Sleep Dissolves Illusion: Sleep Withstands Learning of Visuo-Tactile-Proprioceptive Integration Induced by Repeated Days of Rubber Hand Illusion Training

Multisensory integration is a key factor in establishing bodily self-consciousness and in adapting humans to novel environments. The rubber hand illusion paradigm, in which humans can immediately perceive illusory ownership to an artificial hand, is a traditional technique for investigating multisensory integration and the feeling of illusory ownership. However, the long-term learning properties of the rubber hand illusion have not been previously investigated. Moreover, although sleep contributes to various aspects of cognition, including learning and memory, its influence on illusory learning of the artificial hand has not yet been assessed. We determined the effects of daily repetitive training and sleep on learning visuo-tactile-proprioceptive sensory integration and illusory ownership in healthy adult participants by using the traditional rubber hand illusion paradigm. Subjective ownership of the rubber hand, proprioceptive drift, and galvanic skin response were measured to assess learning indexes. Subjective ownership was maintained and proprioceptive drift increased with daily training. Proprioceptive drift, but not subjective ownership, was significantly attenuated after sleep. A significantly greater reduction in galvanic skin response was observed after wakefulness compared to after sleep. Our results suggest that although repetitive rubber hand illusion training facilitates multisensory integration and physiological habituation of a multisensory incongruent environment, sleep corrects illusional integration and habituation based on experiences in a multisensory incongruent environment. These findings may increase our understanding of adaptive neural processes to novel environments, specifically, bodily self-consciousness and sleep-dependent neuroplasticity.     

Leukoaraiosis Significantly Worsens Driving Performance of Ordinary Older Drivers

Background

Leukoaraiosis is defined as extracellular space caused mainly by atherosclerotic or demyelinated changes in the brain tissue and is commonly found in the brains of healthy older people. A significant association between leukoaraiosis and traffic crashes was reported in our previous study; however, the reason for this is still unclear.

Method

This paper presents a comprehensive evaluation of driving performance in ordinary older drivers with leukoaraiosis. First, the degree of leukoaraiosis was examined in 33 participants, who underwent an actual-vehicle driving examination on a standard driving course, and a driver skill rating was also collected while the driver carried out a paced auditory serial addition test, which is a calculating task given verbally. At the same time, a steering entropy method was used to estimate steering operation performance.

Results

The experimental results indicated that a normal older driver with leukoaraiosis was readily affected by external disturbances and made more operation errors and steered less smoothly than one without leukoaraiosis during driving; at the same time, their steering skill significantly deteriorated.

Conclusions

Leukoaraiosis worsens the driving performance of older drivers because of their increased vulnerability to distraction.     

Controlled Administration of Penicillamine Reduces Radiation Exposure in Critical Organs during 64Cu-ATSM Internal Radiotherapy: A Novel Strategy for Liver Protection

Purpose

⁶⁴Cu-diacetyl-bis (N ⁴-methylthiosemicarbazone) (⁶⁴Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with ⁶⁴Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during ⁶⁴Cu-ATSM IRT.

Methods

Biodistribution was evaluated in HT-29 tumor-bearing mice injected with ⁶⁴Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between ⁶⁴Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after ⁶⁴Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic ⁶⁴Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses.

Results

Penicillamine reduced ⁶⁴Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after ⁶⁴Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic ⁶⁴Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine.

Conclusions

We developed a novel strategy to reduce radiation exposure in critical organs during ⁶⁴Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other ⁶⁴Cu-labeled compounds.     

Mutations affecting gonadal development in Medaka, Oryzias latipes

A gonad is formed from germ cells and somatic mesodermal cells through their interactions. Its development is coupled with the determination and differentiation of the sex and sex-associated traits. We carried out a large-scale screening of Medaka mutants in which gonadal development is affected. Screening was performed on larvae at 8 days posthatching for abnormal abundance and/or distribution of germ cells detected by the in situ hybridization for olvas (Medaka vasa). We describe here 16 mutants of 13 genes, which are classified into four groups. Group 1, consisting of four mutants of three genes kon, tot) characterised by an increase in germ cell number. An adult tot homozygote fish has the characteristic feature of possessing hypertrophic gonads filled with immature oocytes. Group 2, represented by a single gene (zen) mutant characterized by a gradual loss of germ cells. Group 3, consisting of four mutants of distinct genes (eko, eki, sht, ano) showing irregular clustering of germ cells. Group 4, consisting of seven mutants of five genes (arr, hyo, mzr, hdr, fbk) showing fragmented clusters of germ cells. In some mutants belonging to Groups 1, 3 and 4, the expression level of ftz-f1 (sf-1/Ad4BP) in gonadal somatic cells significantly decreased, suggesting that interaction between somatic and germ cells is affected.     

Expansion of unconventional T cells with natural killer markers in malaria patients

Immunological states during human malarial infection were examined. In parallel with parasitemia and anemia, granulocytosis was induced in the blood of patients, especially those infected with Plasmodium (P.) falciparum. At that time, the level of lymphocytes remained unchanged or slightly increased in the blood. However, the distribution of lymphocyte subsets was modulated, showing that the proportion of CD56(+)T cells, CD57(+)T cells, and gammadeltaT cells (i.e. all unconventional T cells) had increased in patients infected with P. falciparum or P. vivax. This phenomenon occurred at the early phase of infection and disappeared in the course of recovery. The data from patients with multiple attacks of P. vivax infection showed that there was no augmentation of these responses. In adult cases, the increase in the proportion of unconventional T cells seemed to closely parallel disease severity. However, all these responses were weak in children, even those infected with P. falciparum. In conjunction with accumulating evidence from mouse malaria experiments, the present results suggest that the immunological state induced by malarial infection might mainly be an event of unconventional T cells and that the immunological memory might not be long-lasting, possibly due to the properties of unconventional T cells.     

