress) were included in the domain of challenges related to medical transition. Unique sources of stress for South Korean TGNC younger adults included high risk of being outed due to Korean resident registration numbers, dissatisfaction with bodily changes when transitioning, and misgendering caused by Korean's different honorific titles depending on gender., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The stimulator of the interferon gene (STING) signaling pathway acts as a primary defense system against DNA pathogens. Because of the crucial role of STING in type I interferon (IFN) response and innate immunity, extensive research has been conducted to elucidate the roles of various effector molecules involved in STING-mediated signal transduction. However, despite the substantial contribution of microtubules to the immune system, the association between the STING signaling pathway and microtubules remains unclear. In this study, we revealed that the modulation of STING via microtubule-destabilizing agents (MDAs) specifically induced type I IFN responses rather than inflammatory responses in human monocytes. Co-treatment of MDAs with STING agonists induced the elevation of phospho-TANK-binding kinase 1 (TBK1), amplifying the innate immune response. However, during the deficiency of TBK1, the non-canonical signaling pathway through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) contributed to MDA-induced STING activation in type I IFN response which suggested the versatile regulation of MDA in STING-mediated immunity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Endogenous stem cell-based in-situ tissue regeneration has recently gained considerable attention. In this study, we investigated the potential of a chemokine, SDF-1-mimic peptide (SMP), to promote endogenous stem cell-based in-situ wound healing. Our approach involved the development of a click crosslinked hyaluronic acid scaffold loaded with SMP (Cx-HA + SMP) to release SMP in a wound site. The Cx-HA scaffold maintained its structural integrity throughout the wound healing process and also captured endogenous stem cells. Gradual SMP release from the Cx-HA + SMP scaffold established a concentration gradient at the wound site. In animal wound experiments, Cx-HA + SMP exhibited faster wound contraction compared to Cx-HA + SDF-1. Additionally, Cx-HA + SMP resulted in approximately 1.2-1.6 times higher collagen formation compared to Cx-HA + SDF-1. SMP released from the Cx-HA + SMP scaffold promoted endogenous stem cell migration to the wound site 1.5 times more effectively than Cx-HA + SDF-1. Moreover, compared to Cx-HA + SDF-1, Cx-HA + SMP exhibited higher expression of CXCR4 and CD31, as well as the positive markers CD29 and CD44 for endogenous stem cells. The endogenous stem cells that migrated through Cx-HA + SMP regenerated into wound skin with minimal scar granule formation, similar to the normal tissue. In conclusion, SMP peptide offers greater convenience, while efficiently attracting migrating endogenous stem cells compared to the SDF protein. Our findings suggest that Cx-HA + SMP scaffolds hold promise as a strategy to enhance endogenous stem cell-based in-situ wound healing., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: Dabie bandavirus (DBV) is an emerging tick-borne virus that causes severe fever with thrombocytopenia syndrome (SFTS) in infected patients. Human SFTS symptoms progress from fever, fatigue, and muscle pain to the depletion of white blood cells and platelets with fatality rates up to 30%. The recent spread of its vector tick to over 20 states in the United States increases the potential for outbreaks of the SFTS beyond the East Asia. Thus, the development of vaccine to control this rapidly emerging virus is a high priority. In this study, we applied self-assembling ferritin (FT) nanoparticle to enhance the immunogenicity of DBV Gn head domain (GnH) as a vaccine target. Mice immunized with the GnH-FT nanoparticle vaccine induced potent antibody responses and cellular immunity. Immunized aged ferrets were fully protected from the lethal challenge of DBV. Our study describes the GnH-FT nanoparticle vaccine candidate that provides protective immunity against the emerging DBV infection., Competing Interests: A patent for the presented DBV GnH-ferritin nanoparticle is filed via Cleveland Clinic Foundation Innovations Office.

Histone deacetylases (HDACs) are key epigenetic regulators and classified into four subtypes. Despite the various roles of each HDAC isoform, the lack of selective HDAC inhibitors has limited the elucidation of their roles in biological systems. HDAC11, the sole class-IV HDAC, is highly expressed in the brain, however, the role of HDAC11 in microglia is not fully understood. Based on the modification of MC1568, we developed a novel HDAC inhibitor, 5. Interestingly, 5 suppresses lipopolysaccharide-induced microglial activation by the initiation of autophagy and subsequent inhibition of nitric oxide production. Furthermore, we demonstrated that 5 significantly alleviates depression-like behavior by inhibiting microglial activation in mouse brain. Our discovery reveals that specific pharmacological regulation of HDAC11 induces autophagy and reactive nitrogen species balance in microglia for the first time, which makes HDAC11 a new therapeutic target for depressive disorder., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Extracellular vesicles (EVs) contain a variety of biomolecules and provide information about the cells that produce them. EVs from cancer cells found in urine can be used as biomarkers to detect cancer, enabling early diagnosis and treatment. The potential of alpha-2-macroglobulin (A2M) and clusterin (CLU) as novel diagnostic urinary EV (uEV) biomarkers for bladder cancer (BC) was demonstrated previously. To validate the diagnostic value of these proteins in uEVs in a large BC cohort, urine handling conditions before uEV isolation should be optimized during sample transportation from medical centers. In this study, we analyzed the uEV protein quantity, EV particle number, and uEV-A2M/CLU after urine storage at 20°C and 4°C for 0-6 days, each. A2M and CLU levels in uEVs were relatively stable when stored at 4°C for a maximum of three days and at 20°C for up to 24 h, with minimal impact on analysis results. Interestingly, pre-processing to remove debris and cells by centrifugation and filtration of urine did not show any beneficial effects on the preservation of protein biomarkers of uEVs during storage. Here, the importance of optimizing shipping conditions to minimize the impact of pre-analytical handling on the uEVs protein biomarkers was emphasized. These findings provide insights for the development of clinical protocols that use uEVs for diagnostic purposes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

