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Takahashi, R.

Publications and source records attributed to Takahashi, R..

At least 19 recordsLinked to original sources

Integrated Continuous Biomanufacturing of Recombinant Adeno-Associated Virus

Recombinant adeno-associated virus (rAAV) manufacturing remains constrained by low yields, costly purification, and process complexity, limiting cost-effective access to gene therapy. Here, we demonstrate an integrated continuous biomanufacturing platform that transfers proven antibody-manufacturing technology to rAAV production by coupling perfusion to semi-continuous twin-column affinity capture (CaptureSMB). This architecture enables continuous harvest of extracellular rAAV without cell lysis, depth filtration, or endonuclease treatment, sustaining stable operation over five days. Relative to conventional batch processing, perfusion improved capsid or vector genome yield depending on the production process, while affinity capture alone reduced total DNA to batch-comparable levels, with no measurable loss in impurity clearance or potency. By consolidating multiple manual unit operations into one continuous workflow, the platform may reduce manual intervention and process footprint. Its modular design may generalize to other rAAV serotypes, inducible producer cell lines, and viral vector classes, offering a potential route toward more efficient gene therapy manufacturing.

bioengineering↗

Height-induced postural threat selectively facilitates spinal reflex in the tibialis anterior muscle during quiet standing

Long-latency stretch reflex and corticospinal excitability in the tibialis anterior muscle (TA) are facilitated when balance is threatened, even without background TA activity, suggesting supraspinal modulation as preparatory tuning for ankle stabilization. However, it remains unclear whether such tuning is evident at the spinal level and specific to the TA among lower-limb muscles. We therefore examined the effects of height-induced postural threat on multi-segmental monosynaptic spinal reflexes (MMR) in lower-limb muscles during quiet standing. Seventeen healthy young males performed 90-s standing tasks under three postural threat conditions, created by combining real and virtual reality (VR) heights: (1) Low-threat (real ground & VR ground), (2) Medium-threat (real table & VR ground), and (3) High-threat (real table & VR bridge). During each condition, transcutaneous spinal cord stimulation (tSCS) was applied to the lumbar spine to elicit MMR in lower-limb muscles. Electromyograms (EMG) were recorded from six muscles of the right leg: vastus medialis (VM), biceps femoris (BF), TA, soleus (SOL), medial (MG), and lateral gastrocnemius (LG). MMR excitability was quantified as peak-to-peak EMG amplitude. Fear ratings and electrodermal activity were higher in High-threat than Low-threat (all p < 0.05), confirming successful threat induction. Peak-to-peak EMG amplitude in the TA was significantly higher in High-threat than Low-threat (17.1% increase, p = 0.0393), whereas background TA activity remained absent across conditions. These results indicate that TA has unique function to facilitate spinal excitability as a preparatory tuning for ankle stabilization. Key pointsO_LIPrevious studies have shown the supraspinal facilitation of the tibialis anterior muscle without background muscle activation as a preparatory tuning for ankle stabilization. C_LIO_LITo test the hypothesis that such tuning is also evident at the spinal level and specific to the tibialis anterior muscle, this study examined whether height-induced postural threat modulates multi-segmental monosynaptic reflex excitability in lower-limb muscles using transcutaneous spinal cord stimulation. C_LIO_LIElectrodermal activity and fear ratings increased under height-induced postural threat, confirming the successful induction of postural threat. C_LIO_LIUnder height-induced postural threat, the multi-segmental monosynaptic reflex was selectively facilitated in the tibialis anterior muscle, while its background activity remained absent. C_LIO_LIOur findings demonstrate selective facilitation of spinal excitability in the tibialis anterior muscle, which may serve as preparatory tuning for ankle stabilization under threat to balance. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/742625v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@19fde78org.highwire.dtl.DTLVardef@c6aa8dorg.highwire.dtl.DTLVardef@e73a76org.highwire.dtl.DTLVardef@af393d_HPS_FORMAT_FIGEXP M_FIG C_FIG Abstract figure legendWhen balance is threatened, corticospinal excitability and long-latency stretch reflex in the tibialis anterior muscle (TA) are facilitated even in the absence of background TA activity, suggesting supraspinal preparatory tuning for ankle stabilization. This study tested the hypothesis that such facilitation is also expressed at the spinal level and is specific to the TA. Participants completed 90-s quiet standing trials under three different height-induced postural threat conditions. During each trial, transcutaneous spinal cord stimulation was delivered over the lumbar spine to elicit multi-segmental monosynaptic reflexes (MMR) in multiple lower-limb muscles. High-threat condition increased fear ratings and electrodermal activity, indicating successful threat induction. Moreover, MMR excitability was selectively increased in the TA under High-threat condition despite the absence of background TA activity. These findings suggest that spinal facilitation is selectively expressed in the TA and may reflect preparatory tuning for ankle stabilization under threat to balance.