Large-Scale Gene Disruption in Magnaporthe oryzae Identifies MC69, a Secreted Protein Required for Infection by Monocot and Dicot Fungal Pathogens

To search for virulence effector genes of the rice blast fungus, Magnaporthe oryzae, we carried out a large-scale targeted disruption of genes for 78 putative secreted proteins that are expressed during the early stages of infection of M. oryzae. Disruption of the majority of genes did not affect growth, conidiation, or pathogenicity of M. oryzae. One exception was the gene MC69. The mc69 mutant showed a severe reduction in blast symptoms on rice and barley, indicating the importance of MC69 for pathogenicity of M. oryzae. The mc69 mutant did not exhibit changes in saprophytic growth and conidiation. Microscopic analysis of infection behavior in the mc69 mutant revealed that MC69 is dispensable for appressorium formation. However, mc69 mutant failed to develop invasive hyphae after appressorium formation in rice leaf sheath, indicating a critical role of MC69 in interaction with host plants. MC69 encodes a hypothetical 54 amino acids protein with a signal peptide. Live-cell imaging suggested that fluorescently labeled MC69 was not translocated into rice cytoplasm. Site-directed mutagenesis of two conserved cysteine residues (Cys36 and Cys46) in the mature MC69 impaired function of MC69 without affecting its secretion, suggesting the importance of the disulfide bond in MC69 pathogenicity function. Furthermore, deletion of the MC69 orthologous gene reduced pathogenicity of the cucumber anthracnose fungus Colletotrichum orbiculare on both cucumber and Nicotiana benthamiana leaves. We conclude that MC69 is a secreted pathogenicity protein commonly required for infection of two different plant pathogenic fungi, M. oryzae and C. orbiculare pathogenic on monocot and dicot plants, respectively.     

Procyanidin B3 prevents articular cartilage degeneration and heterotopic cartilage formation in a mouse surgical osteoarthritis model

Osteoarthritis (OA) is a common disease in the elderly due to an imbalance in cartilage degradation and synthesis. Heterotopic ossification (HO) occurs when ectopic masses of endochondral bone form within the soft tissues around the joints and is triggered by inflammation of the soft tissues. Procyanidin B3 (B3) is a procyanidin dimer that is widely studied due to its high abundance in the human diet and antioxidant activity. Here, we evaluated the role of B3 isolated from grape seeds in the maintenance of chondrocytes in vitro and in vivo. We observed that B3 inhibited H(2)O(2)-induced apoptosis in primary chondrocytes, suppressed H(2)O(2)- or IL-1?-induced nitric oxide synthase (iNOS) production, and prevented IL-1?-induced suppression of chondrocyte differentiation marker gene expression in primary chondrocytes. Moreover, B3 treatment enhanced the early differentiation of ATDC5 cells. To examine whether B3 prevents cartilage destruction in vivo, OA was surgically induced in C57BL/6J mice followed by oral administration of B3 or vehicle control. Daily oral B3 administration protected articular cartilage from OA and prevented chondrocyte apoptosis in surgically-induced OA joints. Furthermore, B3 administration prevented heterotopic cartilage formation near the surgical region. iNOS protein expression was enhanced in the synovial tissues and the pseudocapsule around the surgical region in OA mice fed a control diet, but was reduced in mice that received B3. Together, these data indicated that in the OA model, B3 prevented OA progression and heterotopic cartilage formation, at least in a part through the suppression of iNOS. These results support the potential therapeutic benefits of B3 for treatment of human OA and heterotopic ossification.     

Claudin 1 mediates TNFα-induced gene expression and cell migration in human lung carcinoma cells

Epithelial-mesenchymal transition (EMT) is an important mechanism in carcinogenesis. To determine the mechanisms that are involved in the regulation of EMT, it is crucial to develop new biomarkers and therapeutic targets towards cancers. In this study, when TGFβ1 and TNFα were used to induce EMT in human lung carcinoma A549 cells, we found an increase in an epithelial cell tight junction marker, Claudin 1. We further identified that it was the TNFα and not the TGFβ1 that induced the fibroblast-like morphology changes. TNFα also caused the increase in Claudin-1 gene expression and protein levels in Triton X-100 soluble cytoplasm fraction. Down-regulation of Claudin-1, using small interfering RNA (siRNA), inhibited 75% of TNFα-induced gene expression changes. Claudin-1 siRNA effectively blocked TNFα-induced molecular functional networks related to inflammation and cell movement. Claudin-1 siRNA was able to significantly reduce TNF-enhanced cell migration and fibroblast-like morphology. Furthermore, over expression of Claudin 1 with a Claudin 1-pcDNA3.1/V5-His vector enhanced cell migration. In conclusion, these observations indicate that Claudin 1 acts as a critical signal mediator in TNFα-induced gene expression and cell migration in human lung cancer cells. Further analyses of these cellular processes may be helpful in developing novel therapeutic strategies.