It is well known that the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons increase appetite and decrease thermogenesis. Previous studies demonstrated that optogenetic and/or chemogenetic manipulations of NPY/AgRP neuronal activity alter food intake and/or energy expenditure (EE). However, little is known about intrinsic molecules regulating NPY/AgRP neuronal excitability to affect long-term metabolic function. Here, we found that the G protein-gated inwardly rectifying K+ (GIRK) channels are key to stabilize NPY/AgRP neurons and that NPY/AgRP neuron-selective deletion of the GIRK2 subunit results in a persistently increased excitability of the NPY/AgRP neurons. Interestingly, increased body weight and adiposity observed in the NPY/AgRP neuron-selective GIRK2 knockout mice were due to decreased sympathetic activity and EE, while food intake remained unchanged. The conditional knockout mice also showed compromised adaptation to coldness. In summary, our study identified GIRK2 as a key determinant of NPY/AgRP neuronal excitability and driver of EE in physiological and stress conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Oh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A series of thalidomide analogues, where the fused benzene ring in the phthalimide moiety was converted into two separated diphenyl rings in maleimide moiety and N-aminoglutarimide moiety was replaced by substituted phenyl moiety, were synthesized and evaluated for their NO inhibitory activities on BV2 cells stimulated with lipopolysaccharide (LPS). Among the synthesized compounds, the dimethylaminophenyl analogue 1s (IC 50  = 7.1 μM) showed significantly higher inhibitory activity than the glutarimide analogue 1a (IC 50  > 50 μM) and suppressed NO production dose-dependently without cytotoxicity. In addition, 1s inhibited the production of pro-inflammatory cytokines and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by blocking nuclear factor-kappa B (NF-κB) and p38 MAPK pathways. These results demonstrated that 1s showed good anti-inflammatory activity and could become a leading compound for the treatment of neuroinflammatory diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

T cells expressing chimeric antigen receptors (CAR-T cells) have shown unprecedented clinical responses against hematological malignancies. However, some patients relapse after CAR-T cell therapy due to antigen-negative escape variants. Additionally, CAR-T cell therapies showed limited clinical efficacy in solid tumors with high antigen heterogeneity. To overcome this, we metabolically labeled the glycans on cancer cells to redirect CAR-T cell cytotoxicity regardless of the endogenous antigen expression status of the cancer cells. We found that modifying cancer cells with N -azidoacetylmannosamine and bicyclo[6.1.0]non-4-yne-fluorescein isothiocyanate can elicit selective and durable cytotoxicity of anti-FITC CAR-T cells. Furthermore, we demonstrated that dinitrophenyl-conjugated sialic acid (Sia-DNP) generated DNP-modified glycans on cancer cells in situ that could be effectively targeted by anti-DNP CAR-T cells to eradicate established tumors in xenograft models. Our study illustrates that metabolic glycan labeling using unnatural sugars can be combined with CAR-T cell therapy to provide novel cancer immunotherapy for solid tumors that lack viable target antigens.

(1) Background: This study aimed to identify factors associated with hypertension control among older adults with hypertension based on their socio-demographic and health characteristics. (2) Methods: The sample consisted of a total of 1824 with hypertension and was obtained from the Eighth Korean National Health and Nutrition Examination Survey (VIII-1, VIII-2). (3) Results: As the factors associated with hypertension control among older men, 65-74 years old (OR = 1.76, CI = 1.04-2.96), a lower education level (OR = 2.23, CI = 1.17-4.28), with obesity (OR = 2.05, CI = 1.13-2.05), and under-treatment of hypertension (OR = 22.07, CI = 6.54-7.45) increased the likelihood of rating hypertension control. As the factors associated with hypertension control among older women, trying to weight maintain (OR = 1.70, CI = 1.01-2.85) and under-treatment of hypertension (OR = 12.16, CI = 3.65-40.46) increased the likelihood of rating hypertension control. (4) Conclusion: The factor affecting the control of hypertension differed between the two genders. To improve the control of hypertension, the guidelines for treatment interventions should be gender-specific for the early elderly. There is a need to increase control of hypertension by having health-related behavioral modifications such as reducing obesity for older men and trying weight maintenance for older women.

