Biology subjects

Hirano, M.

Publications and source records attributed to Hirano, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Ancient IL-6-STAT5 signaling orchestrates inflammation in jawless vertebrates

Interleukin-6 (IL-6) is a central regulator of vertebrate immunity, yet its existence in jawless vertebrates has remained obscure because of extreme sequence divergence. The extant jawless vertebrates (lampreys and hagfish), which deploy variable lymphocyte receptors (VLRs) instead of immunoglobulins and T cell receptors, provide a unique window into the earliest interface between cytokines and adaptive immunity. Here, we identify IL-6-like genes in jawless vertebrates by combining computational structural comparisons, phylogenetic reconstruction, and conserved local and long-range synteny analyses. The encoded proteins adopt the canonical four-helix bundle characteristic of immune-related IL-6 family cytokines and align topologically with mammalian IL-6. In sea lamprey, three IL-6 paralogs show distinct leukocyte and tissue expression patterns and are differentially induced by pathogen-associated molecular patterns and skin injury, indicating early functional diversification of IL-6-mediated inflammatory responses. Stimulation of myeloid peritoneal leukocytes with recombinant lamprey IL-6 induces STAT5 phosphorylation and rapid upregulation of SOCS1/3 genes, consistent with an IL-6/STAT5/SOCS regulatory axis. These findings extend the repertoire of immune-related four-helix bundle cytokines to jawless vertebrates and indicate that IL-6-dependent inflammatory programs were already in place before the divergence of VLR-based and Ig/TCR-based adaptive immune systems in vertebrates.

immunology↗

bioRxiv2026

Miniaturized wireless bioelectronics for electrically driven biohybrid robots

Although biohybrid robots offer the potential for soft, adaptive actuation by harnessing living muscle, practical operation in cell culture environments is often limited by the requirement of immersed leads or cumbersome stimulation equipment. Here, we present a thin, miniaturized, wireless bioelectronic stimulator that can electrically drive biohybrid robots while maintaining stability in aqueous cell culture media. Built on a 50-{micro}m liquid crystal polymer (LCP) substrate, the device integrates a planar receiving coil, interconnects, a diode-based rectifier, and a tank capacitor. This enables the device to convert an approximately 4.9-MHz radio-frequency (RF) input into pulsed direct current (DC), which is delivered through integrated stimulation electrodes. The stimulator has a footprint of [~]23 mm2 and a total thickness and mass of [~]100 {micro}m and [~]7 mg, respectively. We integrated the stimulator with a nanopatterned carbon nanotube (CNT)/gelatin hydrogel fin seeded with human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to generate propulsion through fin flapping. By optimizing the thickness of the polydimethylsiloxane (PDMS) encapsulation layer, the density was tuned, and the robot remained freely floating and retained shape integrity during operation. This produced autonomous forward locomotion of [~]70 {micro}m/s. The stimulator generated distance-dependent output voltage pulses of [~]2-6 V and reliably synchronized fin flapping rates of up to 2 Hz without an observable loss of cell attachment or sarcomeric organization. Together, these results establish a compact, media-compatible, wireless, bioelectronic interface suitable for closed-system biohybrid robotics.

bioengineering↗

bioRxiv2026

4,5-dihydroxyhexanoic acid is a robust circulating and urine marker of mitochondrial disease and its severity

