De novo NSF mutations cause early infantile epileptic encephalopathy

N‐ethylmaleimide‐sensitive factor (NSF) plays a critical role in intracellular vesicle transport, which is essential for neurotransmitter release. Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset. When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye development, while the wild‐type allele had no detectable effect under the same conditions. Our findings suggest that the two pathogenic variants exert a dominant negative effect. De novo heterozygous mutations in the NSF gene cause early infantile epileptic encephalopathy

マワル オト プロジェクト オ メグッテ : シュウダン セイサク ノ ジッセン キロク ト コウサツ

From the point of view on art teacher education, we made graduate students and university students in art education course take part in Echigo-Tsumari Art Triennial 2003. And students and us exhibited a work named "the running sound project". The purpose of our participation was to gain new experience by a collaborative art working. The project was led by students from planning to presentation. During the process, we experienced and solved a lot of issues-choosing ideas, search for technical equipments for the synchronization of sounds, and so on. Students and us found the importance of communication and collaboration with local people, and meta-cognition of the process on our group work. Also, we realized the importance to share the issues each other and to build the common image about the work. Our attempts suggested participation in this kind of collaborative art working brought educational effect on students

Cytosolic Double-Stranded DNA as a Damage-Associated Molecular Pattern Induces the Inflammatory Response in Rat Pancreatic Stellate Cells: A Plausible Mechanism for Tissue Injury-Associated Pancreatitis

Pancreatitis is an inflammatory disease of unknown causes. There are many triggers causing pancreatitis, such as alcohol, common bile duct stone, virus and congenital or acquired stenosis of main pancreatic duct, which often involve tissue injuries. Pancreatitis often occurs in sterile condition, where the dead/dying pancreatic parenchymal cells and the necrotic tissues derived from self-digested-pancreas were observed. However, the causal relationship between tissue injury and pancreatitis and how tissue injury could induce the inflammation of the pancreas were not elucidated fully until now. This study demonstrates that cytosolic double-stranded DNA increases the expression of several inflammatory genes (cytokines, chemokines, type I interferon, and major histocompatibility complex) in rat pancreatic stellate cells. Furthermore, these increase accompanied the multiple signal molecules genes, such as interferon regulatory factors, nuclear factor-kappa B, low-molecular-weight protein 2, and transporter associated with antigen processing 1. We suggest that this phenomenon is a plausible mechanism that might explain how cell damage of the pancreas or tissue injury triggers acute, chronic, and autoimmune pancreatitis; it is potentially relevant to host immune responses induced during alcohol consumption or other causes

R26-WntVis reporter mice showing graded response to Wnt signal levels

The canonical Wnt signaling pathway plays a major role in the regulation of embryogenesis and organogenesis, where signal strength-dependent cellular responses are of particular importance. To assess Wnt signal levels in individual cells, and to circumvent the integration site-dependent bias shown in previous Wnt reporter lines, we constructed a new Wnt signal reporter mouse line R26-WntVis. Heptameric TCF/LEF1 binding sequences were combined with a viral minimal promoter to confer a graded response to the reporter depending on Wnt signal strengths. The histone H2B-EGFP fusion protein was chosen as the fluorescent reporter to facilitate single-cell resolution analyses. This WntVis reporter gene was then inserted into the ROSA26 locus in an orientation opposite to that of the endogenous gene. The R26-WntVis allele was introduced into Wnt3a−/− and Wnt3avt/− mutant mouse embryos and compared with wild-type embryos to assess its performance. The R26-WntVis reporter was activated in known Wnt-dependent tissues and responded in a graded fashion to signal intensity. This analysis also indicated that the major Wnt activity early in embryogenesis switched from Wnt3 to Wnt3a around E7.5. The R26-WntVis mouse line will be widely useful for the study of Wnt signal-dependent processes

A novel missense PTEN mutation identified in a patient with macrocephaly and developmental delay

Phosphatase and tensin homolog (PTEN) plays an important role in tumor suppression. A germline mutation in the PTEN gene induces not only PTEN hamartoma tumor syndrome, including Cowden syndrome, but also macrocephaly/autism syndrome. Here, we describe a boy with macrocephaly/ autism syndrome harboring a novel missense heterozygous PTEN mutation, c.959T>C (p.Leu320Ser). Interestingly, a previously reported nonsense mutation resulting in p.Leu320X was found in Cowden syndrome patients. Our case may be suggestive of a genotype-phenotype correlation

A Fully Implantable Wireless ECoG 128-Channel Recording Device for Human Brain–Machine Interfaces: W-HERBS

Brain–machine interfaces (BMIs) are promising devices that can be used as neuroprostheses by severely disabled individuals. Brain surface electroencephalograms (electrocorticograms, ECoGs) can provide input signals that can then be decoded to enable communication with others and to control intelligent prostheses and home electronics. However, conventional systems use wired ECoG recordings. Therefore, the development of wireless systems for clinical ECoG BMIs is a major goal in the field. We developed a fully implantable ECoG signal recording device for human ECoG BMI, i.e., a wireless human ECoG-based real-time BMI system (W-HERBS). In this system, three-dimensional (3D) high-density subdural multiple electrodes are fitted to the brain surface and ECoG measurement units record 128-channel (ch) ECoG signals at a sampling rate of 1 kHz. The units transfer data to the data and power management unit implanted subcutaneously in the abdomen through a subcutaneous stretchable spiral cable. The data and power management unit then communicates with a workstation outside the body and wirelessly receives 400 mW of power from an external wireless transmitter. The workstation records and analyzes the received data in the frequency domain and controls external devices based on analyses. We investigated the performance of the proposed system. We were able to use W-HERBS to detect sine waves with a 4.8-μV amplitude and a 60–200-Hz bandwidth from the ECoG BMIs. W-HERBS is the first fully implantable ECoG-based BMI system with more than 100 ch. It is capable of recording 128-ch subdural ECoG signals with sufficient input-referred noise (3 μVrms) and with an acceptable time delay (250 ms). The system contributes to the clinical application of high-performance BMIs and to experimental brain research

A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways

Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β1-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-β1-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis

A case of autism spectrum disorder with cleft lip and palate carrying a mutation in exon 8 of AUTS2

We report a patient with autism and cleft lip and palate carrying a de novo heterozygous AUTS2 mutation, c.1464_1467del ACTC (p.Tyr488*). Although the causal relationship between cleft lip and palate and this mutation is unclear, this case report may expand the clinical phenotype of AUTS2 syndrome