Inositol polyphosphate multikinase (IPMK) is a pleiotropic enzyme responsible for the production of inositol polyphosphates and phosphoinositide. IPMK in macrophages was identified as a key factor for the full activation of the Toll-like receptor 4 (TLR4) signaling pathway and inflammation by directly interacting with tumor necrosis factor receptor-associated factor 6 (TRAF6). Here, dynamic changes of IPMK levels in lipopolysaccharide (LPS)-stimulated macrophages and their functional significance were investigated. Both the mRNA and protein levels of IPMK were acutely decreased in mouse and human macrophages when cells were stimulated with LPS for between 1 and 6 h. Analysis of the 3' untranslated region (UTR) of mouse IPMK mRNA revealed a highly conserved binding site for miR-181c. Transfection of miR-181c mimics into RAW 264.7 macrophages led to decreased IPMK 3'UTR-luciferase reporter activity and lowered endogenous IPMK levels. When the genomic deletion of a 33-bp fragment containing a putative miR-181c-binding site was introduced within the IPMK 3'UTR of RAW 264.7 macrophages (264.7 Δ3'UTR ), LPS-triggered downregulation of IPMK levels was prevented. LPS treatment in 264.7 Δ3'UTR macrophages decreased TLR4-induced signaling and the expression of proinflammatory cytokines. In response to LPS stimulation, K63-linked ubiquitination of TRAF6 was impaired in 264.7 Δ3'UTR macrophages, suggesting an action of IPMK in the suppression of TRAF6 activation. Therefore, our findings reveal that LPS-mediated suppression of IPMK regulates the full activation of TLR4 signaling and inflammation in macrophages.

A series of rimonabant analogues, where the N-aminopiperidine moiety was replaced by various amines and an additional carbonyl group, were synthesized and their inhibition of nitric oxide (NO) production was evaluated in lipopolysaccharide (LPS)-induced BV2 microglial cells. Among the synthesized compounds, the morpholine analogue 7y (IC 50  = 4.71 ± 0.11 μM) showed significantly higher inhibitory activity than rimonabant (IC 50  = 16.17 ± 0.56 μM), and suppressed NO production dose-dependently without cytotoxicity. In addition, 7y inhibited the expression of iNOS, COX-2 and pro-inflammatory cytokines and attenuated LPS-induced activation of nuclear factor-kappa B (NF-κB) and ERK MAPK phosphorylation in BV2 cells. These results demonstrated that 7y exerted anti-inflammatory effects by ERK pathway in BV2 cells, which can be used for the prevention and treatment of neuroinflammatory diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Although conventional topical approaches for treating psoriasis have been offered as an alternative, there are still unmet medical needs such as low skin-penetrating efficacy and off-target adverse effects. A hyaluronic acid nanoparticle (HA-NP) formed by self-assembly of HA-hydrophobic moiety conjugates has been broadly studied as a nanocarrier for long-term and target-specific delivery of drugs, owing to their excellent physicochemical and biological characteristics. Here, we identify HA-NPs as topical therapeutics for treating psoriasis using in vivo skin penetration studies and psoriasis animal models. Transcutaneously administered HA-NPs were found to be accumulated and associated with pro-inflammatory macrophages in the inflamed dermis of a psoriasis mouse model. Importantly, HA-NP exerted potent therapeutic efficacy against psoriasis-like skin dermatitis in a size-dependent manner by suppressing innate immune responses and restoring skin barrier function without overt toxicity signs. The therapeutic efficacy of HA-NPs on psoriasis-like skin dermatitis was due to the outermost hydrophilic HA shell layer of HA-NPs, independent of the molecular weight of HA and hydrophobic moiety, and comparable with that of other conventional psoriasis therapeutics widely used in the clinical settings. Overall, HA-NPs have the potential as a topical nanomedicine for treating psoriasis effectively and safely.

Background: The study aimed to identify the differences in self-rated health (SRH) and the factors associated with poor SRH among older women who live alone, based on their sociodemographic and health characteristics., Methods: The sample consisted of 812 older women living alone and was obtained from the Seventh Korean National Health and Nutrition Examination Survey (Ⅶ-1, Ⅶ-2, Ⅶ-3). Complex sample analysis was performed using the independent t -test, the Chi-square test, and multiple logistic regression in SPSS/WIN 24.0 program., Results: The study found that SRH status in older women living alone differed according to age, education level, income, occupation, walking practices, sleeping hours, perceived stress, experiencing depression, diabetes, arthritis, and restrictions in daily functions. As the factors associated with poor SRH among older women living alone, a lower education level (OR = 1.89, CI = 1.19-3.02), higher perceived stress (OR = 4.92, CI = 1.84-13.16), experiencing arthritis (OR = 1.52, CI = 1.07-2.16), and higher restrictions in functioning (OR = 6.20, CI = 4.01-9.59) increased the likelihood of rating the poor SRH., Conclusion: SRH is an indicator of overall health status, and physical, psychological, and economic factors affect each other. Therefore, it is necessary to develop effective health education and intervention programs for vulnerable groups, including older women living alone with poor SRH.

