Regulation of RNG105/caprin1 dynamics by pathogenic cytoplasmic FUS and TDP-43 in neuronal RNA granules modulates synaptic loss.

In neurodegenerative diseases, the condensation of FUS and TDP-43 with RNA granules in neurons is linked to pathology, including synaptic disorders. However, the effects of FUS and TDP-43 on RNA granule factors remain unclear. Here, using primary cultured neurons from the mouse cerebral cortex, we show that excess cytoplasmic FUS and TDP-43 accumulated in dendritic RNA granules, where they increased the dynamics of a scaffold protein RNG105/caprin1 and dissociated it from the granules. This coincided with reduced levels of mRNA and translation around the granules and synaptic loss in dendrites. These defects were suppressed by non-dissociable RNG105, suggesting that RNG105 dissociation mediated the defects. In contrast to the model where FUS and TDP-43 co-aggregate with RNA granule factors to repress their activity, our findings provide a novel pathogenic mechanism whereby FUS and TDP-43 dissociate RNA scaffold proteins from RNA granules which are required for local translation that regulates synapse formation.

ILF3 prion-like domain regulates gene expression and fear memory under chronic stress.

The prion-like domain (PrLD) is a class of intrinsically disordered regions. Although its propensity to form condensates has been studied in the context of neurodegenerative diseases, the physiological role of PrLD remains unclear. Here, we investigated the role of PrLD in the RNA-binding protein NFAR2, generated by a splicing variant of the Ilf3 gene. Removal of the PrLD in mice did not impair the function of NFAR2 required for survival, but did affect the responses to chronic water immersion and restraint stress (WIRS). The PrLD was required for WIRS-sensitive nuclear localization of NFAR2 and WIRS-induced changes in mRNA expression and translation in the amygdala, a fear-related brain region. Consistently, the PrLD conferred resistance to WIRS in fear-associated memory formation. Our study provides insights into the PrLD-dependent role of NFAR2 for chronic stress adaptation in the brain.

[Pulmonary Hematoma Likely due to a Contralateral Chest Injury, Requiring Differentiation from Lung Tumor:Report of a Case].

A 23-year-old man was referred to our department for chest abnormal shadow. Computed tomography (CT) of the chest revealed a well-defined 1.2 cm nodule in the S4 segment of the right middle lobe and a well-defined 1.8 cm nodule in the S10 segment of the right lower lobe. The patient was found to have a fracture in the left fifth rib due to the falling accident at playing snowboard, two months before. He was diagnosed with a benign tumor in the right middle lobe and the right lower lobe and was performed surgery. Thoracoscopy revealed a yellowish-brown tumor in the right middle lobe( S4) and a yellow-brown tumor in the right lower lobe( S10). Both lesions were diagnosed as clots by rapid intraoperative pathologic diagnosis. Histopathological diagnosis was an intrapulmonary hematoma.

Implications of RNG140 (caprin2)-mediated translational regulation in eye lens differentiation.

Regulation of gene expression at the translational level is key to determining cell fate and function. An RNA-binding protein, RNG140 (caprin2), plays a role in eye lens differentiation and has been reported to function in translational regulation. However, the mechanism and its role in eyes has remained unclear. Here, we show that RNG140 binds to the translation initiation factor eukaryotic initiation factor 3 (eIF3) and suppresses translation through mechanisms involving suppression of eIF3-dependent translation initiation. Comprehensive ribosome profiling revealed that overexpression of RNG140 in cultured Chinese hamster ovary cells reduces translation of long mRNAs, including those associated with cell proliferation. RNG140-mediated translational regulation also operates in the mouse eye, where RNG140 knockout increased the translation of long mRNAs. mRNAs involved in lens differentiation, such as crystallin mRNAs, are short and can escape translational inhibition by RNG140 and be translated in differentiating lenses. Thus, this study provides insights into the mechanistic basis of lens cell transition from proliferation to differentiation via RNG140-mediated translational regulation.

A Novel Insertion Technique for the Extra-Long Montgomery T-Tube in Patients with a Large Mediastinal Tumor.

The Montgomery T-tube is widely used to stent airway stenotic diseases. Conventional insertion methods can sometimes fail in the case of long-distance subglottic stenosis due to the flexibility of a T-tube made of silicon, which kinks when forced against resistance. Therefore, an alternative approach can assist in the insertion of an extra-long T-tube, especially when using a long proximal limb. We report herein the case of a patient with a large mediastinal tumor caused by neurofibromatosis type 1 in which airway obstruction was avoided through the use of a novel extra-long T-tube placement technique.

Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior.

Seasonal changes in the environment lead to depression-like behaviors in humans and animals. The underlying mechanisms, however, are unknown. We observed decreased sociability and increased anxiety-like behavior in medaka fish exposed to winter-like conditions. Whole brain metabolomic analysis revealed seasonal changes in 68 metabolites, including neurotransmitters and antioxidants associated with depression. Transcriptome analysis identified 3,306 differentially expressed transcripts, including inflammatory markers, melanopsins, and circadian clock genes. Further analyses revealed seasonal changes in multiple signaling pathways implicated in depression, including the nuclear factor erythroid-derived 2-like 2 (NRF2) antioxidant pathway. A broad-spectrum chemical screen revealed that celastrol (a traditional Chinese medicine) uniquely reversed winter behavior. NRF2 is a celastrol target expressed in the habenula (HB), known to play a critical role in the pathophysiology of depression. Another NRF2 chemical activator phenocopied these effects, and an NRF2 mutant showed decreased sociability. Our study provides important insights into winter depression and offers potential therapeutic targets involving NRF2.

Cataloguing and Selection of mRNAs Localized to Dendrites in Neurons and Regulated by RNA-Binding Proteins in RNA Granules.

Spatiotemporal translational regulation plays a key role in determining cell fate and function. Specifically, in neurons, local translation in dendrites is essential for synaptic plasticity and long-term memory formation. To achieve local translation, RNA-binding proteins in RNA granules regulate target mRNA stability, localization, and translation. To date, mRNAs localized to dendrites have been identified by comprehensive analyses. In addition, mRNAs associated with and regulated by RNA-binding proteins have been identified using various methods in many studies. However, the results obtained from these numerous studies have not been compiled together. In this review, we have catalogued mRNAs that are localized to dendrites and are associated with and regulated by the RNA-binding proteins fragile X mental retardation protein (FMRP), RNA granule protein 105 (RNG105, also known as Caprin1), Ras-GAP SH3 domain binding protein (G3BP), cytoplasmic polyadenylation element binding protein 1 (CPEB1), and staufen double-stranded RNA binding proteins 1 and 2 (Stau1 and Stau2) in RNA granules. This review provides comprehensive information on dendritic mRNAs, the neuronal functions of mRNA-encoded proteins, the association of dendritic mRNAs with RNA-binding proteins in RNA granules, and the effects of RNA-binding proteins on mRNA regulation. These findings provide insights into the mechanistic basis of protein-synthesis-dependent synaptic plasticity and memory formation and contribute to future efforts to understand the physiological implications of local regulation of dendritic mRNAs in neurons.

More dynamic, more quantitative, unexpectedly intricate: Advanced understanding on synaptic RNA localization in learning and memory.

Synaptic signaling exhibits great diversity, complexity, and plasticity which necessitates maintenance and rapid modification of a local proteome. One solution neurons actively exploit to meet such demands is the strategic deposition of mRNAs encoding proteins for both basal and experience-driven activities into ribonucleoprotein complexes at the synapse. Transcripts localized in this manner can be rapidly accessed for translation in response to a diverse range of stimuli in a temporal- and spatially-restricted manner. Here we review recent findings on localized RNAs and RNA binding proteins in the context of learning and memory, as revealed by cutting-edge in-vitro and in-vivo technologies capable of yielding quantitative and dynamic information. The new technologies include proteomic and transcriptomic analyses, high-resolution multiplexed RNA imaging, single-molecule RNA tracking in living neurons, animal models and human neuron cell models. Among many recent advances in the field, RNA chemical modification has emerged as one of the new regulatory layers of gene expression at synapse that is complex and yet largely unexplored. These exciting new discoveries have enhanced our understanding of the modulation mechanisms of synaptic gene expression and their roles in cognition.

Liquid- and solid-like RNA granules form through specific scaffold proteins and combine into biphasic granules.