Management of patients with mitochondrial respiratory chain diseases is challenging, in part because of our incomplete understanding of pathogenesis and a lack of biomarkers. Unknown metabolites account for >90% of detected features in modern metabolomics experiments and hold immense untapped promise for new basic and biomedical research. We recently used mass spectrometry-based metabolomics to identify and validate 19 circulating blood-based biomarkers for patients with the mitochondrial DNA (mtDNA) m.3243A>G pathogenic variant, which is the most frequent cause of the mitochondrial disorder MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). However, the most significantly changing biomarker corresponded to an "unknown" metabolite. Here, we combine cheminformatics with analytical chemistry and identify that feature as 4,5-dihydroxyhexanoic acid (4,5-DHHA), a metabolite previously associated with inherited defects of gamma-aminobutyric acid (GABA) catabolism, but with no prior links to mitochondrial respiratory chain disorders. We validate this finding in an independent MELAS cohort and further show that 4,5-DHHA levels correlate with disease severity and are elevated in patients with other forms of mitochondrial disease and sepsis. Furthermore, brain 4,5-DHHA levels were elevated in two genetic mouse models of mitochondrial disease. In vitro and tissue culture experiments indicate that 4,5-DHHA is generated when the GABA catabolite succinic semialdehyde reacts with an intermediate of the pyruvate dehydrogenase reaction and is sensitive to mitochondrial complex I function. Our work identifies 4,5-DHHA as a robust plasma and urine marker of mitochondrial dysfunction in humans and reveals new connections between the respiratory chain and GABA metabolism. Significance StatementInborn errors of the mitochondrial respiratory chain cause severe, progressive diseases, yet effective treatments and biomarkers remain limited. Modern metabolomics detects thousands of molecules in biofluids, but the vast majority are unidentified. In this study, we investigate the most significantly altered blood metabolite in patients with the most common mitochondrial disease - MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) - and identify it as an 4,5-dihydroxyhexanoic acid (4,5-DHHA). We show that 4,5-DHHA is reproducibly elevated and correlates with severity. Levels are increased across multiple mitochondrial disorders as well as in sepsis and rise when respiratory chain function is impaired. These findings establish 4,5-DHHA as a promising biomarker of mitochondrial dysfunction and reveal a link to dysregulated GABA metabolism.

biochemistry↗

bioRxiv2026

Mechanism of ATXN8OS CTA/CTG repeat-associated non-AUG translation revealed by approaches ranging from cell-free translation to live-cell imaging.

Microsatellite repeat expansions contribute to the pathogenesis of many neurodegenerative disorders. In spinocerebellar ataxia type 8 (SCA8), abnormal expansion of CTA/CTG repeats in the 3' untranslated region of the ATXN8OS (ATXN8 Opposite Strand) gene has been implicated in disease pathology. Although the occurrence of repeat-associated non-AUG (RAN) translation from the ATXN8 transcript has been reported, whether and how RAN translation occurs from the ATXN8OS transcript has remained unexplored. Here, using a cell-free translation system and cultured cells, we showed that ATXN8OS undergoes robust AUG-independent translation in a repeat length-dependent manner. Mechanistic analyses revealed that translation of the poly L (0) frame initiates at a non-AUG codon located upstream of the repeats. Moreover, using live-cell imaging at a single mRNA level, we directly visualized ribosomal -1 frameshifting from the poly L (0) frame to the poly T-poly A (+2) frame during translation elongation. We further showed that ATXN8OS translation was enhanced upon activation of the integrated stress response. Together, these findings establish both the occurrence and the molecular mechanisms of ATXN8OS translation from expanded CTA/CTG repeats and provide insights into the pathogenic processes underlying SCA8. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/700793v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1f836fborg.highwire.dtl.DTLVardef@e1b77forg.highwire.dtl.DTLVardef@d605c3org.highwire.dtl.DTLVardef@11475d9_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

An Ehrlich-inspired retrobiosynthesis of pharmaceutical scaffolds

Brewers yeast (Saccharomyces cerevisiae) acquires nitrogen from branched-chain and aromatic amino acids via the Ehrlich pathway, generating flavor (fusel) byproducts. Recently, diverting 4-hydroxyphenylacetaldehyde from Ehrlich catabolism of -tyrosine has enabled microbial production of opioids and other plant benzylisoquinolines. Yet, fusel metabolism is versatile in substrate scope, offering an untapped entry point for synthesizing structurally diverse aldehydes. Here, we repurpose the yeast Ehrlich pathway into a modular biocatalytic conduit for manufacturing privileged pharmaceutical alkaloids. We utilize retrobiosynthetic analysis and enzyme screening to derive scaffolds representative of solifenacin, colchicine, and ephedrine pharmaceuticals from simple amino acids. We survey wild yeasts for catabolism of -phenylglycine and demonstrate Ehrlich conversion to benzyl alcohol or (R)-phenylacetylcarbinol by 29 strains across nine genera. Implementing an {omega}-transaminase enables production of norephedrine from a simple amino acid input. This work unveils a generalizable biocatalytic route to clinically important alkaloids by exploiting metabolic logic from a yeast flavor pathway.

synthetic biology↗

bioRxiv2025

Augmented Feedback Training for Overcoming the Learning Plateau of Motor Expertise