Nanopore sensors are a highly attractive platform for single-molecule sensing for sequencing, disease diagnostics, and drug screening. Outer membrane protein G (OmpG) nanopores have advantages for single-molecule sensing owing to their rigid monomeric structure, which comprises seven flexible loops, providing distinct gating patterns upon analyte binding. Blocking of the protein-protein interaction between B-cell lymphoma-extra-large (Bcl-xL) and the BH3 domain of Bcl-2 homologous antagonist/killer (Bak-BH3) has been reported as a promising strategy for anticancer therapy. Here, we characterized the interaction between Bcl-xL and Bak-BH3 as well as its inhibition by a small-molecule inhibitor using click chemistry-based Bak-BH3 peptide-conjugated OmpG nanopores. The binding of Bcl-xL to Bak-BH3 generated characteristic gating signals involving significant changes in the amplitudes of noise and gating parameters such as gating frequency, open probability, and durations of open and closed states. Notably, specific inhibition of Bcl-xL by the small-molecule antagonist, ABT-737, led to the recovery of the noise and gating parameters. Collectively, these results revealed that the chemically modified OmpG nanopore can serve as a valuable sensor platform for ultrasensitive, rapid, and single-molecule-based drug screening against protein-protein interactions, which are therapeutic targets for various diseases.

Investigating intestinal immune responses is critical to understanding local and systemic immunity. However, obtaining resident intestinal immune cells with high cell viability can be challenging. Here, we provide an optimized protocol to isolate lamina propria lymphocytes from the small and large intestines, including lymphocyte activation for cytokine expression analysis and techniques for surface and intracellular antibody staining and flow cytometry. This protocol can be used for isolating and analyzing tissue-resident immune cells from other tissues with specified modifications. For complete details on the use and execution of this protocol, please refer to Kim et al. (2022)., Competing Interests: Jun R. Huh is a co-founder of Interon laboratories. He is also a consultant for CJ Bioscience., (© 2022 The Authors.)

The microbiota modulates gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (T H 17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits T H 17 cell differentiation 1 . Although it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown, and it was unclear whether 3-oxoLCA and other immunomodulatory bile acids are associated with inflammatory pathologies in humans. Here we identify human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Similar to 3-oxoLCA, isoLCA suppressed T H 17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-γt, a key T H 17-cell-promoting transcription factor. The levels of both 3-oxoLCA and isoLCA and the 3α-hydroxysteroid dehydrogenase genes that are required for their biosynthesis were significantly reduced in patients with inflammatory bowel disease. Moreover, the levels of these bile acids were inversely correlated with the expression of T H 17-cell-associated genes. Overall, our data suggest that bacterially produced bile acids inhibit T H 17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as inflammatory bowel disease., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

In this study, the researchers investigated the factors influencing regional disparities in the practice of healthy living for the elderly in Busan and Gyeongnam. A cross-sectional study was utilized to integrate raw data from the Korea Community Health Survey (KCHS) in 2015, 2017, and 2019. The KCHS included respondents from the Busan Metropolitan and Gyeongnam regions. Based on the socioecological model, healthy living practices were selected as the dependent variable, and other factors, such as personal, interpersonal, and community factors, were selected as independent variables. Bivariate chi-square test, independent t -test, and logistic regression analyses were performed using SPSS/WIN version 26.0. According to the results, community factors were significant predictors of healthy living practices in Busan, while interpersonal factors were the predictors in the Gyeongnam region. Moreover, personal factors impacted healthy living practices but differed significantly between regions. In particular, the living environment and unmet healthcare needs were significant predictors for Busan and Gyeongnam regions, respectively, indicating the need to improve the environment and physical access to healthcare resources in the urban community. Through the results of our study, we highlight the need to implement policies and strategies tailored to personal and environmental factors to improve healthy living practices in older adults.

Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4 + T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders., Competing Interests: Declaration of interests J.R.H. is a consultant for CJ Research Center, LLC, and is on the scientific advisory board for ChunLab., (Copyright © 2021 Elsevier Inc. All rights reserved.)

BACKGROUND Rhabdomyolysis is a clinical syndrome that results from skeletal muscle breakdown and the release of intracellular enzymes into systemic circulation [1,2]. We present a case of non-traumatic rhabdomyolysis with transaminitis, without myoglobinuria or acute kidney injury. Cases reports of rhabdomyolysis with elevation of serum creatine kinase (hyperCKemia) in the absence of myoglobinuria or renal failure are limited in the literature. CASE REPORT A 21-year-old man presented to the Emergency Department following an acute psychotic episode. One week earlier, his bloodwork had been within normal limits. Biochemical investigations on admission revealed hyperCKemia (590 000 U/L), transaminitis (AST, 628; ALT, 160), and normal creatinine (0.83), without myoglobinuria. Non-traumatic rhabdomyolysis was suspected, and the patient was treated with aggressive intravenous fluid resuscitation and transferred to Inpatient Psychiatry on day 10 of hospitalization. The complete metabolic panel was trended daily, without indication of kidney injury. The creatine kinase (CK) and liver function tests trended downward. CONCLUSIONS This report presents a rare case of exertional rhabdomyolysis with CK levels nearly 3000 times the upper limit of normal, without myoglobinuria or acute kidney injury. Acute kidney injury is a dangerous complication of rhabdomyolysis. Traditionally, clinicians use serum CK levels to predict the likelihood of acute kidney injury and/or renal failure in rhabdomyolysis. Ultimately, this patient was diagnosed with exertional rhabdomyolysis with hyperCKemia and transaminitis without myoglobinuria or acute kidney injury. More research is needed to elucidate the protective patient characteristics against rhabdomyolysis-associated acute kidney injury, associations between CK and myoglobinuria, and diagnostic criteria for psychosis-associated hyperCKemia.

