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Okada, S.

Publications and source records attributed to Okada, S..

At least 19 recordsLinked to original sources

Bouncing back: Transient, but not long-lasting, effects of background disturbances on speech processing

Processing and understanding speech in face of occasional background disturbances can be difficult and often leads to distraction and reduced comprehension. However, despite the vast literature on the detrimental effects of processing speech-in-noise, little is known about the time-course of these effects. Here we studied whether reduced speech processing is limited only to the period when disruptions mask target speech, or if processing difficulties linger even after disruptions end, suggesting longer lasting distraction. Using an ecologically-relevant experimental design, we measured neural activity and skin-conductance from participants as they watched an educational video-lecture. Short background speech comments, mimicking plausible classroom disruptions, were occasional embedded in half of the lecture segments. Speech disruptions elicited robust neurophysiological orienting responses, reflected in a neural auditory ERP and a phasic increase in skin conductance. Importantly, when disruptions were presented, we observed a marked reduction in neural tracking of the lecture, increased inter-subject correlation (ISC), and decreased alpha power, suggesting a brief diversion of processing resources away from the target speech. However, these effects were transient in nature, with all neural measures returning to baseline immediately after disruption offset, showing no evidence for prolonged disruption-related costs or impaired comprehension. Interestingly, neurophysiological responses to disruption and return to baseline were not correlated with self-reported symptoms of attention-deficits (ADD). These findings highlight the resilience of auditory attention, demonstrating its ability to maintain a robust representations of target speech over time, despite of transient ecological disturbances.

neuroscience↗

Testing the Cross-Paradigm Convergence of Behavioral and Neural Measures of Attention

Attention abilities, that are critical for most real-life cognitive task, can vary greatly across individuals. A plethora of behavioral and neural metric are commonly utilized to quantify attention; however, these often yield inconsistent and non-replicable results, raising questions as to which measures reliably account for and capture individual differences. To address this tension, here we employed a within-subject cross-paradigm design and quantified both behavioral and EEG-based neural measures associated with attention functioning, to test which measures converged across a gradient of artificial and ecological tasks. We found Inter-Subject Correlation (ISC), which quantifies the similarity in the pattern of neural response across individuals, captured consistent individual differences across both an artificial (Auditory Oddball) and ecological (Attention to Speech) task, with some correlation with performance. Moreover, we found that P300 neural responses to surprising events were qualitatively similar across artificial and ecological tasks, supporting their generalization across contexts. Interestingly, traditional cognitive-behavioral measures of attention - both from speeded response-time tasks and self-report of ADHD symptoms (ASRS) were not correlated with each other nor did they explain variance in neural metrics, nor were they explained by variation in general cognitive abilities (working memory or fluid intelligence). While these results demonstrate the shortcomings of many established measures of attention to generalize across contexts, they also point to the potential of neural measures, and specifically ISC, to serve as reliable indicators of individual differences and to bridge the gap between artificial and ecological studies of attention functioning.

neuroscience↗

Transcriptome-based genome-wide analysis reveals hybridization dynamics and genetic structure of Japanese giant salamanders

AbstractsThe Japanese giant salamander (Andrias japonicus), an apex predator and a Special Natural Monument in Japan, is threatened by hybridization with introduced Chinese giant salamanders (Andrias davidianus). This hybridization has caused genetic introgression and expansion of hybrid populations, posing a serious conservation risk. Because morphological identification of hybrids is occasionally unreliable and current genetic methods rely on limited markers, a genome-wide approach is required. However, the extremely large genome ([~]50 Gb) of giant salamanders has hindered whole-genome analyses. In this study, we conducted transcriptome-based analyses of Japanese giant salamanders, Chinese giant salamanders, and their hybrids, generating RNA-seq data from 34 individuals. A total of over 419,000 SNP candidates were identified, from which 4,457 high-confidence SNPs in highly expressed genes were selected for analysis. Population structure analyses for Nabari colony revealed that hybrid individuals form two major groups, corresponding to different degrees of genetic contribution from Japanese and Chinese lineages. Most hybrids were inferred to be F2 or backcross individuals, while F1 hybrids were rare. Mitochondrial analysis indicated that all hybrids possessed Japanese-type mitochondrial genome, suggesting male-mediated introgression from Chinese salamanders. Differential expression analysis revealed enhanced stress-response pathways in hybrids and stronger antiviral responses in Japanese individuals. Using the axolotl genome as a reference, we constructed a virtual chromosomal map, identifying large haplotype blocks and supporting recent hybridization with limited recombination. This study provides a genome-wide framework for understanding hybridization dynamics and supports future conservation and evolutionary studies.