Skilled performers often encounter a plateau in which further practice yields little improvement of intricate sensorimotor skills. Overcoming such limits requires novel training paradigms that can engage performers in novel ways of exploring and refining their actions. Here, we introduce a training pipeline that integrates high-precision motion sensing with augmented feedback to enhance expert-level motor learning. Using piano performance as a model, trained pianists practiced imitating a prize-winning expert's performance of a technically demanding movement sequence. While conventional auditory-based learning offered limited benefit, augmenting practice with trial-by-trial visualizations of discrepancies between the pianist's own movements and those of the expert enabled learners to refine their performance. This training induced richer movement exploration, facilitated closer convergence toward expert motion patterns, and produced perceptible improvements in sound quality evaluated by expert pianists. These findings demonstrate that augmented feedback can break performance plateaus in experts by providing externally-sensed, task-specific information that expands exploration beyond habitual training strategies. Such augmented learning promises new applications across domains where expertise is constrained by entrenched motor habits, including musical performance, athletics, and surgical training.

neuroscience↗

bioRxiv2025

Mitochondrial Energy Transformation Capacity Influences Brain Activation During Sensory, Affective, and Cognitive Tasks

Mitochondria supply the energy required for brain function, but how energetic capacity constrains human brain activity remains unclear. We compared patients with genetically defined mitochondrial disease to matched controls, testing whether bioenergetic stress selectively limits neural processes assessed with functional magnetic resonance imaging during rest and during tasks probing working memory, sensory perception, and affective responses (cold pain). We report impairment in working memory performance and reduced activation of associated brain networks in a subset of patients with the largest clinical and cognitive impairments. A resilient subgroup showed higher working-memory-related BOLD responses, which were associated with preserved task performance. Neural and behavioral effects scaled with the circulating markers of energetic stress growth differentiation factor 15 (GDF15). Brain activity related to sensory and affective responses and resting-state connectivity were comparable for patients and controls. These findings support an energy-hierarchy model in which complex cognition fails first, while sensory processes remain largely preserved under energetic stress.

neuroscience↗

bioRxiv2025

Proto-MHC signatures in the lamprey genome

Jawless vertebrates, which diverged from jawed vertebrates approximately 550 million years ago, possess an adaptive immune system characterized by two distinct lineages of lymphocytes bearing unique antigen receptors. However, despite decades of research, the mechanism of antigen presentation in these organisms remains unclear. In this study, we report that chromosomes 22, 50, and 59 in the sea lamprey (Petromyzon marinus) exhibit synteny with the human major histocompatibility complex (MHC) region. The syntenic region spans from DHX16 to RING1 (chromosome 6: 30,517,301-33,034,069) in the human genome (T2T-CHM13v2.0). Similar to the human MHC region, P. marinus chromosome 59 harbors homologs of DDX39B, NOTCH, PBX, TNF, and BRD genes, yet notably lacks the core MHC class I, II, and III (complement) genes. Genotyping of three independent lampreys showed no signatures of balancing selection, a characteristic feature of the human MHC. Additionally, these lamprey chromosomes exhibit synteny with chromosome 9 in amphioxus (Branchiostoma lanceolatum), which contains conserved homologs that form its "proto-MHC." These findings suggest that chromosomes 22, 50, and 59 in P. marinus are a proto-MHC or its paralog.

evolutionary biology↗

bioRxiv2025

Immune cell mitochondrial phenotypes are largely preserved in mitochondrial diseases and do not reflect disease severity

ObjectiveTo profile immune cell mitochondrial phenotypes in mitochondrial diseases (MitoD) and evaluate how those phenotypes relate to disease manifestations or biomarkers. MethodsWe profiled mitochondrial content and OxPhos enzymatic activities in isolated monocytes, lymphocytes, neutrophils, platelets, and mixed peripheral blood mononuclear cells (PBMCs) from 37 individuals with MitoD (m.3243A>G, n=23; single, large-scale mitochondrial DNA (mtDNA) deletions, n=14) and 68 healthy women and men from the MiSBIE study. ResultsWe first confirm and quantify robust cell type differences in mitochondrial content, activities of OxPhos complexes I, II, and IV, and the mitochondrial respiratory capacity (MRC) index. In relation to MitoD, neither mitochondrial content nor OxPhos capacity were consistently affected, other than a mild monocyte-specific reduction in complex I (partially mtDNA encoded) relative to complex II (entirely nDNA encoded), consistent with the mtDNA defects examined. Relative to the large differences in cell type-specific mitochondrial phenotypes, differences in MitoD relative to controls were generally small (<25%) across mitochondrial measures. The MitoD biomarkers GDF15 and FGF21, as well as clinical disease severity measures, were most strongly related to mitochondrial abnormalities in platelets, and most weakly related to mitochondrial OxPhos capacity in lymphocytes, which are known to eliminate mtDNA defects. Finally, comparing PBMCs collected in the morning/fasted state to the afternoon/fed state following a stressful experience, we report significant time-dependent changes in mitochondrial biology over the time scale of hours. ConclusionsOverall, these results demonstrate that the dynamic and cell-type specific mitochondrial phenotypes are preserved in mitochondrial diseases and are generally unrelated to the severity of MitoD symptoms.