RNA granules consist of membrane-less RNA-protein assemblies and contain dynamic liquid-like shells and stable solid-like cores, which are thought to function in numerous processes in mRNA sorting and translational regulation. However, how these distinct substructures are formed, whether they are assembled by different scaffolds, and whether different RNA granule scaffolds induce these different substructures remains unknown. Here, using fluorescence microscopy-based morphological and molecular-dynamics analyses, we demonstrate that RNA granule scaffold proteins (scaffolds) can be largely classified into two groups, liquid and solid types, which induce the formation of liquid-like and solid-like granules, respectively, when expressed separately in cultured cells. We found that when co-expressed, the liquid-type and solid-type scaffolds combine and form liquid- and solid-like substructures in the same granules, respectively. The combination of the different types of scaffolds reduced the immobile fractions of the solid-type scaffolds and their dose-dependent ability to decrease nascent polypeptides in granules, but had little effect on the dynamics of the liquid-type scaffolds or their dose-dependent ability to increase nascent polypeptides in granules. These results suggest that solid- and liquid-type scaffolds form different substructures in RNA granules and differentially affect each other. Our findings provide detailed insight into the assembly mechanism and distinct dynamics and functions of core and shell substructures in RNA granules.

Variations of pulmonary vein drainage critical for lung resection assessed by three-dimensional computed tomography angiography.

BACKGROUND: It is important to understand pulmonary vein drainage pattern variations and their frequency in order to perform safe anatomical pulmonary resection. METHODS: Variations and frequencies were assessed using three-dimensional computed tomography angiography (3D-CT) in 194 patients. In cases where the tumor or lymph node caused atelectasis or compression of hilar structures, the involved lobes were excluded from the analyses. RESULTS: We confirmed variant drainage patterns in 15/189 (8.0%) patients in the right upper lobe (RUL), 29/189 (15.3%) in the right middle lobe (RML), 18/192 (9.5%) in the right lower lobe (RLL), and 5/187 (2.6%) in the left upper lobe (LUL). There was no variant type in the left lower lobe (LLL). There were 14 (7.4%) cases of anomalous superior posterior pulmonary vein of RUL (V2 ) drainage: V2 draining to the superior pulmonary vein (SPV) (n = 2, 1.1%), V2 to the inferior pulmonary vein (IPV) (n = 7, 3.7%), V2 to the left atrium (LA) (n = 2, 1.1%), and V6 to the apical pulmonary vein of the RLL (n = 3, 1.6%). There was a posterior pulmonary vein, V3 to RML pulmonary vein in one case (0.5%). The RML pulmonary vein drained into the IPV in 14 (7.4%) and into the LA in 15 (7.9%) cases. The right V6 directly drained into the LA in 15 (7.9%) and V6 into the SPV in 3 (1.6%) cases. The lingular pulmonary vein drained into the IPV in one case (0.5%) and into the LA in two cases (1.1%). The inferior lingular pulmonary vein V5 drained into the IPV and into the LA in one case (0.5%), respectively. CONCLUSION: We describe anomalous pulmonary venous drainage patterns and their frequencies particular to anatomic surgical resection. 3D-CT is useful to find such variations.

RNG105/caprin1, an RNA granule protein for dendritic mRNA localization, is essential for long-term memory formation.

Local regulation of synaptic efficacy is thought to be important for proper networking of neurons and memory formation. Dysregulation of global translation influences long-term memory in mice, but the relevance of the regulation specific for local translation by RNA granules remains elusive. Here, we demonstrate roles of RNG105/caprin1 in long-term memory formation. RNG105 deletion in mice impaired synaptic strength and structural plasticity in hippocampal neurons. Furthermore, RNG105-deficient mice displayed unprecedentedly severe defects in long-term memory formation in spatial and contextual learning tasks. Genome-wide profiling of mRNA distribution in the hippocampus revealed an underlying mechanism: RNG105 deficiency impaired the asymmetric somato-dendritic localization of mRNAs. Particularly, RNG105 deficiency reduced the dendritic localization of mRNAs encoding regulators of AMPAR surface expression, which was consistent with attenuated homeostatic AMPAR scaling in dendrites and reduced synaptic strength. Thus, RNG105 has an essential role, as a key regulator of dendritic mRNA localization, in long-term memory formation.

Comprehensive behavioral analysis of RNG105 (Caprin1) heterozygous mice: Reduced social interaction and attenuated response to novelty.