ecology↗

High extracellular osmolarity promotes yeast thermotolerance through osmotic modulation and glycerol-dependent adaptation.

High-temperature stress is a major constraint on yeast growth and fermentation, and has traditionally been interpreted primarily in terms of intracellular molecular damage such as protein denaturation and aggregation. Despite this extensive focus on intracellular mechanisms, how physical factors within the extracellular environment influence yeast thermotolerance remains poorly understood. Here we demonstrate that increases in extracellular osmolarity markedly attenuate growth inhibition under high-temperature conditions in yeast. This protective effect was consistently observed in multiple laboratory and industrial strains of Saccharomyces cerevisiae, as well as in ascomycetous and basidiomycetous yeasts, indicating that osmotic pressure-dependent thermotolerance is a broadly conserved phenomenon. We also found that extracellular osmolarity dynamically increases during growth and then decreases in a diauxic shift-like pattern after growth arrest. At high temperature, the secretion of glucose-derived metabolites decreased, but that of other solutes increased, suggesting that heat stress alters the composition of extracellular solutes contributing to osmolarity. In addition, intracellular glycerol levels increased at high temperature, and this increase was further enhanced under high-osmolarity conditions. Notably, expression of a constitutively active Hog1 mutant exhibited raised intracellular glycerol levels, enhanced nuclear localization of Hog1, and improved growth under high-temperature conditions. Collectively, these findings support a model in which extracellular osmolarity is modulated to avoid excessive intracellular osmolarity under high-temperature conditions, while the intracellular accumulation of glycerol contributes to yeast adaptation at high-temperature. Our results highlight extracellular-intracellular osmotic coordination as an additional physiological layer of high-temperature stress adaptation in yeast.

microbiology↗

Hyperactive STAT1 Promotes T Follicular Helper Type 1 Cell Differentiation to Trigger Autoimmunity

ABSTRACTSHeterozygous gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause an inborn error of immunity characterized by immune dysregulation, recurrent infections and various autoimmune manifestations. However, the precise pathogenic mechanism by which STAT1 GOF contributes to autoimmunity remains elusive. In our cohort, STAT1-GOF patients exhibit biased circulating follicular helper T (cTfh) populations with CXCR3+ Tfh1-like features. Using a Stat1 GOF mouse model that spontaneously developed autoimmunity, we found that overactivated STAT1 promotes Tfh differentiation and disrupted T cell-dependent humoral responses with skewed immunoglobulin class switching towards IgG2. Furthermore, STAT1 GOF directly targets to Tfh and Th1 cell signature genes and thereby drives the development of Tfh1 cells with excessive IFN-{gamma} production, which implicated in autoantibody production and the development of autoimmunity. Notably, IFN-{gamma} neutralization significantly alleviated autoimmune cellular responses and autoantibody levels in mutant mice, highlighting IFN-{gamma} blockade as a promising targeted therapy for the STAT1-GOF patients with autoimmunity. Our findings suggest that proper regulation of STAT1 activity within a reasonable magnitude is crucial for ensuring optimal host-protective humoral immunity. One-sentence summaryOveractivated STAT1 promotes Tfh1 differentiation to drive autoimmunity.

immunology↗

ADGRG1 blockade drives astrocyte positioning into the extracellular matrix to reduce scar size