pathology↗

bioRxiv2024

Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

Growth Differentiation Factor 15 (GDF15) is a protein that reflects mitochondrial energetic stress and is linked to physical and mental health symptoms, aging, and mortality. Here, we tested the hypothesis that GDF15 is a stress-responsive biomarker through a series of observational and experimental studies. We report four main findings. First, in the UK Biobank (n=53,026) and Framingham Heart Study (FHS) Offspring (n=3,460) cohorts, plasma GDF15 levels were elevated in individuals with symptoms of depression and anxiety. In the FHS cohort, GDF15 was also higher in participants exposed to chronic psychosocial stressors, including lower educational attainment, lower family income, and higher job strain. Second, plasma GDF15 levels in the FHS cohort correlated positively with epigenetic clocks measuring biological aging and effect sizes of GDF15 associations with psychosocial stressors were comparable to those observed for the clocks. Third, in a two-participant intensive-sampling study (n=112 days), saliva GDF15 showed a robust awakening response similar to established stress-related hormones. However, it exhibited a distinct negative pattern, peaking at waking and declining by 42-92% within 30-45 minutes. Finally, in two laboratory experiments (n=148), acute social-evaluative stress significant increased GDF15 levels in plasma and saliva within minutes. Together, these findings suggest that psychosocial stress may contribute to mitochondrial energetic stress indexed by GDF15, with implications for aging and health. This work opens new avenues for using GDF15 as a non-invasive biomarker to study the biological embedding of stress and its impact on aging trajectories. Significance statementGrowth Differentiation Factor 15 (GDF15) is a circulating protein elevated with mitochondrial energetic stress, aging, and diseases. Our findings show that GDF15 is elevated with depressive and anxiety symptoms and in those exposed to chronic psychosocial stress. Elevated plasma GDF15 also correlates with accelerated biological aging, as measured by epigenetic clocks. The effect sizes linking GDF15 to psychosocial stressors were comparable to those observed for the epigenetic clocks. Saliva GDF15 shows a robust negative awakening response characterized by elevated levels at awakening before declining within 30-45 minutes. Acute social-evaluative stress induced increase in plasma and saliva GDF15. Together, these findings suggest GDF15 can be used to study the energetic mechanisms for the biological embedding of stress across the lifespan.

physiology↗

bioRxiv2024

Comparison of monomeric variants of StayGold

StayGold is a bright and highly photostable fluorescent protein (FP) that forms an obligate dimer, thereby limiting its application as a soluble marker. On the basis of the structural information of this FP, we disrupted the dimerization to generate a monomeric variant, mStayGold, which inherits both the extremely high photostability and the high practical brightness of StayGold, for molecular fusion and membrane-targeting applications. Meanwhile, two other research groups have independently monomerized StayGold using different strategies. As a result, multiple StayGold monomers are currently available, creating confusion in the research community. In the present study, we investigated the three basic properties--photostability, brightness, and dispersibility--of these monomers by performing detailed side-by-side comparisons. This study highlights the difficulties of StayGold monomerization with emphasis on the tradeoff between photostability and brightness in FP technology.

bioengineering↗

bioRxiv2024

A specialized inhibitory function sharpens somatosensory hand representation and enhances the production and perception of fast multifinger movements in pianists