RNG105 (also known as Caprin1) is a major RNA-binding protein in neuronal RNA granules, and is responsible for mRNA transport to dendrites and neuronal network formation. A recent study reported that a heterozygous mutation in the Rng105 gene was found in an autism spectrum disorder (ASD) patient, but it remains unclear whether there is a causal relation between RNG105 deficiency and ASD. Here, we subjected Rng105(+/-) mice to a comprehensive behavioral test battery, and revealed the influence of RNG105 deficiency on mouse behavior. Rng105(+/-) mice exhibited a reduced sociality in a home cage and a weak preference for social novelty. Consistently, the Rng105(+/-) mice also showed a weak preference for novel objects and novel place patterns. Furthermore, although the Rng105(+/-) mice exhibited normal memory acquisition, they tended to have relative difficulty in reversal learning in the spatial reference tasks. These findings suggest that the RNG105 heterozygous knockout leads to a reduction in sociality, response to novelty and flexibility in learning, which are implicated in ASD-like behavior.

Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity.

Disrupted-in-schizophrenia 1 (DISC1) is a susceptibility gene for major psychiatric disorders, including schizophrenia. DISC1 has been implicated in neurodevelopment in relation to scaffolding signal complexes. Here we used proteomic analysis to screen for DISC1 interactors and identified several RNA-binding proteins, such as hematopoietic zinc finger (HZF), that act as components of RNA-transporting granules. HZF participates in the mRNA localization of inositol-1,4,5-trisphosphate receptor type 1 (ITPR1), which plays a key role in synaptic plasticity. DISC1 colocalizes with HZF and ITPR1 mRNA in hippocampal dendrites and directly associates with neuronal mRNAs, including ITPR1 mRNA. The binding potential of DISC1 for ITPR1 mRNA is facilitated by HZF. Studies of Disc1-knockout mice have revealed that DISC1 regulates the dendritic transport of Itpr1 mRNA by directly interacting with its mRNA. The DISC1-mediated mRNA regulation is involved in synaptic plasticity. We show that DISC1 binds ITPR1 mRNA with HZF, thereby regulating its dendritic transport for synaptic plasticity.

RNA granule assembly and disassembly modulated by nuclear factor associated with double-stranded RNA 2 and nuclear factor 45.

RNA granules are large messenger ribonucleoprotein complexes that regulate translation and mRNA translocation to control the timing and location of protein synthesis. The regulation of RNA granule assembly and disassembly is a structural basis of translational control, and its disorder is implicated in degenerative disease. Here, we used proteomic analysis to identify proteins associated with RNA granule protein 105 (RNG105)/caprin1, an RNA-binding protein in RNA granules. Among the identified proteins, we focused on nuclear factor (NF) 45 and its binding partner, nuclear factor associated with dsRNA 2 (NFAR2), and we demonstrated that NF45 promotes disassembly of RNA granules, whereas NFAR2 enhances the assembly of RNA granules in cultured cells. The GQSY domain of NFAR2 was required to associate with messenger ribonucleoprotein complexes containing RNG105/caprin1, and it was structurally and functionally related to the low complexity sequence domain of the fused in sarcoma protein, which drives the assembly of RNA granules. Another domain of NFAR2, the DZF domain, was dispensable for association with the RNG105 complex, but it was involved in positive and negative regulation of RNA granule assembly by being phosphorylated at double-stranded RNA-activated kinase sites and by association with NF45, respectively. These results suggest a novel molecular mechanism for the modulation of RNA granule assembly and disassembly by NFAR2, NF45, and phosphorylation at double-stranded RNA-activated kinase PKR sites.

Left lobectomy might be a risk factor for atrial fibrillation following pulmonary lobectomy.

OBJECTIVE: To identify risk factors for atrial fibrillation (AF) following lobectomy for a pulmonary malignant tumour. METHODS: The outcomes of patients who underwent lobectomy from February 2005 to September 2010 were analysed with respect to the development of postoperative AF. RESULTS: Among 186 patients, 20 developed AF and these had significantly higher preoperative B-type natriuretic peptide (BNP) than those without AF. A significantly high incidence of AF following pulmonary lobectomy was demonstrated in the group of patients who were male, underwent a thoracotomy, had a high preoperative value of BNP and underwent a left lobectomy. Multivariate analysis revealed that left lobectomy is the only independent risk factor. The area under the receiver-operating characteristic curve for BNP to predict postoperative AF following a left lobectomy for a pulmonary malignant tumour was 0.82 (95% confidence interval 0.70-0.93; P<0.05). A BNP level of 24.1 pg/ml had a sensitivity of 90.9% and a specificity of 56% for predicting postoperative AF following left lobectomy for a pulmonary malignant tumour. CONCLUSIONS: Left lobectomy is the only independent risk factor for postoperative AF. Elevated BNP is the risk factor for postoperative AF in patients undergoing left pulmonary lobectomy.