After the central nervous system (CNS) injury, inflammatory cells enter the lesion core and a fibrotic extracellular matrix accumulates. Astrocytes subsequently cluster around this matrix, forming a glial scar, but the role of the extracellular matrix in scar formation remains poorly understood. Here, we identify type III collagen, a major fibrotic extracellular matrix component after spinal cord injury, as a key regulator of astrocyte behavior. Using single-nucleus transcriptomics, spatial transcriptomics, and time-lapse cell imaging, we show that type III collagen positions astrocytes at the boundary of the fibrotic matrix by activating the adhesion G protein-coupled receptor G1 (ADGRG1) and its downstream effector RhoA. Blocking ADGRG1 genetically or pharmacologically allows astrocytes to enter the fibrotic matrix, resulting in a smaller scar, improved neuronal regeneration, and better motor recovery. The migration of human-induced pluripotent stem cell-derived astrocytes was inhibited by type III collagen via the ADGRG1-RhoA pathway, supporting their therapeutic potential. Our findings reveal the importance of controlling glial scar positioning via the type III collagen-ADGRG1 axis, providing a novel therapeutic target for CNS injury.

neuroscience↗

INVA8001, a Novel and Highly Selective Chymase Inhibitor, Ameliorates Liver Inflammation, Fibrosis, and Hyperplasia in Mdr2 Knockout Mice

Background and aimsMast cells (MCs) play a significant role in autoimmune diseases by mediating inflammatory responses, innate and adaptive responses, angiogenesis, and various pathological processes. MC numbers are significantly increased in chronic liver disease and liver cancer, and degranulation leads to a release of MC mediators, including chymase, which increases inflammation, activates hepatic stellate cells (HSCs), ultimately leading to fibrosis. Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease characterized by inflammation, fibrosis, ductular reaction, and eventual liver failure. MCs and their mediators, particularly chymase, have been implicated in PSC pathogenesis; however, targeting chymase therapeutically has remains largely unexplored. In this study, we aimed to evaluate the efficacy of INVA8001, a highly selective chymase inhibitor, on PSC pathogenesis in the Mdr2 knockout mouse (Mdr2-/- mice) model of PSC. Approach and ResultsWe evaluated the levels of chymase and other MC markers in liver biopsy samples collected from late-stage PSC patients. The effect of chymase inhibition was evaluated using a highly selective and potent small molecule chymase inhibitor, INVA8001, in Mdr2-/- mice. Ten-week-old male Mdr2-/- mice were injected intraperitoneally (IP) with 20 mg/kg of INVA8001 daily for two weeks and varying parameters of disease pathogenesis, including MC activation, inflammation, fibrosis, biliary pathology, and cholestasis were evaluated. In addition, histological, immunohistochemical, biochemical, and molecular analyses were conducted to evaluate the effects of INVA8001 treatment in Mdr2-/- mice. The liver biopsies of PSC patients showed an increased number of chymase-positive cells compared with control samples (collected from non-diseased patients). INVA8001 treatment resulted in a reduction of MC accumulation, inflammation, histological damage, fibrosis, ductular reaction, and biliary senescence in Mdr2-/- mice. The current data show the pathophysiological role of chymase in PSC and the impact of a selective chymase inhibitor on PSC disease pathogenesis. This can further be extrapolated to various MC-driven diseases such as chronic urticaria, atopic dermatitis, asthma, metabolic dysfunction-associated steatohepatitis (MASH), and eosinophilic gastrointestinal diseases, among others, where chymase is central to the disease pathogenesis. ConclusionsOur findings identify chymase as a key driver of PSC pathogenesis establishing INVA8001 as a promising new therapeutic candidate for hepatobiliary disorders, including PSC. Chymase inhibition simultaneously targets MC activation, inflammation, fibrosis, and biliary senescence, and offers a multifaceted approach to treating PSC and other MC-related disorders.

pathology↗

LOBSTERS: a modular vector series with a diverse set of Cas nucleases and plasmid selection markers for multiplex genome editing in Saccharomyces cerevisiae