neuroscience↗

Selective depletion of AMH-expressing granulosa cells in vivo impairs follicular development and fertility in female mice

In mammals, ovarian follicle development is a highly coordinated process that underlies female fertility. Granulosa cells expressing anti-Mullerian hormone (AMH) are widely used as a marker of growing follicles. However, the in vivo roles of granulosa cells in follicular development and female fertility remain unclear. Here, we analyzed AMH-toxin receptor-mediated cell knockout (AMH-TRECK) transgenic (Tg) mice on a NOG background, in which AMH-expressing granulosa cells are specifically depleted by diphtheria toxin (DT). We first found that, after a single DT injection into postnatal AMH-TRECK Tg females, AMH-expressing granulosa cells in primary and secondary follicles exhibited cleaved caspase-3 signals 1 day later and were depleted 4 days later. Second, after repeated DT injections weekly from 1 to 7 weeks of age in AMH-TRECK Tg females, antral follicles and corpora lutea were rarely observed, and the numbers of primordial, primary, and secondary follicles were decreased. Following PMSG and hCG stimulation, repeated DT-injected Tg females exhibited a reduced number of ovulated oocytes with a low proportion of mature oocytes, resulting in reduced IVF rates and fertility. Further, after a cessation of repeated DT treatment, ovarian weight and follicular development recovered: the numbers of primary, secondary, and antral follicles were recovered, whereas the primordial follicle pool remains reduced. We conclude that selective depletion of AMH-expressing granulosa cells in vivo impairs follicular development and fertility. Our model enables assessment of the in vivo effects of granulosa cell depletion and may provide a useful platform for future transplantation-based studies to understand complex follicular dynamics.

developmental biology↗

OxyBLI: A Genetics-Based Approach for In Vivo Real-Time Visualization of Tissue Oxygenation Dynamics

Accurate measurement of cellular oxygen levels is essential for understanding the balance between oxygen demand and supply in tissues. However, conventional methods only yield compromised results. We harnessed the oxygen dependence of bioluminescence to develop OxyBLI--a noninvasive optical method that directly monitors oxygen levels in specific cell populations of intact experimental animals. We characterized OxyBLI signals across various critical situations associated with common interventions. Hypoxic breathing and subsequent systemic tissue hypoxia caused blood to be redistributed in a way that prioritized brain oxygenation. In contrast, hyperoxic breathing sharply increased tissue oxygenation, which promptly returned to the target level owing to a vasoconstrictor response. These findings are expected to help resolve the long-standing clinical issue regarding the risks and benefits of administering supplemental oxygen to acutely ill patients. Our multifaceted approach, which presents multiple challenges to individual animals over time, will advance our understanding of the delicate interaction between hypoxia and hyperoxia.

physiology↗

Continuous Capture of recombinant AAV Particles Using Twin-Column CaptureSMB

Recombinant adeno-associated viruses (rAAVs) have gained increasing importance in gene therapy due to their safe and precise gene delivery. However, certain indications require substantially higher vector doses, pushing manufacturing capacity and cost of goods (COG) to its limits. In this study, we present for the first time a continuous twin-column capture process (CaptureSMB) enabling direct purification of rAAV5 from unprocessed perfusion harvest without prior concentration or processing. This approach differs fundamentally from conventional batch workflows which typically mandate clarification and concentration before affinity capture and offers a novel process integration in viral vector manufacturing. A single-column batch capture process was developed first and subsequently compared to continuous CaptureSMB configurations. Optimized CaptureSMB operation achieved consistent yields over four cycles, with recoveries exceeding batch operation (+ 14.3%) with concomitant higher productivity (+ 11.4%) and reduced buffer consumption (- 79.2%). Critical quality attribute analysis showed lower host cell protein levels and lower residual DNA in early CaptureSMB cycles, while full capsid ratios, thermal stability and transduction efficiency of rAAV5 particles remained unaltered across cycles and process modes. These findings highlight that continuous twin-column CaptureSMB directly from perfusion harvest can not only improve yield and manufacturing efficiency but also maintain and in some respects enhance product quality. This novel strategy provides a promising route to address manufacturing capacity and cost challenges in rAAV gene therapy production.

