Biology subjects

Takahashi, H.

Publications and source records attributed to Takahashi, H..

6 recordsLinked to original sources

bioRxiv2018

Harmonization of resting-state functional MRI data across multiple imaging sites via the separation of site differences into sampling bias and measurement bias

When collecting large neuroimaging data associated with psychiatric disorders, images must be acquired from multiple sites because of the limited capacity of a single site. However, site differences represent the greatest barrier when acquiring multi-site neuroimaging data. We utilized a traveling-subject dataset in conjunction with a multi-site, multi-disorder dataset to demonstrate that site differences are composed of biological sampling bias and engineering measurement bias. Effects on resting-state functional MRI connectivity because of both bias types were greater than or equal to those because of psychiatric disorders. Furthermore, our findings indicated that each site can sample only from among a subpopulation of participants. This result suggests that it is essential to collect large neuroimaging data from as many sites as possible to appropriately estimate the distribution of the grand population. Finally, we developed a novel harmonization method that removed only the measurement bias by using traveling-subject dataset and achieved the reduction of the measurement bias by 29% and the improvement of the signal to noise ratios by 40%.

neuroscience↗

bioRxiv2018

Overlapping but asymmetrical relationships between schizophrenia and autism revealed by brain connectivity

(Abstract included 248 words)Although the relationship between schizophrenia spectrum disorder (SSD) and autism spectrum disorder (ASD) has long been debated, it has not yet been fully elucidated. To address this issue, we took advantage of dual (ASD and SSD) classifiers that discriminate patients from their controls based on resting state brain functional connectivity. An SSD classifier using sophisticated machine-learning algorithms that automatically selected SSD- specific functional connections was applied to Japanese datasets including adult patients with SSD in a chronic stage. We demonstrated good performance of the SSD classification for independent validation cohorts. The generalizability was tested by USA and European cohorts in a chronic stage, and one USA cohort including first episode schizophrenia. The specificity was tested by two adult Japanese cohorts of ASD and major depressive disorder, and one European cohort of attention-deficit hyperactivity disorder. The weighted linear summation of the classifiers functional connections constituted the biological dimensions representing neural liability to the disorders. Our previously developed robust ASD classifier constituted the ASD dimension. Distributions of individuals with SSD, ASD and healthy controls were examined on the SSD and ASD biological dimensions. The SSD and ASD populations exhibited overlapping but asymmetrical patterns on the two biological dimensions. That is, the SSD population showed increased liability on the ASD dimension, but not vice versa. Furthermore, the two dimensions were correlated within the ASD population but not the SSD population. Using the two biological dimensions based on resting-state functional connectivity enabled us to quantify and visualize the relationships between SSD and ASD.

neuroscience↗

bioRxiv2018

Anti-CD137 monoclonal antibody enhances trastuzumab-induced, natural killer cell-mediated cytotoxicity against pancreatic cancer cell lines with low human epidermal growth factor-like receptor 2 expression

BackgroundBecause human epidermal growth factor-like receptor (HER) 2 is expressed on the surface of human pancreatic carcinoma cells to varying degrees, trastuzumab, an anti-HER2 monoclonal antibody (mAb), is expected to exert antibody-dependent, natural killer (NK) cell-mediated cytotoxicity (ADCC) against the cells. However, some reports found that the effect of trastuzumab against human pancreatic carcinoma cells was limited because most express only limited HER2.\n\nMethodsWe examined whether anti-CD137 stimulating mAb could enhance trastuzumab-mediated ADCC against Panc-1, a human pancreatic cancer cell line with low HER2 expression, in vitro.\n\nResultsSupplementation of anti-CD137 mAb could improve trastuzumab-mediated ADCC against Panc-1 which was insufficient without this stimulating antibody. The ADCC differed in individual cells, and this was related to the expression of CD137 on the surface of NK cells after trastuzumab stimulation in association with the Fc{gamma}-RIIIA polymorphism. NK cells with Fc{gamma}-RIIIA-VV/VF showed high levels of ADCC against Panc-1, but those with Fc{gamma}-RIIIA-FF did not show optimal ADCC. In addition, trastuzumab-mediated ADCC against the human pancreatic cancer cell line Capan-1 with high HER2 expression was generally high and not affected by the Fc{gamma}-RIIIA polymorphism.\n\nConclusionsThese results demonstrated that in Fc{gamma}-RIIIA-VV/VF-carrying hosts, trastuzumab plus CD137 mAb could induce effective ADCC against HER2-low-expressing pancreatic cancer cells. This also indicates the therapeutic potential for unresectable human pancreatic cancer, in which HER-2 expression is generally low.