RNG105 deficiency impairs the dendritic localization of mRNAs for Na+/K+ ATPase subunit isoforms and leads to the degeneration of neuronal networks.

mRNA transport and local translation in dendrites play key roles in use-dependent synaptic modification and in higher-order brain functions. RNG105, an RNA-binding protein, has previously been identified as a component of RNA granules that mediate dendritic mRNA localization and local translation. Here, we demonstrate that RNG105 knock-out in mice reduces the dendritic localization of mRNAs for Na+/K+ ATPase (NKA) subunit isoforms (i.e., α3, FXYD1, FXYD6, and FXYD7). The loss of dendritic mRNA localization is accompanied by the loss of function of NKA in dendrites without affecting the NKA function in the soma. Furthermore, we show that RNG105 deficiency affects the formation and maintenance of synapses and neuronal networks. These phenotypes are partly explained by an inhibition of NKA, which is known to influence synaptic functions as well as susceptibility to neurotoxicity. The present study first demonstrates the in vivo role of RNG105 in the dendritic localization of mRNAs and uncovers a novel link between dendritic mRNA localization and the development and maintenance of functional networks.

RNA granule protein 140 (RNG140), a paralog of RNG105 localized to distinct RNA granules in neuronal dendrites in the adult vertebrate brain.

RNA granules mediate the transport and local translation of their mRNA cargoes, which regulate cellular processes such as stress response and neuronal synaptic plasticity. RNA granules contain specific RNA-binding proteins, including RNA granule protein 105 (RNG105), which is likely to participate in the transport and translation of mRNAs. In the present report, an RNG105 paralog, RNG140 is described. A homolog of RNG105/RNG140 is found in insects, echinoderms, and urochordates, whereas vertebrates have both of the two genes. RNG140 and RNG105 are similar in that both bind to mRNAs and inhibit translation in vitro, induce the formation of RNA granules, are most highly expressed in the brain, and are localized to dendritic RNA granules, part of which are accumulated at postsynapses. However, they differ in several characteristics; RNG105 is highly expressed in embryonic brains, whereas RNG140 is highly expressed in adult brains. Furthermore, the granules where RNG105 or RNG140 is localized are distinct RNA granules in both cultured cells and neuronal dendrites. Thus, RNG140 is an RNA-binding protein that shows different expression and localization patterns from RNG105. Knockdown experiments in cultured neurons also are performed, which demonstrate that suppression of RNG140 or RNG105 reduces dendrite length and spine density. Knockdown effects of RNG140 were not rescued by RNG105, and vise versa, suggesting distinct roles of RNG105 and RNG140. These results suggest that RNG140 has roles in the maintenance of the dendritic structure in the adult vertebrate brain through localizing to a kind of RNA granules that are distinct from RNG105-containing granules.

Isolation and characterization of l-rhamnose-binding lectin, which binds to microsporidian Glugea plecoglossi, from ayu (Plecoglossus altivelis) eggs.

A rhamnose-binding lectin, named SFL, was isolated from the eggs of ayu (sweet fish, Plecoglossus altivelis) by affinity and ion-exchange chromatographies. SFL revealed 287 amino acid residues with 3 tandemly repeated domains, and contained 8 half-Cys residues in each domain. The lectin was shown to have a highly specific binding affinity to globotriaosylceramide (Gb3) by frontal affinity chromatography using 100 oligosaccharides. SFL was localized in several tissues and serum of both male and female ayu, such as gill, liver, ovary, testis, intestine, stomach, brain, kidney and serum. The lectin agglutinated the spores of the microsporidian Glugea plecoglossi, which is a pathogen of ayu. Although SFL bound to glycoproteins and glycolipids of G. plecoglossi spores, Gb3 could not be detected in either of them. The results suggest that SFL could interact with various glycoconjugates of pathogens to play a role in the adhesion of microorganisms invading in the body.