bioengineering↗

A lethal mouse model of Oz virus infection reveals hepatic involvement and enables evaluation of antiviral and vaccine efficacy

Oz virus (OZV), a member of the genus Thogotovirus in the family Orthomyxoviridae, is an emerging tick-borne virus reported in Japan. A fatal human case and seroepidemiological evidence of widespread exposure among wild animals and humans suggest its potential public health significance. However, no animal models suitable for pathogenic studies or evaluation of countermeasures are available for OZV. Here, we have established a lethal mouse model of OZV infection using cell-adapted virus and mice lacking type I interferon signaling (B6 Ifnar1 KO mice). OZV infection resulted in 100% mortality and was characterized by robust viral replication in the liver and spleen, severe hepatitis, and acute liver injury. Using this model, we also demonstrated that oral administration of T-705, an antiviral drug widely used against RNA viruses, as well as immunization with an inactivated whole virus particle vaccine, protected B6 Ifnar1 KO mice from lethal OZV infection by mitigating the acute hepatitis. The present study provides critical insights into OZV pathogenesis and establishes a practical in vivo platform for the development of countermeasures against OZV infection. Significance statementEmerging tick-borne viruses pose a growing public health concern, yet progress in understanding their pathogenesis and in developing countermeasures is often limited by the lack of relevant animal models. Oz virus (OZV), a recently identified thogotovirus associated with a fatal human case, exemplifies this challenge. Here, we establish a lethal mouse model of OZV infection that reveals pronounced hepatic involvement as a central pathological feature. Using this model, we demonstrate effective protection by both an antiviral drug and an inactivated vaccine against lethal OZV challenge. This study provides a practical in vivo platform for investigating OZV pathogenesis and for accelerating the development of medical countermeasures against this emerging tick-borne virus.

microbiology↗

Tegmental atrophy in isolated REM sleep behaviour disorder: Ex vivo-informed in vivo imaging

Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is an early-stage synucleinopathy characterized by brainstem pathology. In rodents, the pontine tegmentum contains an REM sleep centre, the sublaterodorsal nucleus (SLD), which expresses corticotropin-releasing hormone binding protein (CRHBP). While the involvement of brainstem pathophysiology is thus implicated in iRBD, its solid evidence remains scarce in humans due to the difficulty in identifying small brainstem nuclei with conventional MRI technology alone. Here, we aimed to detect tegmental atrophy in iRBD with voxel-based morphometry (VBM) analysis combined with a novel human brainstem atlas. Structural MRIs from 98 patients with iRBD and 114 controls were analysed to investigate grey matter volume (GMV) using VBM. Our unique approach involved detailed assessments of the VBM results, guided by a high-resolution MRI-based atlas of the human brainstem. This brainstem atlas was founded on ex vivo MRI of 10 postmortem human specimens. We validated it with CRHBP immunostaining, which aided in identifying putative REM sleep-regulating nuclei in humans. We applied this brainstem atlas to identify atrophy in specific brainstem regions in iRBD and correlate their volumes with clinical measures, including autonomic functions. VBM revealed a focal cluster of grey matter atrophy in the dorsal pontine tegmentum of iRBD patients, including the laterodorsal tegmental nucleus, ventral part (LDTgV) and the pedunculopontine tegmental nucleus (PTg). Our atlas-based analysis confirmed the LDTgV as the site of most conspicuous atrophy, revealing a significant volume reduction in iRBD patients compared to controls with a moderate effect size (Cohens d = 0.46, Bonferroni-corrected p = 0.019). Furthermore, greater atrophy in the LDTgV and the PTg was associated with more severe autonomic dysfunction as measured by Scales for Outcomes in Parkinsons Disease-Autonomic dysfunction (SCOPA-AUT) scores (partial r = -0.237, p = 0.019 and partial r = -0.236, p = 0.019, respectively). Histological analysis confirmed that the LDTgV is selectively enriched with CRHBP-positive neurons, a putative marker for REM sleep-on neurons. We provided novel evidence for the involvement of LDTgV, the putative human homolog of the murine SLD, in iRBD. The present findings advance our understanding of the neuroanatomical basis of iRBD and will contribute to the development of early biomarkers for -synucleinopathies.