The budding yeast Saccharomyces cerevisiae is a central model organism in genetics and synthetic biology, yet efficient multiplex genome editing remains difficult because many toolkits are restricted by limited plasmid selection markers and reduced efficiency when targeting multiple loci. In our previous work, we introduced a CRISPR-based system incorporating three nucleases with distinct PAM specificities but it was available only with the URA3 marker. Here we present LOBSTERS, an expanded modular vector series that retains the PAM-diverse nucleases (SpCas9, SaCas9, and enAsCas12a) while extending marker options to seven. This design enables the simultaneous use of multiple plasmids in one transformation, supporting scalable and flexible genome editing. Proof-of-concept experiments demonstrated efficient ADE2 and ADE3 deletions with colorimetric readouts, coordinated tagging of essential proteins (Cdc3 and Cse4) without compromising function, and recapitulation of three quantitative trait variants (RME1, TAO3, and MKT1) underlying sporulation efficiency. Together these results establish LOBSTERS as a robust and versatile platform for multiplex genome editing in S. cerevisiae. By enabling coordinated modification of essential proteins, genetic interactions, and quantitative trait variants, LOBSTERS provides a broadly applicable resource for functional cell biology and synthetic biology in yeast. Significance StatementO_LILOBSTERS integrates three PAM-diverse nucleases with seven plasmid selection markers, overcoming the single-marker limitation of previous yeast genome editing toolkits. C_LIO_LIThe system enables efficient simultaneous editing at multiple loci, demonstrated by functional tagging of essential proteins and recapitulation of quantitative trait variants. C_LIO_LIBy broadening the editable space and lowering barriers to complex genotype construction, LOBSTERS provides a widely applicable resource for yeast cell biology and synthetic biology. C_LI

molecular biology↗

The Renowned Flavor Compound Cinnamaldehyde Induces Sweet Taste by Targeting the Transmembrane Domain of T1R3 in the Sweet Taste Receptor

Numerous flavor compounds are known to evoke sweet taste sensations, yet their direct interaction with the sweet taste receptor remains poorly understood. Traditionally, flavor-induced sweetness was attributed to aromatic properties rather than the taste qualities of these compounds. This study aims to elucidate whether the sweet taste receptor mediates flavor-induced sweet sensations by investigating the agonistic activities of 94 flavor compounds on cultured cells expressing the sweet taste receptor (T1R2/T1R3). The results demonstrated that cinnamaldehyde (CA) and p-methoxycinnamaldehyde (PMCA) activate the sweet taste receptor. These compounds not only induce the receptor response but also enhance receptor activity when combined with various sweeteners or sweet proteins. Due to PMCAs structural similarity to lactisole, a well-known negative allosteric modulator (NAM) of the sweet taste receptor interacting with the transmembrane domain (TMD) of T1R3, CA and PMCA are hypothesized to interact with the T1R3 TMD as ago-PAMs (agonists and positive allosteric modulators). Mutational analyses confirmed that CA and PMCA interact with the T1R3 TMD, with distinct binding sites compared to lactisole. Additionally, because of structural parallels between PMCA and lactisole, we investigated the structure-activity relationships among 79 compounds to determine whether they function as ago-PAMs or NAMs. Most compounds acted as inhibitors, while those with specific planar structures acted as ago-PAMs. In conclusion, this study identified CA and PMCA as novel ago-PAMs that interact with the T1R3 TMD of the sweet taste receptor. These findings significantly advance our understanding of how flavor compounds influence sweet taste perception at the molecular level. Significance StatementNumerous flavor compounds evoke sweet taste sensations, yet their interaction with the sweet taste receptor is not well understood. This study identifies cinnamaldehyde (CA) and p-methoxycinnamaldehyde (PMCA) as activators of the sweet taste receptor, interacting with the transmembrane domain (TMD) of T1R3. CA and PMCA also act as positive allosteric modulators of other sweeteners (ago-PAMs). We discovered two binding sites in the T1R3 TMD, with CA and PMCA binding to different sites than lactisole, a known negative allosteric modulator. These findings identify CA and PMCA as novel ago-PAMs and significantly advance our understanding of how flavor compounds influence sweet taste perception at the molecular level.

