Measuring integrated information from the decoding perspective

Accumulating evidence indicates that the capacity to integrate information in the brain is a prerequisite for consciousness. Integrated Information Theory (IIT) of consciousness provides a mathematical approach to quantifying the information integrated in a system, called integrated information, $\Phi$. Integrated information is defined theoretically as the amount of information a system generates as a whole, above and beyond the sum of the amount of information its parts independently generate. IIT predicts that the amount of integrated information in the brain should reflect levels of consciousness. Empirical evaluation of this theory requires computing integrated information from neural data acquired from experiments, although difficulties with using the original measure $\Phi$ precludes such computations. Although some practical measures have been previously proposed, we found that these measures fail to satisfy the theoretical requirements as a measure of integrated information. Measures of integrated information should satisfy the lower and upper bounds as follows: The lower bound of integrated information should be 0 when the system does not generate information (no information) or when the system comprises independent parts (no integration). The upper bound of integrated information is the amount of information generated by the whole system and is realized when the amount of information generated independently by its parts equals to 0. Here we derive the novel practical measure $\Phi^*$ by introducing a concept of mismatched decoding developed from information theory. We show that $\Phi^*$ is properly bounded from below and above, as required, as a measure of integrated information. We derive the analytical expression $\Phi^*$ under the Gaussian assumption, which makes it readily applicable to experimental data

Nrf2-p62ダブルノックアウトを用いたオートファジー異常による肝発癌の解析

科学研究費助成事業 研究成果報告書：基盤研究(B)2015-2017課題番号 : 15H0491

Medication-Related Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) is a common side effect of antiresorptive drugs that are administered to cancer patients for bone metastasis, multiple myeloma, and osteoporosis. Since both bisphosphonate (BP) and denosumab show anti-bone resorption effects with ONJ, antiresorptive agent-related ONJ (ARONJ) has been suggested as a comprehensive term encompassing both BP-related osteonecrosis of the jaw (BRONJ) and denosumab-related osteonecrosis of the jaw (DRONJ). The term medication-related osteonecrosis of the jaw (MRONJ) is proposed as ARONJ with the antiangiogenic inhibitors or molecularly targeted drugs-related ONJ. Suppression of bone remodeling may contribute to the development of osteonecrosis and results in inadequate osteoclast activity to allow healing of the extraction socket. Infection is a major factor in the development of MRONJ. The major treatment goals for patients at risk of developing or who have MRONJ are prioritization and support of continued oncologic treatment in patients receiving antiresorptive and antiangiogenic therapy. To minimize the development of MRONJ in patients at risk, regular dental examinations are encouraged. Oral hygiene should be improved and local infection is managed as early as possible. The use of antibiotics before and after oral surgical procedures has been demonstrated to lower the risk of MRONJ

Targeted expression of stepfunction opsins in transgenic rats for optogenetic studies

Abstract Rats are excellent animal models for experimental neuroscience. However, the application of optogenetics in rats has been hindered because of the limited number of established transgenic rat strains. To accomplish cell-type specific targeting of an optimized optogenetic molecular tool, we generated ROSA26/CAG-floxed STOP-ChRFR(C167A)-Venus BAC rats that conditionally express the step-function mutant channelrhodopsin ChRFR(C167A) under the control of extrinsic Cre recombinase. In primary cultured cortical neurons derived from this reporter rat, only Cre-positive cells expressing ChRFR(C167A) became bi-stable, that is, their excitability was enhanced by blue light and returned to the baseline by yellow~red light. In bigenic pups carrying the Phox2B-Cre driver, ChRFR(C167A) was specifically expressed in the rostral parafacial respiratory group (pFRG) in the medulla, where endogenous Phox2b immunoreactivity was detected. These neurons were sensitive to blue light with an increase in the firing frequency. Thus, this transgenic rat actuator/reporter system should facilitate optogenetic studies involving the effective in vivo manipulation of the activities of specific cell fractions using light of minimal intensity

Exercise training enhances in vivo clearance of endotoxin and attenuates inflammatory responses by potentiating Kupffer cell phagocytosis

The failure of Kupffer cells (KCs) to remove endotoxin is an important factor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In this study, the effects of exercise training on KC function were studied in terms of in vivo endotoxin clearance and inflammatory responses. Mice were allocated into rest and exercise groups. KC bead phagocytic capacity and plasma steroid hormone levels were determined following exercise training. Endotoxin and inflammatory cytokine levels in plasma were determined over time following endotoxin injection. KC bead phagocytic capacity was potentiated and clearance of exogenously-injected endotoxin was increased in the exercise group. Inflammatory cytokine (TNF-α and IL-6) levels were lower in the exercise group. We found that only DHEA was increased in the plasma of the exercise group. In an in vitro experiment, the addition of DHEA to RAW264.7 cells increased bead phagocytic capacity and attenuated endotoxin-induced inflammatory responses. These results suggest that exercise training modulates in vivo endotoxin clearance and inflammatory responses in association with increased DHEA production. These exercise-induced changes in KC capacity may contribute to a slowing of disease progression in NAFLD patients

Exercise habituation is effective for improvement of periodontal disease status: a prospective intervention study