Using in-depth interviews, this study identified the experiences of five people with mental illness who participated in art activities. Findings indicated that the life journey that led to the participants' art activities and the impact of these activities in their lives were different and unique. The voices of the individuals with mental illness who participated in this study provided deeper understanding of how art activities have changed their lives. In addition, it was confirmed that art activities in which people with mental illness participate, bring positive inner changes and have the potential to improve their interpersonal relationships and social interactions.

In cancer immunotherapy, the cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from 'cold' to 'hot' through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in cancer treatment.

Although osteoarthritis (OA) is the most prevalent degenerative joint disease, there is no effective disease-modifying therapy. We report an empty self-assembled hyaluronic acid nanoparticle (HA-NP) as a potential therapeutic agent for OA treatment. In mouse primary articular chondrocytes, HA-NPs blocked the receptor-mediated cellular uptake of free low-molecular-weight HA, and the cellular uptake of HA-NPs increased by ectopic expression of CD44, using an adenoviral delivery system (Ad-Cd44). HA-NP showed in vitro resistance to digestion with hyaluronidase and in vivo long-term retention ability in knee joint, compared with free high-molecular-weight (HMW) HA. CD44 expression increased in the damaged articular cartilage of patients and mice with OA. Ad-Cd44 infection and IL-1β treatment induced in vitro phenotypes of OA by enhancing catabolic gene expression in primary articular chondrocytes, and these effects were attenuated by HA-NP, but not HMW HA. Both Cd44 deficiency and intra-articular injection of HA-NP protected joint cartilage against OA development in the OA mouse model. NF-κB was found to mediate CD44-induced catabolic factor expression and HA-NP inhibited CD44-induced NF-κB activation in chondrocytes. Our results identify an empty HA-NP as a potential therapeutic agent targeting CD44 for OA treatment, and the CD44-NF-κB-catabolic gene axis as an underlying mechanism of destructive cartilage disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Mitochondria play important roles in diverse cellular processes such as energy production, cellular metabolism, and apoptosis to promote cell death. To investigate mitochondria-associated biological processes such as structure, dynamics, morphological change, metabolism, and mitophagy, there exists a continuous demand for visualizing and monitoring techniques elucidating mitochondrial biology and disease-relevancy. Due to the advantages of high sensitivity and practicality, fluorescence phenomena have been most widely used as scientific techniques for the visualization of biological phenomena and systems. In this review, we briefly overview the different types of fluorescent materials such as chemical probes, peptide- or protein-based probes, and nanomaterials for monitoring mitochondrial biology.

Various bioorthogonal chemistries have been used for fluorescent imaging owing to the advantageous reactions they employ. Recent advances in bioorthogonal chemistry have revolutionized labeling strategies for fluorescence imaging, with inverse electron demand Diels-Alder (iEDDA) reactions in particular attracting recent attention owing to their fast kinetics and excellent specificity. One of the most interesting features of the iEDDA labeling strategy is that tetrazine-functionalized dyes are known to act as fluorogenic probes. In this review, we will focus on the synthesis, molecular-design strategies, and bioimaging applications of tetrazine-functionalized fluorogenic probes. Traditional Pinner reaction and "Pinner-like" reactions for tetrazine synthesis are discussed here, as well as metal-catalyzed C-C bond formations with convenient tetrazine intermediates and the fabrication of tetrazine-conjugated fluorophores. In addition, four different quenching mechanisms for tetrazine-modified fluorophores are presented.

Based on our previous report that 3-morpholino-1-phenylpropan-1-one 2, one of the fluoxetine's simplified morpholino analogue, inhibited nitric oxide (NO) production, in this paper, various substituted benzene analogues with morpholine hydrochloride of 2 were synthesized and their inhibitory effects on NO production in lipopolysaccharide (LPS)-induced BV2 cells were tested. Among the synthesized compounds, 2-trifluoromethyl analogue 16n (IC 50  = 8.6 μM) showed a significantly higher inhibitory activity than that of the parent compound 2a (IC 50  > 50 μM) and suppressed NO production dose-dependently without cytotoxicity. Compound 16n also inhibited iNOS expression in LPS-induced BV2 cells at 2, 10 and 20 μM concentrations. These results suggest that compound 16n inhibited NO production by suppressing the expression of iNOS and can be used as a lead structure for developing new inhibitor of NO production., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Multiplexed analysis allows simultaneous measurements of multiple targets, improving the detection sensitivity and accuracy. However, highly multiplexed analysis has been challenging for point-of-care (POC) sensing, which requires a simple, portable, robust, and affordable detection system. In this work, we developed paper-based POC sensing arrays consisting of kaleidoscopic fluorescent compounds. Using an indolizine structure as a fluorescent core skeleton, named Kaleidolizine (KIz), a library of 75 different fluorescent KIz derivatives were designed and synthesized. These KIz derivatives are simultaneously excited by a single ultraviolet (UV) light source and emit diverse fluorescence colors and intensities. For multiplexed POC sensing system, fluorescent compounds array on cellulose paper was prepared and the pattern of fluorescence changes of KIz on array were specific to target chemicals adsorbed on that paper. Furthermore, we developed a machine-learning algorithm for automated, rapid analysis of color and intensity changes of individual sensing arrays. We showed that the paper sensor arrays could differentiate 35 different volatile organic compounds using a smartphone-based handheld detection system. Powered by the custom-developed machine-learning algorithm, we achieved the detection accuracy of 97% in the VOC detection. The highly multiplexed paper sensor could have favorable applications for monitoring a broad-range of environmental toxins, heavy metals, explosives, pathogens.

Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.

It is important to focus on urgent needs in clinics and develop optimal materials. For successful augmentation of vocal folds, the ideal filler should be injectable through a syringe, and should stably maintain its volume for a long time without toxicity. To achieve these criteria, a click chemistry-based PEG (polyethylene glycol) hydrogel was developed and applied for vocal fold augmentation in vivo. The PEG hydrogel enables fast gelation in vivo after injection and provides long-term stability. Azide- and dibenzocyclooctyne (DBCO)-modified 4-arm PEG were cross-linked by chemical conjugation via click chemistry and yielded gelation within several minutes. After subcutaneous injection into mice and rats, the PEG hydrogel showed higher stability after 1 month compared to the traditionally used calcium hydroxyapatite-carboxymethyl cellulose (CaHA-CMC) filler. In rabbit models with vocal fold paralysis, the PEG hydrogel stably fixed the paralyzed vocal fold in 4 months and minimized the glottic gap. It was an improved therapeutic result compared to CaHA-CMC, demonstrating the potential of a click chemistry-based PEG hydrogel for vocal fold therapy.

A series of salicylic acid analogues of celecoxib where the phenylsulfonamide moiety in the structure of celecoxib is replaced by salicylic acid moiety was synthesized and tested for in vitro cyclooxygenase (COX)-1 and COX-2 enzyme inhibition. Among the series, 5-substituted-2-hydroxy-benzoic acid analogues (7a-7h) generally showed better inhibitory activities on both enzymes than 4-substituted-2-hydroxy-benzoic acid analogues (12a-12h). In particular, the chloro analogue 7f which had the highest inhibitory effect (IC 50  = 0.0057 µM) to COX-1 with excellent COX-1 selectivity (SI = 768) can be classified as a new potent and selective COX-1 inhibitor. The high inhibitory potency of 7f was rationalized through the docking simulation of this analogue in the active site of COX-1 enzyme.

Type I Interferon (IFN) signaling plays an important role in the immune defense system against virus infection and in the innate immune response, thus IFNs are widely used as anti-viral agents and treatment for immune disorder or cancer. However, there is a growing demand for novel small-molecule IFN inducer due to tolerance, toxicity, or short duration of action following direct administration of IFNs. In this study, we assessed arylpiperazine (ARP) as a new core skeleton of IFN inducer. To investigate structure-activity relationship, we designed and synthesized a series of ARP analogues and evaluated the ability to stimulate IFN response in THP-1 human monocyte cells. Compound 5i was identified as a potent type I IFN inducer as it significantly increased cytokine secretion and increased expression of various IFN-stimulating genes which are representative biomarkers of type I IFN pathway. Our results suggested a beneficial therapeutic potential of 5i as an anti-viral agent., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

By taking advantage of a unique mechanism of aggregation-induced emission (AIE) phenomena, AIE luminogens (AIEgens) have been provided as a solution to overcome the limitations of conventional fluorophores bearing the feature of aggregation-caused quenching (ACQ) phenomena. Especially, AIEgens paved the way to develop fluorogenic probes ideal for fluorescent imaging in live cell conditions. Despite the high demand for discovery of new AIEgens, it is still challenging to find a versatile molecular platform to generate diverse AIEgens. Herein, we report a new colorful molecular framework, Kaleidolizine (KIz), as a molecular platform for AIEgen generation. The KIz system allows systematic tuning of the emission wavelength from 455 to 564 nm via perturbation of the electron density of substituents on the indolizine core. Increasing the water fraction of the KIz solution in the THF/water mixture induces the fluorescence intensity increase up to 120-fold. Crystal structure analysis, computational calculations, and solvatochromism studies suggest that a synergistic effect between the intramolecular charge transfer and restriction of intramolecular rotation acts as the AIE mechanism in the KIz system. Conjugation of the triphenylphosphonium moiety to KIz allows successful development of triphenylphosphonium (TPP)-KIz for real-time bioimaging of innate mitochondria in live cells, thereby revealing the potential of KIz as a versatile molecular platform to generate fluorogenic probes based on AIE phenomena. We do believe the KIz system could serve as a new, reliable, and generally applicable molecular platform to develop various AIEgens having desired photophysical properties along with an excellent signal-to-noise ratio and with experimental convenience especially for fluorogenic live cell imaging.

Reviews of employment among people with schizophrenia have primarily encompassed quantitative research. This study analyzes eight qualitative research studies published from 2000 to 2018 on the job experiences of people with schizophrenia to identify participants' job motivations, negative and positive experiences working with schizophrenia, and adaptations to gain social roles and values. We found that the core theme encompassing participants' experiences was the need for social support to facilitate reentry into society from the schizophrenic cave. These results could inform the development of targeted nursing interventions to provide social support and foster job adaptation for people with schizophrenia.