molecular biology↗

Eukaryotes' closest relatives are internally simple syntrophic archaea

Eukaryotes are theorized to have originated from an archaeal phylum Promethearchaeota (formerly Asgard archaea)1,2. The first cultured representatives revealed valuable insight3,4 but are distantly related to the first eukaryotic common ancestor (FECA), leaving many unknowns regarding this archaeons biology. Here, we report isolation of two strains belonging to the order proposed as FECAs closest relative, Hodarchaeales,5 as members of a pure co- and tri-culture with methanogenic partners. Both are obligately anaerobic, syntrophic, peptide-degrading, and mesophilic archaea that have simple internal cell structure and produce protrusions and vesicles, like Promethearchaeales3,4. All strains demonstrate behavior focused on cell construction rather than division, unlike typical prokaryotes6. Strain HC1 possesses genes associated with aerobic lifestyles but lacks complete pathways for aerobic respiration and co-cultures cannot grow under (micro)aerobic conditions, suggesting the genes support oxygen detoxification rather than respiration. Reflecting this, HC1 can survive and grow under microaerobic conditions only when aerobic organisms are present. Phylogenetic analyses indicate FECA may have possessed these genes and thus some aerotolerance. Physiological, genomic, and phylogenetic observations indicate FECA was a simple-celled anaerobic syntrophic peptide-degrading archaeon with a non-growth-centric lifestyle and potential adaptations towards an oxygenated planet--the archaea-eukaryote transition was steep in both cell structure and aerobiosis.

microbiology↗

Strategic targeting of Cas9 nickase expands tandem gene arrays

Expanding tandem gene arrays facilitates adaptation through dosage effects and gene family formation via sequence diversification. However, experimental induction of such expansions remains challenging. Here we introduce a method termed break-induced replication (BIR)-mediated tandem repeat expansion (BITREx) to address this challenge. BITREx strategically places Cas9 nickase adjacent to a tandem gene array to break the replication fork that has replicated the array, forming a single-end double-strand break. This break is subsequently end-resected to become single-stranded. Since there is no repeat unit downstream of the break, the single-stranded DNA often invades an upstream unit to initiate ectopic BIR, resulting in array expansion. BITREx has successfully expanded gene arrays in budding yeast, with the CUP1 array reaching [~]1 Mb. Furthermore, appropriate splint DNA allows BITREx to generate tandem arrays de novo from single-copy genes. We have also demonstrated BITREx in mammalian cells. Therefore, BITREx will find various unique applications in genome engineering.

genomics↗

Claudin-11 regulates immunological barrier formation and spermatogonial proliferation through stem cell factor

Tight junctions (TJs) between adjacent Sertoli cells are believed to form immunological barriers that protect spermatogenic cells expressing autoantigens from autoimmune responses. However, there is no direct evidence that Sertoli cell TJs (SCTJs) do indeed form immunological barriers. Here, we analyzed male mice lacking claudin-11 (Cldn11), which encodes a SCTJ component, and found autoantibodies against antigens of spermatocytes/spermatids in their sera. Defective spermatogenesis was not restored in Cldn11-deficient mice on a genetic background mimicking a severely impaired adaptive immune system. This suggests that defective spermatogenesis is not caused by autoimmune responses against spermatogenic cells. Further analyses showed that Cldn11 knockout impaired Sertoli cell polarization, localization of stem cell factor (SCF) (a key molecule for maintaining differentiating spermatogonia) to the basal compartment of seminiferous tubules, and also proliferation of differentiating spermatogonia. We propose that CLDN11 creates a microenvironment for SCF-mediated spermatogonial proliferation at the basal compartment via Sertoli cell polarization.

developmental biology↗

Bleomycin induced EBV-specific gastric epithelial cell death is enhanced by LMP2A