neuroscience↗

CNS-penetrant NLRP3 inhibitor achieves durable weight loss and reverses hypothalamic inflammation in diet-induced obesity

The NLRP3 inflammasome is a key mediator of innate immunity that integrates inflammatory and metabolic stress signals. Increased and/or chronic activation of this critical pathway has been implicated in obesity, with hypothalamic neuroinflammation linked to dysregulation of energy balance. TN-783 is an investigational, CNS-penetrant, small-molecule NLRP3 inhibitor that potently suppressed inflammasome activation across multiple in vitro assays. In diet-induced obese (DIO) mice, only TN-783, and not the peripherally restricted NLRP3 inhibitor TN-101, produced progressive and sustained weight loss, underscoring the requirement for central target engagement. Weight loss was driven by a persistent reduction in food intake across both acute and chronic phases, without altering energy expenditure. This effect was further characterized by selective reduction of fat mass, with minimal impact on lean tissues. Mechanistically, NLRP3 inhibition attenuated DIO-induced hypothalamic neuroinflammation and partially reversed obesity-associated molecular changes based on transcriptomic and proteomic profiling of the hypothalamus. Beyond monotherapy, TN-783 enhanced the effects of the GLP-1 receptor agonist semaglutide by amplifying weight loss, reinitiating weight loss after semaglutide effect had plateaued, and maintaining the weight loss benefit after semaglutide withdrawal. Discontinuation of TN-783 resulted in reversal of both weight and feeding effects, indicating that its therapeutic activity requires ongoing target engagement rather than permanent remodeling of metabolic pathways. Collectively, these observations support central NLRP3 inhibition as a distinct and promising approach for obesity treatment, offering robust induction and sustained maintenance of weight loss while preserving reversibility.

neuroscience↗

All spectral frequencies of neural activity reveal semantic representation in the human anterior ventral temporal cortex

Intracranial electrophysiology offers a unique insight into the nature of information representation in the brain - it can be used to disentangle information encoded in local neuronal activity (gamma and high gamma frequencies) from information encoded via long-range interactions (lower frequencies). We used regularised logistic regression to decode animacy from time-frequency power and phase extracted from electrocorticography (ECoG) grid electrode data recorded on the surface of human vATL. Power in gamma (30 - 60 Hz) and high gamma (60 - 200 Hz) produced reliable decoding, indicating that semantic information is indeed expressed by local populations in vATL. However, power from a wide range of frequencies (4 - 200 Hz) produced significantly higher decoding accuracy and also exhibited the same rapidly-changing dynamic code previously observed when decoding voltage. These findings support the theory that semantic information is encoded by a local vATL "hub" that interacts with distributed cortical "spokes".

neuroscience↗

Modulation of cortico-muscular coupling associated with split-belt locomotor adaptation

