Complementary Domain Adaptation and Generalization for Unsupervised Continual Domain Shift Learning

Continual domain shift poses a significant challenge in real-world applications, particularly in situations where labeled data is not available for new domains. The challenge of acquiring knowledge in this problem setting is referred to as unsupervised continual domain shift learning. Existing methods for domain adaptation and generalization have limitations in addressing this issue, as they focus either on adapting to a specific domain or generalizing to unseen domains, but not both. In this paper, we propose Complementary Domain Adaptation and Generalization (CoDAG), a simple yet effective learning framework that combines domain adaptation and generalization in a complementary manner to achieve three major goals of unsupervised continual domain shift learning: adapting to a current domain, generalizing to unseen domains, and preventing forgetting of previously seen domains. Our approach is model-agnostic, meaning that it is compatible with any existing domain adaptation and generalization algorithms. We evaluate CoDAG on several benchmark datasets and demonstrate that our model outperforms state-of-the-art models in all datasets and evaluation metrics, highlighting its effectiveness and robustness in handling unsupervised continual domain shift learning

Phospholipase C-beta 1 Hypofunction in the Pathogenesis of Schizophrenia

Schizophrenia is a mental disorder that is characterized by various abnormal symptoms. Previous studies indicate decreased expression of phospholipase c-beta 1 (PLc-beta 1) in the brains of patients with schizophrenia. PLC-beta 1 -null (PLC-beta 1) mice exhibit multiple endophenotypes of schizophrenia. Furthermore, a study of PLC beta 1 knockdown in the medial prefrontal cortex of mice has shown a specific behavioral deficit, impaired working memory. These results support the notion that disruption of PLC-beta 1-linked signaling in the brain is strongly involved in the pathogenesis of schizophrenia. In this review, we broadly investigate recent studies regarding schizophrenia-related behaviors as well as their various clinical and biological correlates in PLC-beta 1- and knockdown mouse models. This will provide a better understanding of the pathological relevance of the altered expression of PLC p1 in the brains of patients with schizophrenia. Evidence accumulated will shed light on future in-depth studies, possibly in human subjects.1341scopu

Neural stem cell transplantation : neuroprotection and LTP-induced facilitation of neurogenesis

Transplantation of neural progenitor cells (NPC) constitutes a putative therapeutic maneuver for use in treatment of neurodegenerative diseases. At present, effects of NPC transplantation in the Alzheimer’s disease (AD) brain are largely unknown and a primary objective of this work is to demonstrate possible efficacy of NPC administration in an AD animal model. The benefits of transplantation could involve a spectrum of effects including replacement of endogenous neurons, conferring neuroprotection with enhancement of neurotrophic factors, and diminishing levels of neurotoxic agents. Additionally, since chronic inflammation is a characteristic property of the AD brain, I considered NPC transplantation could have a particular utility in inhibiting ongoing inflammatory reactivity. Accordingly, intra-hippocampal transplantation of NPC has been examined for efficacy in attenuating inflammatory responses and conferring neuroprotection in the hippocampus. These findings indicate efficacy for NPC transplantation with effects consistent with cellular actions to attenuate inflammatory reactivity. Synaptic plasticity, such as long-term potentiation (LTP), is thought to play a critical role in modification of neuronal circuitry in learning and memory, but the role in neurogenesis is not well known. A critical aspect of my study was to examine potential roles of N-methyl-D-aspartate receptor (NMDAR)-dependent LTP in promoting neurogenesis by facilitating proliferation/survival and neuronal differentiation of endogenous NPCs in the dentate gyrus (DG) and exogenously transplanted neural stem cells (NSCs) in the CA1. I found that LTP induction significantly facilitates proliferation/survival and neuronal differentiation of endogenous NPCs and exogenously transplanted NSCs in the hippocampus. These effects were eliminated by a NMDAR competitive antagonist, CPP. Accordingly, chemical LTP stimulation reproduced enhanced proliferation/survival and neuronal differentiation of NSCs when co-cultured with hippocampal neurons. These effects were eliminated by a NMDAR competitive antagonist, D-APV and inhibited by the tyrosine kinase inhibitor, K252a. ELISA and biotinylation results revealed that NMDAR-mediated LTP facilitates the release of a neurotrophic factor, BDNF. The conditioned media from cLTP-induced hippocampal neurons were sufficient to activate the BDNF receptor, TrkB. Overall, my results suggest that NMDAR-dependent LTP plays a critical role in neurogenesis and may contribute to the utility of NSC transplantation as an effective cell therapy for a variety of neurodegenerative diseases.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat

Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD brain

Abstract Background Transplantation of neural progenitor cells (NPC) constitutes a putative therapeutic maneuver for use in treatment of neurodegenerative diseases. At present, effects of NPC transplantation in Alzheimer's disease (AD) brain are largely unknown and a primary objective of this work was to demonstrate possible efficacy of NPC administration in an animal model of AD. The benefits of transplantation could involve a spectrum of effects including replacement of endogenous neurons or by conferring neuroprotection with enhancement of neurotrophic factors or diminishing levels of neurotoxic agents. Since chronic inflammation is a characteristic property of AD brain, we considered that transplantation of NPC could have particular utility in inhibiting ongoing inflammatory reactivity. We have tested intrahippocampal transplantation of NPC for efficacy in attenuating inflammatory responses and for neuroprotection in beta-amyloid (Aβ1-42) peptide-injected rat hippocampus. Methods Spheres of neural progenitor cells were grown from dissociated telencephalon tissue of rat embryos. NPC were infected with lentiviral vector green fluorescent protein (GFP) with subsequent cell transplantation into rat hippocampus previously injected (3 d prior) with Aβ1-42 peptide or PBS control. Immunohistochemical analysis was carried out (7 d post-NPC transplantation, 10 d post-peptide/PBS injection) for GFP, microgliosis (Iba-1 marker), astrogliosis (GFAP marker), neuron viability (MAP-2 marker) and levels of the proinflammatory cytokine, TNF-α. Results Successful infection of cultured NPC with lentiviral vector green fluorescent protein (GFP) was demonstrated prior to cell transplantation into rat hippocampus. In vivo, immunohistochemical staining showed migration of GFP-positive cells, in a region of dentate gyrus between Aβ1-42/PBS injection site and NPC transplantation site, was increased ×2.8-fold with Aβ1-42 compared to PBS injection. Double immunostaining in peptide-injected brain indicated GFP association with nestin and GFAP, but not MAP-2. Cell-specific immunostaining showed marked increases in microgliosis and astrogliosis in Aβ1-42-injected brain (respective increases of ×4.3- and ×4.6-fold compared with PBS injection). NPC transplantation significantly reduced microgliosis (by 38%) but not astrogliosis in peptide-injected hippocampus. The proinflammatory cytokine TNF-α was elevated by 6.7-fold (peptide vs PBS injection) with NPC administration attenuating levels of TNF-α (by 40%). Peptide-injected brain demonstrated neuronal loss (MAP-2 staining reduced by 45% vs PBS injection) with NPC transplantation effective in conferring neuroprotection (26% recovery of neurons). Conclusions These findings indicate efficacy for NPC transplantation in an animal model of AD with effects consistent with cellular actions to attenuate inflammatory reactivity induced by intrahippocampal peptide injection.</p

Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD brain

Background: Transplantation of neural progenitor cells (NPC) constitutes a putative therapeutic maneuver for use in treatment of neurodegenerative diseases. At present, effects of NPC transplantation in Alzheimer's disease (AD) brain are largely unknown and a primary objective of this work was to demonstrate possible efficacy of NPC administration in an animal model of AD. The benefits of transplantation could involve a spectrum of effects including replacement of endogenous neurons or by conferring neuroprotection with enhancement of neurotrophic factors or diminishing levels of neurotoxic agents. Since chronic inflammation is a characteristic property of AD brain, we considered that transplantation of NPC could have particular utility in inhibiting ongoing inflammatory reactivity. We have tested intrahippocampal transplantation of NPC for efficacy in attenuating inflammatory responses and for neuroprotection in beta-amyloid (Aβ1-42) peptide-injected rat hippocampus. Methods: Spheres of neural progenitor cells were grown from dissociated telencephalon tissue of rat embryos. NPC were infected with lentiviral vector green fluorescent protein (GFP) with subsequent cell transplantation into rat hippocampus previously injected (3 d prior) with Aβ1-42 peptide or PBS control. Immunohistochemical analysis was carried out (7 d post-NPC transplantation, 10 d post-peptide/PBS injection) for GFP, microgliosis (Iba-1 marker), astrogliosis (GFAP marker), neuron viability (MAP-2 marker) and levels of the proinflammatory cytokine, TNF-α. Results: Successful infection of cultured NPC with lentiviral vector green fluorescent protein (GFP) was demonstrated prior to cell transplantation into rat hippocampus. In vivo, immunohistochemical staining showed migration of GFP-positive cells, in a region of dentate gyrus between Aβ1-42/PBS injection site and NPC transplantation site, was increased ×2.8-fold with Aβ1-42 compared to PBS injection. Double immunostaining in peptide-injected brain indicated GFP association with nestin and GFAP, but not MAP-2. Cell-specific immunostaining showed marked increases in microgliosis and astrogliosis in Aβ1-42-injected brain (respective increases of ×4.3- and ×4.6-fold compared with PBS injection). NPC transplantation significantly reduced microgliosis (by 38%) but not astrogliosis in peptide-injected hippocampus. The proinflammatory cytokine TNF-α was elevated by 6.7-fold (peptide vs PBS injection) with NPC administration attenuating levels of TNF-α (by 40%). Peptide-injected brain demonstrated neuronal loss (MAP-2 staining reduced by 45% vs PBS injection) with NPC transplantation effective in conferring neuroprotection (26% recovery of neurons). Conclusions: These findings indicate efficacy for NPC transplantation in an animal model of AD with effects consistent with cellular actions to attenuate inflammatory reactivity induced by intrahippocampal peptide injection.Anesthesiology, Pharmacology and Therapeutics, Department ofMedicine, Faculty ofReviewedFacult

Scalable Neural Architecture Search for 3D Medical Image Segmentation

In this paper, a neural architecture search (NAS) framework is proposed for 3D medical image segmentation, to automatically optimize a neural architecture from a large design space. Our NAS framework searches the structure of each layer including neural connectivities and operation types in both of the encoder and decoder. Since optimizing over a large discrete architecture space is difficult due to high-resolution 3D medical images, a novel stochastic sampling algorithm based on a continuous relaxation is also proposed for scalable gradient based optimization. On the 3D medical image segmentation tasks with a benchmark dataset, an automatically designed architecture by the proposed NAS framework outperforms the human-designed 3D U-Net, and moreover this optimized architecture is well suited to be transferred for different tasks

LARGE, an intellectual disability-associated protein, regulates AMPA-type glutamate receptor trafficking and memory

Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability. © 2018 National Academy of Sciences. All Rights Reserved11Nsciescopu