Aim: Colon cancer is one of the leading causes of cancer-related mortality. However, specific biomarkers for its diagnosis or treatment are not established well., Methods: We developed a colon-cancer specific peptide probe using phage display libraries. We validated the specificity of this probe to colon cancer cells with immunohistochemical staining and FACS analysis using one normal cell and five colon cancer cell lines., Results: This peptide probe maintained binding affinity even after serum incubation. For therapeutic applications, this peptide probe was conjugated to hematoporphyrin, a photosensitizer, which showed a significantly enhanced cellular uptake and high photodynamic effect to kill tumor cells. As another application, we made a nanoparticle modified from the peptide probe. It efficiently delivered SN-38, an anticancer drug, into tumor cells, and its tumor-targeting ability was observed in vivo after intravenous injection to the same xenograft model., Conclusion: The noble dodecapeptide probe can be a promising candidate for both colon tumor diagnosis and targeted drug delivery., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is a rapidly increasing chronic liver disorder worldwide accompanied by hepatic steatosis, inflammation, fibrosis, and severe liver failure. Unfortunately, an effective treatment strategy for NAFLD has not yet been established, which has been hampered by the limited understanding of the pathophysiological drivers for NAFLD. To examine the unknown cellular and molecular mechanisms in the pathogenesis of NAFLD, there is an increasing need for the direct in vivo observation of hepatic microenvironments over extended periods of time. In this work, using a custom-built intravital imaging system and a novel fluorescent lipid droplet labeling dye, Seoul-Fluor 44 (SF44), we established an intravital imaging method to visualize individual lipid droplets and microvasculature simultaneously in the liver of live mice in vivo . In addition, in the nonalcoholic steatosis and steatohepatitis mouse model induced by a methionine and choline-deficient diet, we longitudinally visualized and quantitatively analyzed the development of lipid droplets in hepatocytes and sinusoid at a subcellular resolution during the progression of NAFLD up to 21 days in vivo ., Competing Interests: The authors declare that there are no conflicts of interest related to this article., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Toll-like receptors (TLRs) play a fundamental role in the inflammatory response against invading pathogens. However, the dysregulation of TLR-signaling pathways is implicated in several autoimmune/inflammatory diseases. Here, we show that a novel small molecule TLR-inhibitor (TAC5) and its derivatives TAC5-a, TAC5-c, TAC5-d, and TAC5-e predominantly antagonized poly(I:C) (TLR3)-, imiquimod (TLR7)-, TL8-506 (TLR8)-, and CpG-oligodeoxynucleotide (TLR9)-induced signaling pathways. TAC5 and TAC5-a significantly hindered the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), reduced the phosphorylation of mitogen-activated protein kinases, and inhibited the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6. Besides, TAC5-a prevented the progression of psoriasis and systemic lupus erythematosus (SLE) in mice. Interestingly, TAC5 and TAC5-a did not affect Pam 3 CSK 4 (TLR1/2)-, FSL-1 (TLR2/6)-, or lipopolysaccharide (TLR4)-induced TNF-α secretion, indicating their specificity towards endosomal TLRs (TLR3/7/8/9). Collectively, our data suggest that the TAC5 series of compounds are potential candidates for treating autoimmune diseases such as psoriasis or SLE.

Elucidation of upconversion nanoparticles (UCNPs) that can be excited by near-infrared (NIR) light is an interesting topic in the field of photodynamic therapy (PDT). However, the PDT efficiency of conventional UCNPs is limited due to the low quantum yield and overheating effect of the 980 nm light source. In this study, a light source with a wavelength of 808 nm was used as an excitation source for Nd-doped UCNPs to solve the overheating effect. UCNPs with a core@shell structure (NaYF 4 :Yb,Er,Nd@NaYF 4 :Yb,Nd) were synthesized to increase the upconversion emission efficiency. Dual-color emitting Er-doped UCNPs and dual photosensitizers (Chlorin e6 and Rose Bengal) were used for enhanced PDT. Each photosensitizer could absorb red and green emissions of the UCNPs to generate reactive oxygen species (ROS), respectively. The ROS generation in a dual photosensitizer system is significantly higher than that in a single photosensitizer system. Additionally, PDT induces immunogenic apoptosis. In this study, by utilizing a highly efficient PDT agent, PDT-induced apoptosis was studied by biomarker analysis., (Copyright © 2020 Lee, Lee, Kim, Lee and Park.)

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Loss of functional β-cell mass is an essential feature of type 2 diabetes, and maintaining mature β-cell identity is important for preserving a functional β-cell mass. However, it is unclear how β-cells achieve and maintain their mature identity. Here we demonstrate a novel function of protein arginine methyltransferase 1 (PRMT1) in maintaining mature β-cell identity. Prmt1 knockout in fetal and adult β-cells induced diabetes, which was aggravated by high-fat diet-induced metabolic stress. Deletion of Prmt1 in adult β-cells resulted in the immediate loss of histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) and the subsequent loss of β-cell identity. The expression levels of genes involved in mature β-cell function and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult β-cells. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing analyses revealed that PRMT1-dependent H4R3me2a increases chromatin accessibility at the binding sites for CCCTC-binding factor (CTCF) and β-cell transcription factors. In addition, PRMT1-dependent open chromatin regions may show an association with the risk of diabetes in humans. Together, our results indicate that PRMT1 plays an essential role in maintaining β-cell identity by regulating chromatin accessibility., (© 2019 by the American Diabetes Association.)

A substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking. Therefore, genetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Disease-causing variants, including newly discovered variants, were identified in 57.5% of the probands of the KND cohort. Among the patients with the previous reported pathogenic variants, 35.1% inherited these variants in a recessive manner. Genes that cause recessive disorders in our cohort tend to be less constrained by loss-of-function variants and were enriched in lipid metabolism and mitochondrial functions. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.

Efforts to develop a safe, effective, and affordable dengue vaccine have focused on providing simultaneous immunity against all four serotypes of the dengue virus (DENV). In the current study, Salmonella Typhimurium (ST) lysed by gene E activation was genetically constructed to deliver the envelope protein domain III (EDIII) of all four serotypes of DENV using a foreign antigen delivery and expression vector, pJHL184. Each DENV-EDIII protein expressed in the constructed strain was validated by immunoblot analysis. To assess the immunogenicity and protective efficacy of the constructs against dengue infection, BALB/c mice were injected once orally with either the individual ST-EDIII constructs or a mix of all four ST-EDIII constructs followed by intramuscular administration of the purified EDIII protein. Significantly elevated titers of EDIII-specific IgG, IgG1, and IgG2a were observed in the immunized mice (P < 0.01). Furthermore, lymphocyte proliferative activity and CD3 + CD4 + T-cell subpopulations increased significantly in vitro in re-pulsed splenic T cells compared with those from non-immunized mice. In addition, a lower viral load was detected in the BG-EDIII vaccinated group after challenge with DENV-infected K562 cells. Collectively, the results demonstrate that DENV-EDIII expressed in the inactivated ST strain could induce robust humoral and cell-mediated immunity specific to the target antigen and could provide significant protective potential., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (T H 17 cells) or regulatory T cells (T reg cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of T H 17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-γt (RORγt) and isoalloLCA increased the differentiation of T reg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of T reg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase T reg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced T H 17 cell differentiation and increased T reg cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of T H 17 and T reg cells.

Proper mRNA quality control prevents immune activation; when it goes awry, mice and flies develop abnormal behavioral phenotypes. In this issue of Neuron, Johnson et al. (2019) report that inhibiting nonsense-mediated mRNA decay (NMD) contributes to the pathogenesis of neurodevelopmental disorder (NDD) phenotypes by triggering aberrant immune activation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A facile turn-on chemical sensor array was developed for hydrazine detection by means of fluorescence pattern recognition. Taking advantage of the unique properties of the azo group, four different fluorogenic probes, Seoul-Fluor (SF)-Azo 01 - 04 , were designed and prepared. SF-Azo 01 - 04 displayed fluorescence enhancement of up to 800-fold upon reaction with hydrazine, and all probes exhibited excellent selectivity in the presence of various anions and nucleophiles. By employing the probes in a cellulose paper-based array system, the hydrazine concentration was successfully determined by monitoring the change in fluorescent patterns., Competing Interests: The authors declare no competing financial interest.

Recently, click chemistry has provided important advances in biomedical research fields. Particularly, copper-free click chemistry including strain-promoted azide-alkyne cycloaddition (SPAAC) and inverse-electron-demand Diels-Alder (iEDDA) reactions enable fast and specific chemical conjugation under aqueous conditions without the need for toxic catalysts. Click chemistry has resulted in a change of paradigm, showing that artificial chemical reactions can occur on cell surfaces, in cell cytosol, or within the body, which is not easy with most other chemical reactions. Click chemistry in vitro allows specific labelling of cellular target proteins and studying of drug target engagement with drug surrogates in live cells. Furthermore, cellular membrane lipids and proteins could be selectively labelled with click chemistry in vitro and cells could be adhered together using click chemistry. Click chemistry in vivo enables efficient and effective molecular imaging and drug delivery for diagnosis and therapy. Click chemistry ex vivo can be used to develop molecular tools to understand tissue development, diagnosis of diseases, and therapeutic monitoring. Overall, the results from research to date suggest that click chemistry has emerged as a valuable tool in biomedical fields as well as in organic chemistry., (This journal is © The Royal Society of Chemistry 2019.)

For efficient drug delivery, we introduce a click-chemistry-mediated two-step tumor-targeting strategy for nanoparticles (NPs). We modified HER2-binding trastuzumab with trans-cyclooctene (TCO-Trb), and fabricated tetrazine-modified NPs containing the anticancer drug, SN38 (SN38-Tz-NPs). To target tumor cells with the Tz-NPs, the tumor cells are first treated with TCO-Trb. The TCO-Trb binds HER2s and presents multiple TCO groups on the cell surface. Subsequently, the cells are treated with SN38-Tz-NPs that can bind the cell surface via click chemistry between Tz and TCO. This click chemistry-mediated binding resulted in enhanced tumor-targeting of Tz-NPs to the target tumor cells. In our study, this strategy was performed and analyzed in vitro and in vivo, and the results show that this is a promising strategy for tumor-targeted drug delivery by NPs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton's tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP 6 ) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP 6 -mediated Btk regulation is more prominent in IgM + plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling., Competing Interests: The authors declare no conflict of interest.