Humans can adjust their walking patterns according to the demands of their internal and external environments, referred to as locomotor adaptation. Although significant functional coupling (i.e. cortico-muscular coherence [CMC]) has been shown between cortical and lower-limb muscle activity during steady-state walking, little is known about CMC in locomotor adaptation. Therefore, we investigated the adaptation-dependent modulation of the CMC between the sensorimotor region and the tibialis anterior muscle using a split-belt locomotor adaptation paradigm that can impose an asymmetric perturbation. We hypothesized that the CMC would temporarily decrease after exposure to the asymmetric perturbation and removal of the perturbation because of a mismatch between the predicted and actual sensory feedback. We also hypothesized that the CMC would increase as adaptation and de-adaptation to perturbation progressed because the motor system could become able to predict sensory feedback. Our findings revealed that the CMC temporarily decreased after exposure to and removal of the perturbation. Moreover, the CMC increased with adaptation and de-adaptation to perturbation. Although these results depend on the leg, frequency bands, and gait phases, they partially support our hypothesis. These findings suggest that flexible updating of cortico-muscular coupling in the motor system is a key mechanism underlying locomotor adaptation in humans. The results from our study on healthy young individuals contribute to the understanding of neuromuscular control of gait and provide valuable insight for optimising gait rehabilitation. Key pointsO_LILocomotor adaptation plays a crucial role in our daily activities and gait rehabilitation. C_LIO_LIAlthough knowledge regarding the brain and muscle activities associated with locomotor adaptation has been accumulated, little is known about the functional coupling of the brain and muscle activities. C_LIO_LIUsing high-density EEG and lower limb EMG, we demonstrated the modulation of cortico-muscular coherence between the sensorimotor region and the tibialis anterior muscle with adaptation and de-adaptation during a split-belt treadmill walking paradigm. C_LIO_LIOur findings suggest that flexible updating of cortico-muscular coupling in the motor system underlies locomotor adaptation in humans. C_LIO_LIUnderstanding the human brains control of muscles during split-belt locomotor adaptation will deepen our knowledge of neuromuscular control of gait and provide valuable insights for gait rehabilitation. C_LI

neuroscience↗

Endemic demographics of the Jomon people estimated based on complete mitogenomes reveal their regional diversity

The Jomon culture that spread across Japanese archipelago began about 16,000 years ago and lasted for over 10,000 years. The genetic diversity of the Jomon people, prehistoric hunter-gatherers bearing the Jomon culture, is of great interest in understanding prehistoric East Eurasians. Until now, their demographic history has been estimated using archaeological sites and present-day genomes, but detailed studies using Jomon genomes have been insufficient. To investigate the Jomon demography, we determined the complete mitochondrial genome (mitogenome) sequences from 13 Jomon individuals and conducted population genetic analysis on 40 Jomon genomes including previously published data. Our results revealed an effective population size increase during the Incipient - Initial phase of the Jomon period, which had not been observed in analysis of mitogenome sequences from present-day Japanese populations. This endemic demographic pattern is pronounced in the eastern part of the archipelago, under the assumption of no gene flow between the Eastern and Western Jomon.

genomics↗

Cold adaptation in Upper Paleolithic hunter-gatherers of eastern Eurasia

Previous genomic studies understanding the dispersal of Homo sapiens have suggested that present-day East Eurasians and Native Americans can trace their ancestry to migrations from Southeast Asia. However, ineluctable adaptations during the Last Glacial Maximum (LGM) remain unclear. By analyzing 42 genomes of up to 30-fold coverage from prehistoric hunter-gatherers, Jomon, we reveal their descent from Upper Paleolithic (UP) foragers who migrated to and isolated in the Japanese archipelago during Late Pleistocene. We provide compelling evidence suggesting that these UP people underwent positive selection for cold environments, aiding their survival through the LGM facilitated by non-shivering thermogenesis and detecting it polygenically across multiple loci in the Jomon lineage. Our study pioneers the close estimation of the physiological adaptation of ancient humans by the paleogenomic approach.

evolutionary biology↗

DNL343 is an investigational CNS penetrant eIF2B activator that prevents and reverses the effects of neurodegeneration caused by the Integrated Stress Response

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation. DNL343 reduced CNS ISR activity and neurodegeneration in a dose-dependent manner in two established in vivo models - the optic nerve crush injury and an eIF2B loss of function (LOF) mutant - demonstrating neuroprotection in both and preventing motor dysfunction in the LOF mutant mouse. Treatment with DNL343 at a late stage of disease in the LOF model reversed elevation in plasma biomarkers of neuroinflammation and neurodegeneration and prevented premature mortality. Several proteins and metabolites that are dysregulated in the LOF mouse brains were normalized by DNL343 treatment, and this response is detectable in human biofluids. Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic.

neuroscience↗

Wistar rats raised in an affectionate environment display lifesaving-like behaviors while distinguishing life from death