Background and purpose: Periodontal disease is closely related to lifestyle-related diseases and obesity. It is widely known that moderate exercise habits lead to improvement in lifestyle-related diseases and obesity. However, little research has been undertaken into how exercise habits affect periodontal disease. The purpose of this study was to examine the effect of exercise habits on periodontal diseases and metabolic pathology.Methods: We conducted a prospective intervention research for 12 weeks. The subjects were 71 obese men who participated in an exercise and/or dietary intervention program. Fifty subjects were assigned to exercise interventions (exercise intervention group) and 21 subjects were assigned to dietary interventions (dietary intervention group). This research was conducted before and after each intervention program.Results: In the exercise intervention group, the number of teeth with a probing pocket depth (PPD) ≥4 mm significantly decreased from 14.4% to 5.6% (P<0.001), and the number of teeth with bleeding on probing (BOP) significantly decreased from 39.8% to 14.4% (P<0.001). The copy counts of Tannerella forsythia and Treponema denticola decreased significantly (P=0.001). A positive correlation was found between the change in the copy count of T. denticola and the number of teeth with PPD ≥4 mm (P=0.003) and the number of teeth with BOP (P=0.010). A positive correlation was also found between the change in the copy count of T. denticola and body weight (P=0.008), low-density lipoprotein cholesterol (P=0.049), and fasting insulin (P=0.041). However, in the dietary intervention group the copy count of T. denticola decreased significantly (P=0.007) and there was no correlation between the number of periodontal disease-causing bacteria and PPD and BOP.Conclusion: Our results are the first to show that exercise might contribute to improvements in periodontal disease

Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B

Calcium/calmodulin-dependent serine protein kinase (CASK) is a membrane-associated guanylate kinase (MAGUK) protein that is associated with neurodevelopmental disorders. CASK is thought to have both pre- and postsynaptic functions, but the mechanism and consequences of its functions in the brain have yet to be elucidated, because homozygous CASK-knockout (CASK-KO) mice die before brain maturation. Taking advantage of the X-chromosome inactivation (XCI) mechanism, here we examined the synaptic functions of CASK-KO neurons in acute brain slices of heterozygous CASK-KO female mice. We also analyzed CASK-knockdown (KD) neurons in acute brain slices generated by in utero electroporation. Both CASK-KO and CASK-KD neurons showed a disruption of the excitatory and inhibitory (E/I) balance. We further found that the expression level of the N-methyl-d-aspartate receptor subunit GluN2B was decreased in CASK-KD neurons and that overexpressing GluN2B rescued the disrupted E/I balance in CASK-KD neurons. These results suggest that the down-regulation of GluN2B may be involved in the mechanism of the disruption of synaptic E/I balance in CASK-deficient neurons

Deletion of both p62 and Nrf2 spontaneously results in the development of nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is one of the leading causes of chronic liver disease worldwide. However, details of pathogenetic mechanisms remain unknown. Deletion of both p62/Sqstm1 and Nrf2 genes spontaneously led to the development of NASH in mice fed a normal chow and was associated with liver tumorigenesis. The pathogenetic mechanism (s) underlying the NASH development was investigated in p62:Nrf2 double-knockout (DKO) mice. DKO mice showed massive hepatomegaly and steatohepatitis with fat accumulation and had hyperphagia-induced obesity coupled with insulin resistance and adipokine imbalance. They also showed dysbiosis associated with an increased proportion of gram-negative bacteria species and an increased lipopolysaccharide (LPS) level in feces. Intestinal permeability was elevated in association with both epithelial damage and decreased expression levels of tight junction protein zona occludens-1, and thereby LPS levels were increased in serum. For Kupffer cells, the foreign body phagocytic capacity was decreased in magnetic resonance imaging, and the proportion of M1 cells was increased in DKO mice. In vitro experiments showed that the inflammatory response was accelerated in the p62:Nrf2 double-deficient Kupffer cells when challenged with a low dose of LPS. Diet restriction improved the hepatic conditions of NASH in association with improved dysbiosis and decreased LPS levels. The results suggest that in DKO mice, activation of innate immunity by excessive LPS flux from the intestines, occurring both within and outside the liver, is central to the development of hepatic damage in the form of NASH

Development of a novel automatic ascites filtration and concentration equipment with multi‐ring‐type roller pump units for cell‐free and concentrated ascites reinfusion therapy

Cell‐free and concentrated ascites reinfusion therapy (CART) is an effective therapy for refractory ascites. However, CART is difficult to perform as ascites filtration and concentration is a complicated procedure. Moreover, the procedure requires the constant assistance of a clinical engineer or/and the use of an expensive equipment for the multi‐purpose blood processing. Therefore, we developed a CART specialized equipment (mobility CART [M‐CART]) that could be used safely with various safety measures and automatic functions such as automatic washing of clogged filtration filter and self‐regulation of the concentration ratio. Downsizing, lightning of the weight, and automatic processing in M‐CART required the use of newly developed multi‐ring‐type roller pump units. This equipment was approved under Japanese regulations in 2018. In performing 41 sessions of CART (for malignant ascites, 22 sessions; and hepatic ascites, 19 sessions) using this equipment in 17 patients, no serious adverse event occurred. An average of 4494 g of ascites was collected and the total amount of ascites was processed in all the sessions without any trouble. The mean weight of the processed ascites was 560 g and the mean concentration ratio was 8.0. The ascites were processed at a flow rate of 50 mL/min. The mean ascites processing time was 112.5 minutes and a 106.5‐minutes (95.2%) ascites processing was performed automatically. The operator responded to alarms or support information 3.2 times on average (3.1 minutes, 2.1% of ascites processing time). Human errors related to ascites processing were detected by M‐CART at 0.4 times per session on average and were appropriately addressed by the operator. The frequencies of automatic washing of clogged filtration filter and self‐regulation of the concentration ratio were 31.7% and 53.7%, respectively. The mean recovery rates (recovery dose) of protein, albumin, and immunoglobulin G were 72.9%, 72.9%, and 71.2% (65.9 g, 34.9 g, and 13.2 g), respectively. Steroids were administered in 92.7% of the sessions to prevent fever and the mean increase in body temperature was 0.53°C. M‐CART is a compact and lightweight automatic CART specialized equipment that can safely and easily process a large quantity of ascites without the constant assistance of an operator