Biology subjects

Nakamura, M.

Publications and source records attributed to Nakamura, M..

4 recordsLinked to original sources

bioRxiv2018

Machine learning approach to identify resting-state functional connectivity pattern serving as an endophenotype of autism spectrum disorder

Endophenotype refers to a measurable and heritable component between genetics and diagnosis and exists in both individuals with a diagnosis and their unaffected siblings. We aimed to identify a pattern of endophenotype consisted of multiple connections. We enrolled adult male individuals with autism spectrum disorder (ASD) endophenotype (i.e., individuals with ASD and their unaffected siblings) and individuals without ASD endophenotype (i.e., pairs of typical development (TD) siblings) and utilized a machine learning approach to classify people with and without endophenotypes, based on resting-state functional connections (FCs). A sparse logistic regression successfully classified people as to the endophenotype (area under the curve=0.78, classification accuracy=75%), suggesting the existence of endophenotype pattern. A binomial test identified that nine FCs were consistently selected as inputs for the classifier. The least absolute shrinkage and selection operator with these nine FCs predicted severity of communication impairment among individuals with ASD (r=0.68, p=0.021). In addition, two of the nine FCs were statistically significantly correlated with the severity of communication impairment (r=0.81, p=0.0026 and r=-0.60, p=0.049). The current findings suggest that an ASD endophenotype pattern exists in FCs with a multivariate manner and is associated with clinical ASD phenotype.

neuroscience↗

bioRxiv2018

GnasR201C Induces Murine Pancreatic Cystic Neoplasms through Suppression of YAP1 Signaling and Transcriptional Reprogramming

Background & AimsSomatic \"hotspot\" mutations of GNAS, which encodes for the alpha subunit of stimulatory G-protein, are present in ~60% of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. There are currently no cognate animal models that recapitulate the biology of mutant Gnas-induced IPMNs, and the underlying mechanisms that lead to the cystic pathway of neoplasia in the pancreas remain unknown.\n\nMethodsWe generated p48-Cre; LSL-KrasG12D; Rosa26R-LSL-rtTA-TetO-GnasR201C mice (Kras; Gnas mice) where pancreas-specific GnasR201C expression was induced by doxycycline administration. In this model, mutant Kras is constitutively expressed, and control mice were produced through absence of doxycycline. Separate cohorts of mice were utilized for timed necropsies and for Kaplan-Meier survival analysis. Isogenic cell lines (with doxycycline inducible mutant Gnas expression) were propagated from the resulting pancreatic ductal adenocarcinoma (PDAC).\n\nResultsCo-expression of KrasG12D and GnasR201C resulted in the development of pancreatic cystic lesions resembling human IPMNs in 100% of mice, with higher grades of epithelial dysplasia observed over time. Approximately one-third of Kras; Gnas mice developed PDAC at a median of 38 weeks post doxycycline induction. GnasR201C did not accelerate oncogenic transformation with KrasG12D, but rather, reprogrammed Ras-induced neoplasms towards a well-differentiated phenotype. GnasR201C induction led to activation of the inhibitory Hippo kinase cascade and cytoplasmic sequestration of phosphorylated YAP1 protein, a phenomenon that was also observed in human IPMN with GNAS mutations.\n\nConclusionsGNASR201C functions not as a traditional oncogene, but rather as an \"oncomodulator\" of KRAS-mediated pancreatic neoplasia, through suppression of YAP1 and transcriptional reprogramming towards a differentiated (large ductal) phenotype.

cancer biology↗

bioRxiv2017

CLASP stabilizes microtubule plus ends after severing to facilitate light-induced microtubule reorientation

Central to building and reorganizing cytoskeletal arrays is the creation of new polymers. While nucleation has been the major focus of study for new microtubule generation, severing has been proposed as an alternative mechanism to create new polymers, a mechanism recently shown to drive the reorientation of cortical arrays of higher plants in response to blue light perception. As severing produces new plus ends behind the stabilizing GTP-cap, an important and unanswered question is how these are stabilized in vivo to promote net microtubule generation. Here we identify the conserved protein CLASP as a potent stabilizer of new plus ends created by katanin severing and find that CLASP is required for rapid cortical array reorientation. In clasp mutants both rescue of shrinking plus ends and the regrowth of plus ends immediately after severing are reduced, computational modeling reveals that it is the specific stabilization of severed ends that explains CLASPs function in promoting microtubule amplification by severing and cortical array reorientation.

cell biology↗

bioRxiv2017

The FACT complex is required for DNA demethylation at heterochromatin during reproduction in Arabidopsis

The DEMETER (DME) DNA glycosylase catalyzes genome-wide DNA demethylation and is required for endosperm genomic imprinting and embryo viability. Targets of DME-mediated DNA demethylation reside in small, euchromatic, AT-rich transposons and at the boundaries of large transposons, but how DME interacts with these diverse chromatin states is unknown. The STRUCTURE SPECIFIC RECOGNITION PROTEIN 1 (SSRP1), subunit of the chromatin remodeler FAcilitates Chromatin Transactions (FACT), was previously shown to be involved in the DME-dependent regulation of genomic imprinting in Arabidopsis endosperm. Therefore, to investigate the interaction between DME and chromatin, we focused on the activity of the two FACT subunits, SSRP1 and SUPPRESSOR of TY16 (SPT16), during reproduction in Arabidopsis. We find that FACT co-localizes with nuclear DME in vivo, and that DME has two classes of target sites, the first being euchromatic and accessible to DME, but the second, representing over half of DME targets, requiring the action of FACT for DME-mediated DNA demethylation genome-wide. Our results show that the FACT-dependent DME targets are GC-rich heterochromatin domains with high nucleosome occupancy enriched with H3K9me2 and H3K27me1. Further, we demonstrate that heterochromatin-associated linker histone H1 specifically mediates the requirement for FACT at a subset of DME-target loci. Overall, our results demonstrate that FACT is required for DME targeting by facilitating its access to heterochromatin.

plant biology↗