It is generally believed that humans are the only species that values life. However, it is not well understood whether animals have a nature that values life. In this study, we attempted to determine whether male Wistar rats have this nature. Normally-reared rats did not show lifesaving-like actions towards anesthesia-induced comatose rats, although they seemed to distinguish life from death. Considering the possibility that different rearing conditions may foster a life-valuing nature, male Wistar rat pups were reared in several ways: normal rearing, loving rearing (LR; rats reared as if they were cute pets), rearing in an enriched environment, reared with gentle stroking of the back, and normal rearing of offspring of rats raised under LR conditions. When placed in an anxiety-producing environment, only LR rats escaped into the hands of the person who reared them, indicating attachment. Only the LR rats displayed lifesaving-like actions towards unknown comatose rats or drowning pups. LR rats also stopped attacks by biting ICR mice that were attacking C57BL/6 mice. Thus, rearing in an affectionate environment may foster a life-valuing nature, even in rats, suggesting that the valuing of life may be neither innate nor human-specific.

animal behavior and cognition↗

Collagen of ancient bones gives an indication of endogenous DNA preservation based on the next generation sequencing technology

Ancient genome analysis has become an indispensable tool in studies of human population history and evolution after the breakthrough of whole genome sequencing technology. Meanwhile, the problem has been not resolved that ancient genome cannot be analyzed without crushing non-small pieces of precious specimens; in spite of that, in many cases, there is no DNA remaining sufficiently in the piece of samples for obtaining the whole genome sequences. In previous studies, therefore, a couple of indicators (e.g., racemization ratios) have been proposed to estimate the endogenous DNA in ancient samples. However, these studies have used polymerase chain reaction (PCR) to test whether endogenous DNA is remaining, which has been inadequate because the success or failure of PCR amplification does not necessarily reflect DNA remaining. To assess the amount of endogenous DNA, we use the ratios of reads generated by the next-generation sequencer (NGS) mapped to the human reference genome sequence. We investigate 40 Jomon remains and find a significant association between the collagen residual ratios (CRRs) in rib bones and the mapping ratios (MRs). Because the weight of bone required to measure collagen residual is much less than that required to obtain DNA needed for NGS analysis, which is always necessary for dating, the collagen in ribs can be a good indicator for successful ancient genome analyses.

genomics↗

State-dependent role of interhemispheric pathway for motor recovery in primates

Whether and how the interhemispheric pathway is involved in post-injury motor recovery is controversial. Unidirectional chemogenetic blockade of the interhemispheric pathway from the contralesional to ipsilesional premotor cortex impaired dexterous hand movements during the early recovery stage after lesioning the lateral corticospinal tract in macaques. Furthermore, electrocorticographical recording showed that the low frequency band activity of the ipsilesional premotor cortex around the movement onset was decreased by the blockade during the early recovery stage, while it was increased by blockade during the intact state and the late recovery stage. These results demonstrate that the action of the interhemispheric pathway changed from inhibition to facilitation, leading to the involvement of the ipsilesional sensorimotor cortex in hand movements during the early recovery stage. The present study offers new insights into the state-dependent role of the interhemispheric pathway and a therapeutic target in the early recovery stage after lesioning of the corticospinal tract.

neuroscience↗

Representational similarity learning reveals a graded multi-dimensional semantic space in the human anterior temporal cortex

Neurocognitive models of semantic memory have proposed that the ventral anterior temporal lobes (vATLs) encode a graded and multidimensional semantic space--yet neuroimaging studies seeking brain regions that encode semantic structure rarely identify these areas. In simulations we show that this discrepancy may arise from a crucial mismatch between theory and analysis approach. Utilizing an analysis recently formulated to investigate graded multidimensional representations, representational similarity learning (RSL), we decoded semantic structure from ECoG data collected from the vATL cortical surface while participants named line drawings of common items. The results reveal a graded, multidimensional semantic space encoded in neural activity across the vATL, which evolves over time and simultaneously expresses both broad and finer-grained semantic structure amongst animate and inanimate concepts. The work resolves the apparent discrepancy within the semantic cognition literature and, more importantly, suggests a new approach to discovering representational structure in neural data more generally. Conflict of interestThe Department of Epilepsy, Movement Disorders, and Physiology, Kyoto University Graduate School of Medicine conducts Industry-Academia Collaboration Courses, supported by Eisai Co., Ltd, Nihon Kohden Corporation, Otsuka Pharmaceutical Co., and UCB Japan Co., Ltd.

neuroscience↗

Spinal cord extracts from sporadic ALS induce and propagate TDP-43 pathology in cerebral organoids

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS.

neuroscience↗