immunology↗

bioRxiv2018

mitoNEET Regulates Mitochondrial Iron Homeostasis Interacting with Transferrin Receptor

Iron is an essential trace element for regulation of redox and mitochondrial function, and then mitochondrial iron content is tightly regulated in mammals. We focused on a novel protein localized at the outer mitochondrial membrane. Immunoelectron microscopy revealed transferrin receptor (TfR) displayed an intimate relationship with the mitochondria, and mass spectrometry analysis also revealed mitoNEET interacted with TfR in vitro. Moreover, mitoNEET was endogenously coprecipitated with TfR in the heart, which indicates that mitoNEET also interacts with TfR in vivo. We generated mice with cardiac-specific deletion of mitoNEET (mitoNEET-knockout). Iron contents in isolated mitochondria were significantly increased in mitoNEET-knockout mice compared to control mice. Mitochondrial reactive oxygen species (ROS) were higher, and mitochondrial maximal capacity and reserve capacity were significantly decreased in mitoNEET-knockout mice, which was consistent with cardiac dysfunction evaluated by echocardiography. The complex formation of mitoNEET with TfR may regulate mitochondrial iron contents via an influx of iron. A disruption of mitoNEET could thus be involved in mitochondrial ROS production by iron overload in the heart.

cell biology↗

bioRxiv2018

The axon initial segment drives the neuron’s extracellular action potential

Extracellular voltage fields produced by a neurons action potentials provide a primary means for studying neuron function, yet their biophysical sources remain ambiguous. The neurons soma and dendrites are thought to drive the extracellular action potential (EAP), while the axon is usually ignored. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices at hundreds of sites, we find instead that the axon initial segment dominates the EAP, and, surprisingly, the soma shows little or no influence. As expected, this signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage field is important for interpreting results from all electrical readout schemes. Moreover, this finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology.\n\nKey points summaryO_LIThe neurons soma and dendrites are thought to give rise to its extracellular voltage signal, while signals from the axon are usually considered negligible.\nC_LIO_LIInstead, we found that the largest amplitude of the extracellular signal originates from the axon initial segment, not from the soma.\nC_LIO_LIThis finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology.\nC_LI\n\nAbbreviations

neuroscience↗

bioRxiv2017

A prediction model of working memory across health and psychiatric disease using whole-brain functional connectivity

Individual differences in cognitive function have been shown to correlate with brain-wide functional connectivity, suggesting a common foundation relating connectivity to cognitive function across healthy populations. However, it remains unknown whether this relationship is preserved in cognitive deficits seen in a range of psychiatric disorders. Using machine learning methods, we built a prediction model of working memory function from whole-brain functional connectivity among a healthy population (N = 17, age 19-24 years). We applied this normative model to a series of independently collected resting state functional connectivity datasets (N = 968), involving multiple psychiatric diagnoses, sites, ages (18-65 years), and ethnicities. We found that predicted working memory ability was correlated with actually measured working memory performance in both schizophrenia patients (partial correlation,{rho} = 0.25, P = 0.033, N = 58) and a healthy population (partial correlation,{rho} = 0.11, P = 0.0072, N = 474). Moreover, the model predicted diagnosis-specific severity of working memory impairments in schizophrenia (N = 58, with 60 controls), major depressive disorder (N = 77, with 63 controls), obsessive-compulsive disorder (N = 46, with 50 controls), and autism spectrum disorder (N = 69, with 71 controls) with effect sizes g = -0.68, -0.29, -0.19, and 0.09, respectively. According to the model, each diagnosiss working memory impairment resulted from the accumulation of distinct functional connectivity differences that characterizes each diagnosis, including both diagnosis-specific and diagnosis-invariant functional connectivity differences. Severe working memory impairment in schizophrenia was related not only with fronto-parietal, but also widespread network changes. Autism spectrum disorder showed greater negative connectivity that related to improved working memory function, suggesting that some non-normative functional connections can be behaviorally advantageous. Our results suggest that the relationship between brain connectivity and working memory function in healthy populations can be generalized across multiple psychiatric diagnoses. This approach may shed new light on behavioral variances in psychiatric disease and suggests that whole-brain functional connectivity can provide an individual quantitative behavioral profile in a range of psychiatric disorders.

neuroscience↗