Accurate control of fast, coordinated movements across multiple body parts characterizes experts skills, such as playing musical instruments. While performing such skillful movements, the somatosensory system is challenged to successively and in parallel process a large amount of somatosensory information originating from different body parts within a short period. Over decades, it has been posited that the cortical representations of distinct body parts are more isolated from each other in trained than untrained individuals. Several recent studies, however, have re-examined and failed to replicate it. Here, we provide compelling evidence that expert pianists possess a unique inhibitory function that isolates the somatosensory processing of different body parts in the somatosensory cortex (S1). A behavioural experiment demonstrated a superior ability to perceive fast multifinger movements in pianists than musically untrained individuals, suggesting the specialized neural process of somatosensory information originating from multiple fingers within a short period in pianists. A series of neurophysiological experiments demonstrated that pianists have a unique inhibitory function in the S1, which was activated by weak electrical stimulation to the ulnar nerve. This stimulation also increased the representational distance between fingers, which was assessed based on cortical activation patterns elicited by the passive finger movements. This indicates the strengthened independence of the individual finger representation in the somatosensory processes specifically in pianists. This stimulation also augmented both the perception and execution of the fast and complex multifinger sequential movements. In nonmusicians, neither the inhibitory effects on the somatosensory process nor enhancement of the perception of multifinger movements was induced by this stimulation. Together, these findings provide the first evidence of the experience-dependent plasticity of inhibition of the somatosensory system, which highlights its pivotal role in the isolated somatosensory processing of multiple body parts in trained individuals and enables them to control fast and complex multifinger movements.

neuroscience↗

bioRxiv2023

StayGold Photostability under Different Illumination Modes

StayGold is a bright fluorescent protein (FP) that is over one order of magnitude more photostable than any of the currently available FPs across the full range of illumination intensities used in widefield microscopy and structured illumination microscopy, the latter of which is a widefield illumination-based technique. To compare the photostability of StayGold under other illumination modes with that of three other green-emitting FPs, namely EGFP, mClover3, and mNeonGreen, we expressed all four FPs as fusions to histone 2B in HeLa cells. Unlike the case of widefield microscopy, the photobleaching behavior of these FPs in laser scanning confocal microscopy (LSCM) is complicated. The outstanding photostability of StayGold observed in multi-beam LSCM was variably attenuated in single-beam LSCM, which produces intermittent and instantaneously strong illumination. We systematically examined the effects of different single-beam LSCM beam-scanning patterns on the photostability of the FPs. This study offers relevant guidelines for researchers who aim to achieve sustainable imaging by resolving problems related to FP photostability.

cell biology↗

bioRxiv2023

Accelerated physiology and increased energy expenditure in animals and humans with mitochondrial defects: A meta-analysis

Mitochondria are key energy transforming organelles in mammalian cells. However, how defects in oxidative phosphorylation (OxPhos) and other mitochondrial functions influence whole-body energy expenditure (EE) has not been rigorously studied. Cellular and organismal responses to OxPhos defects likely involve a combination of functional downregulation to conserve energy and compensatory upregulation of stress responses. If the energy cost of compensatory responses exceeds the potential energy savings of functional downregulation, as recent work suggests, the result would be an increase in total EE. To address the hypothesis that OxPhos defects increase the energetic cost of living, we performed a meta-analysis of available studies reporting EE in animal models with mitochondrial gene defects. Of all reported experimental conditions (n = 91, from 29 studies), 51% reported a >10% elevation in EE relative to control animals, compared to 11% reporting <10% reduction in EE (p<0.0001, Chi-square). Of the experimental conditions where locomotor activity was also quantified, 39% showed that OxPhos-deficient animals had elevated EE despite reduced locomotor activity, which would be expected to decrease EE. To extend this finding in humans, we re-analyzed a high-quality clinical and multi-omics dataset (Sharma et al. 2021) of mitochondrial disease patients with the m.3243A>G mutation. This analysis similarly indicates an upregulation of energetically costly physiological, immune, and metabolic parameters in people with OxPhos deficiency. These results suggest that animals and humans with mitochondrial defects must expend more energy to sustain life, a state clinically called hypermetabolism. High-quality human energetics studies are needed to understand the magnitude, mechanisms, and modifiability of hypermetabolism in mitochondrial disorders.

cell biology↗

bioRxiv2023

Hagfish genome illuminates vertebrate whole genome duplications and their evolutionary consequences