Epstein-Barr virus (EBV) infects more than 90% of the global population, leading to EBV-related cancers, such as EBV-associated gastric cancer and nasopharyngeal carcinoma. Despite the rarity of p53 mutations in tumor cells, there is a lack of specific therapies targeting EBV-associated gastric cancers. Our study demonstrated that EBV-infected gastric epithelial cells exhibited high sensitivity to the bleomycin family, encompassing bleomycin and zeocin, compared to uninfected cells. Zeocin treatment induces a DNA damage response (DDR) and promotes the expression of BZLF1, triggering the expression of EBV lytic genes. This cascade leads to apoptosis via a p53 dependent pathway, coinciding with the activation of caspase-3. Cells infected with the BZLF1-deficient virus could not induce apoptosis by zeocin treatment, and the cells maintained a tight latent infection but initiated a robust DDR. Conversely, neither lytic infection nor DDR was induced by zeocin treatment in cells infected with LMP2A-deficient virus. These findings indicate that LMP2A augments DDR in EBV-infected gastric epithelial cells, facilitating the transition from latent to lytic infection, and consequently inducing cell death. Bleomycin derivatives are expected to serve as fundamental components in the development of specific anticancer drugs targeting EBV-positive epithelial cancer cells. IMPORTANCEBecause of its ubiquitous infection in the human population, the number of patients suffering from EBV-related diseases, including malignant tumors and severe active infections, is substantial. Previous research has reported the potential of drugs such as HDAC inhibitors and poly ADP-ribose polymerase inhibitors to induce cell death in EBV-infected cells. However, a clinical therapeutic agent specifically reducing EBV-infected cells has not yet been available. In this study, we report that bleomycin, or its derivative, which has been used for over half a century, induces apoptotic cell death in EBV-infected cells by triggering lytic viral replication associated with DNA damage response. Particularly, we discovered that the viral latent gene LMP2A unexpectedly enhances bleomycin-induced EBV-infected epithelial cell death by promoting DDR.

microbiology↗

Observation of electromyogram and electrocardiogram changes with deqi for the development of an objective evaluation index of the occurrence of deqi

A unique sensation called "deqi" occurs in acupuncture, which is considered an essential variable in the study of the mechanisms and effects of acupuncture. However, an objective method for evaluating deqi is yet to be established. Therefore, we aimed to create an objective evaluation index for deqi using electromyogram (EMG) and electrocardiogram (ECG), which are expected to present characteristic changes based on the findings of previous studies. This study included 16 healthy adult male subjects. ST36 stimulation was performed three times after a one-week washout (N=48). EMG was used to calculate myopotentials, and ECG was used to calculate the heart rate (HR) immediately after stimulation. The subjects declared whether Deqi occurred, and the characteristic reactions of deqi in EMG and ECG were evaluated. In 48 trials, Deqi occurred 42 times and did not occur 6 times. Myopotentials were significantly higher when deqi occurred than when it did not. Furthermore, a positive correlation was identified between subjective sensation and the rate of change in myopotential. Deqi significantly increased the myopotential levels, indicating that it induced involuntary muscle activity. This involuntary muscle activity may be related to the stretch reflexes and nerve stimulation. For the HR immediately after stimulation, no change with deqi was identified, although a significant decrease in HR was found in cases without deqi. Deqi could induce a transient stress response and inhibit the decrease in the HR caused by acupuncture. The results of this study indicate two characteristics of deqi obtained from EMG and ECG: an increase in myopotential and an inhibition of the decrease in HR expected with acupuncture. These characteristics could provide objective evidence for the occurrence of deqi. Future studies with larger sample sizes are required toto further strengthen the objective assessment of deqi.

neuroscience↗

Latent taste diversity revealed by a vertebrate-wide catalogue of T1R receptors

Taste is a vital chemical sense for feeding behavior. In mammals, the umami and sweet taste receptors are composed of three members of the taste receptor type 1 (T1R/TAS1R) family: T1R1, T1R2, and T1R3. Because their functional homologs exist in teleosts, only three TAS1R genes generated by gene duplication are believed to have been inherited from the common ancestor of bony vertebrates. Here, we report five previously uncharacterized TAS1R members in vertebrates, named TAS1R4, 5, 6, 7, and TAS1Rcf, through a genome-wide survey of diverse taxa. For TAS1R2 and TAS1R3, mammalian and teleost fish genes were found to be paralogous. Phylogenetic analysis suggests that the bony vertebrate ancestor had nine TAS1Rs due to multiple gene duplications, and some TAS1Rs were lost independently in each lineage; ultimately, mammals and teleosts have retained only three TAS1Rs, whereas other lineages have retained more TAS1Rs. Functional assays and expression analysis in non-teleost fishes suggest that the novel T1Rs form heterodimers in taste receptor cells and contribute to the recognition of a broad range of ligands such as essential amino acids, including branched-chain amino acids, which were not previously considered as T1R ligands. These results highlight an unexpected diversity of taste sensations in both modern and the ancestors of vertebrates. The complex evolution of the taste receptor family might have enabled vertebrates to adapt to diverse habitats on Earth.