Whole genome duplications (WGDs) are major events that drastically reshape genome architecture and are causally associated with organismal innovations and radiations1. The 2R Hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution2, 3. However, the veracity and timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved4-6 and whether these WGD events underlie vertebrate phenotypic diversification remains elusive7. Here we present the genome of the inshore hagfish, Eptatretus burgeri. Through comparative analysis with lamprey and gnathostome genomes, we reconstruct the early events in cyclostome genome evolution, leveraging insights into the ancestral vertebrate genome. Genome-wide synteny and phylogenetic analyses support a scenario in which 1R occurred in the vertebrate stem-lineage during the early Cambrian, and the 2R event occurred in the gnathostome stem-lineage in the late Cambrian after its divergence from cyclostomes. We find that the genome of stem-cyclostomes experienced two additional, independent genome duplications (herein CR1 and CR2). Functional genomic and morphospace analyses demonstrate that WGD events generally contribute to developmental evolution with similar changes in the regulatory genome of both vertebrate groups. However, appreciable morphological diversification occurred only after the 2R event, questioning the general expectation that WGDs lead to leaps of morphological complexity7.

genomics↗

bioRxiv2023

Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate in aging fibroblasts

The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in non-human species 1-3 and recently demonstrated to occur in rare instances from one human generation to the next 4. Here we investigated numtogenesis dynamics in humans in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples from different individuals. Compared to circulating immune cells (n=389), post-mitotic brain tissue (n=798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, more brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts using a repeated-measures WGS design in a human fibroblast model that recapitulates several molecular hallmarks of aging 5. These longitudinal experiments revealed a gradual accumulation of one Numt every [~]13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7- fold faster than healthy donors. Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human post-mitotic tissues produce functionally-relevant human Numts over timescales shorter than previously assumed.

genomics↗

bioRxiv2022

A phenotypic screen of Marfan syndrome iPSC-derived vascular smooth muscle cells uncovers GSK3β as a new target

Marfan syndrome (MFS) is a rare connective tissue disorder caused by mutations in FBN1. Patients with MFS notably suffer from aortic aneurysm and dissection. Despite considerable effort, animal models have proven to be poorly predictive for therapeutic intervention in human aortic disease. Using a "humanised" model system may be more appropriate in identifying new therapeutic targets. Patient-derived induced pluripotent stem cells can be differentiated into vascular smooth muscle cells (VSMCs) and recapitulate major features of MFS. We have screened 1,022 small molecules in our in vitro model, exploiting the highly-proteolytic nature of MFS-VSMCs, and identified 36 effective compounds. Further analysis identified GSK3{beta} as a recurring target in the compound screen. GSK3{beta} inhibition/knockdown did not ameliorate the proliferation defect in MFS-VSMCs but improved MFS-VSMC apoptosis and proteolysis. To conclude, we have identified GSK3{beta} as a novel target for MFS, forming the foundation for future work in MFS and other aortic diseases.

cell biology↗

bioRxiv2022

Multisensory interactions on auditory and somatosensory information in expert pianists

Fine-tuned sensory functions are bases of efficient motor control and learning and typically characterize skilled individuals. Although numerous studies demonstrated enhanced unimodal sensory functions at both neural and behavioral levels in skilled individuals, little is known about their multisensory interaction, especially multisensory integration and selective attention that involve volitional control of information derived from multiple sensory organs. Here, we show unique multisensory interaction functions of expert pianists. Expert pianists and musically untrained individuals performed five sets of intensity discrimination tasks at the auditory and somatosensory modalities with different conditions: (1) auditory stimulus, (2) somatosensory stimulus, (3) congruent auditory and somatosensory stimuli (i.e., multisensory integration), (4) auditory and task-irrelevant somatosensory stimuli, and (5) somatosensory and task-irrelevant auditory stimuli. In the fourth and fifth conditions, participants were instructed to ignore a task-irrelevant stimulus and to pay attention to a task-relevant stimulus (i.e., selective attention). The unimodal intensity discrimination of the pianists was superior to that of the nonmusicians at the auditory modality but not at the somatosensory modality. While the discrimination perception was superior in the condition (3) compared to the better one of the individual unimodal conditions (i.e., conditions 1 and 2) only in the pianists, the task-irrelevant somatosensory stimulus worsened the auditory discrimination more in the pianists than the nonmusicians. These findings indicate efficient processing of multisensory information in expert pianists, which enables to benefit from multisensory integration of the auditory and somatosensory information, but exacerbates top-down selective inhibition of somatosensory information during auditory processing.

neuroscience↗