evolutionary biology↗

Crosstalk between AQP4-dependent ATP/Adenosine release and dopamine neurotransmission in depressive behavior during cocaine withdrawal

Our previous study has demonstrated the AQP4-dependent ATP release and following elevation of extracellular adenosine in hippocampal slices during hypo-osmotic treatment. In the present study, we examined the crosstalk between AQP4-dependent adenosine elevation and dopaminergic neurotransmissions, especially focusing on the mouse depressive behavior during cocaine withdrawal. The depressive behavior was mitigated in AQP4 knockout mice, and was sensitive to adenosine A1 receptor antagonists. Thus, the influence of cocaine withdrawal on the adenosine or dopamine elevation in the slices from the striatum or medial prefrontal cortex, which is the focus of depression was analyzed by the originally-developed biosensor cells, which elevates intracellular Ca2+ in response to adenosine or dopamine. We have found that the evoked-dopamine release in the striatum is tonically suppressed via A1 receptor in a AQP4 dependent manner, and this suppression is augmented by the cocaine withdrawal. In contrast, the evoked dopamine elevation in the medial prefrontal cortex was suppressed by treating slices with adenosine or an A1 receptor antagonist, and the cocaine withdrawal abolished the suppression by A1 receptor antagonist alone in an AQP4-dependent manner. Since a GABAA or group II metabotropic glutamate receptor antagonist occluded the suppression by A1 receptor antagonist, it has been suggested that the glutamatergic and GABAergic terminals suppressing dopamine releases have A1 receptors, which the cocaine withdrawal down-regulates in a AQP4-dependent manner. These results indicate that astrocytes modulate dopaminergic neurotransmissions via A1 receptor in an AQP4-dependent manner, and suggest that cocaine causes depression by changing this modulation.

neuroscience↗

The SARS-CoV-2 Omicron BA.1 spike G446S potentiates HLA-A*24:02-restricted T cell immunity

Although the Omicron variant of the SARS-CoV-2 virus is resistant to neutralizing antibodies, it retains susceptibility to cellular immunity. Here, we characterized vaccine-induced T cells specific for various SARS-CoV-2 variants and identified HLA-A*24:02-restricted CD8+ T cells that strongly suppressed Omicron BA.1 replication. Mutagenesis analyses revealed that a G446S mutation, located just outside the N-terminus of the cognate epitope, augmented TCR recognition of this variant. In contrast, no enhanced suppression of replication was observed against cells infected with the prototype, Omicron BA.2, and Delta variants that express G446. The enhancing effect of the G446S mutation was lost when target cells were treated with inhibitors of tripeptidyl peptidase II, a protein that mediates antigen processing. These results demonstrate that the G446S mutation in the Omicron BA.1 variant affects antigen processing/presentation and potentiates antiviral activity by vaccine-induced T cells, leading to enhanced T cell immunity towards emerging variants.

immunology↗

Germinal center-derived broadly neutralizing antibodies adapt to SARS-CoV-2 antigenic drift

The outbreak of SARS-CoV-2 variant Omicron which harbors a striking number of mutations in the spike protein has been raising concerns about the effectiveness of vaccines and antibody treatment1. Here, we confirmed a substantial reduction in neutralizing potency against Omicron in all convalescent and vaccinated sera. However, we found that some people infected by the early strain show relatively higher neutralization to Omicron. From those B cells, we developed neutralizing antibodies inhibiting broad variants including Delta and Omicron. Unlike reported antibodies, one had an extremely large interface and widely covered receptor binding motif of spike, thereby interfering with diversified variants. Somatic mutations introduced by long-term germinal center reaction contributed to the key structure of antibodies and the universal interaction with spike variants. Recalling such rare B cells may confer sustainable protection against SARS-CoV-2 variants emerging one after another.

immunology↗