Cleavage of Hsp70.1 causes lysosomal cell death under stress conditions.

Autophagy mediates the degradation of intracellular macromolecules and organelles within lysosomes. There are three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Heat shock protein 70.1 (Hsp70.1) exhibits dual functions as a chaperone protein and a lysosomal membrane stabilizer. Since chaperone-mediated autophagy participates in the recycling of ∼30% cytosolic proteins, its disorder causes cell susceptibility to stress conditions. Cargo proteins destined for degradation such as amyloid precursor protein and tau protein are trafficked by Hsp70.1 from the cytosol into lysosomes. Hsp70.1 is composed of an N-terminal nucleotide-binding domain (NBD) and a C-terminal domain that binds to cargo proteins, termed the substrate-binding domain (SBD). The NBD and SBD are connected by the interdomain linker LL1, which modulates the allosteric structure of Hsp70.1 in response to ADP/ATP binding. After the passage of the Hsp70.1-cargo complex through the lysosomal limiting membrane, high-affinity binding of the positive-charged SBD with negative-charged bis(monoacylglycero)phosphate (BMP) at the internal vesicular membranes activates acid sphingomyelinase to generate ceramide for stabilizing lysosomal membranes. As the integrity of the lysosomal limiting membrane is critical to ensure cargo protein degradation within the acidic lumen, the disintegration of the lysosomal limiting membrane is lethal to cells. After the intake of high-fat diets, however, ß-oxidation of fatty acids in the mitochondria generates reactive oxygen species, which enhance the oxidation of membrane linoleic acids to produce 4-hydroxy-2-nonenal (4-HNE). In addition, 4-HNE is produced during the heating of linoleic acid-rich vegetable oils and incorporated into the body via deep-fried foods. This endogenous and exogenous 4-HNE synergically causes an increase in its serum and organ levels to induce carbonylation of Hsp70.1 at Arg469, which facilitates its conformational change and access of activated µ-calpain to LL1. Therefore, the cleavage of Hsp70.1 occurs prior to its influx into the lysosomal lumen, which leads to lysosomal membrane permeabilization/rupture. The resultant leakage of cathepsins is responsible for lysosomal cell death, which would be one of the causative factors of lifestyle-related diseases.

Synchrotron speciation of umbilical cord mercury and selenium after environmental exposure in Niigata.

The insidious and deadly nature of mercury's organometallic compounds is informed by two large scale poisonings due to industrial mercury pollution that occurred decades ago in Minamata and Niigata, Japan. The present study examined chemical speciation for both mercury and selenium in a historic umbilical cord sample from a child born to a mother who lived near the Agano River in Niigata. The mother had experienced mercury exposure leading to more than 50 ppm mercury measured in her hair and was symptomatic 9 years prior to the birth. We sought to determine the mercury and selenium speciation in the child's cord using Hg Lα1 and Se Kα1 high-energy resolution fluorescence detected X-ray absorption spectroscopy, the chemical speciation of mercury was found to be predominantly organometallic and coordinated to a thiolate. The selenium was found to be primarily in an organic form and at levels higher than those of mercury, with no evidence of mercury-selenium chemical species. Our results are consistent with mercury exposure at Niigata being due to exposure to organometallic mercury species.

Prenatal and postnatal methyl mercury exposure in Niigata, Japan: adult outcomes.

Methyl mercury (MeHg) poisoning or Minamata disease (MD) from fish consumption is a public health concern throughout the world because all fish contain small amounts. The lowest exposure level needed to impair children's development is controversial. Actual poisoning with MeHg from fish consumption has been reliably reported only two times. It occurred in Minamata, Japan in the 1950s and then in Niigata, Japan in the 1960s. On each occasion, massive industrial pollution led to local fish having mercury levels as high as 40ppm. In Niigata the pollution was on the Agano River and there were over 2000 commercial fishermen active at that time. We studied adult subjects who had been exposed perinatally to MeHg from fish consumption during the Niigata poisoning to determine the long-term impact of exposure. We identified mothers with elevated levels of exposure during the epidemic and those diagnosed with MeHg poisoning. The subjects of the study were their adult children, born during the epidemic. The evaluation consisted of a questionnaire (administered by interview) focusing on development, symptoms, and current function and a standard medical and neurological examination. The subjects were divided into four groups based upon prenatal levels of mercury in maternal hair or the presence of MD. For Group A the hair mercury levels were 50ppm or more, for Group B the mercury levels were 25-49ppm, and for Group C 10-24ppm. The subjects in Group D were born to mothers diagnosed with MD, but their mercury levels were not measured. Exposure was predominantly prenatal, but some mothers also breast fed their infants. Group A included 13 subjects among whom two were diagnosed with congenital MeHg poisoning and in two others it was suspected. Group B included 10 subjects, of whom three had symptoms compatible with MeHg poisoning. Group C had nine subjects including one with intellectual deficit and another with hearing loss. Group D had eight subjects of whom four had symptoms compatible with MeHg exposure, but only one had abnormal neurological findings. Among the subjects thought to have congenital or childhood MeHg poisoning, intelligence did not appear to have declined over time. More children were affected by prenatal and postnatal MeHg exposure at Niigata than was previously reported.

Congenital Minamata disease: a description of two cases in Niigata.

Minamata disease or methyl mercury poisoning from industrial pollution was first described from Minamata, Japan in the 1950s. Subsequently, a similar poisoning episode occurred at Niigata, Japan in the 1960s. This paper describes the Minamata event and then presents two case reports believed to be prenatal poisoning from consumption of contaminated fish at Niigata. Case number one is of special interest because it is the only subject with congenital Minamata disease for whom exposure was actually measured near the time of birth.

Explanation of Fitts' law in Reaching Movement based on Human Arm Dynamics.

Why does Fitts' law fit various human behavioural data well even though it is not a model based on human physical dynamics? To clarify this, we derived the relationships among the factors applied in Fitts' law-movement duration and spatial endpoint error-based on a multi-joint forward- and inverse-dynamics models in the presence of signal-dependent noise. As a result, the relationship between them was modelled as an inverse proportion. To validate whether the endpoint error calculated by the model can represent the endpoint error of actual movements, we conducted a behavioural experiment in which centre-out reaching movements were performed under temporal constraints in four directions using the shoulder and elbow joints. The result showed that the distributions of model endpoint error closely expressed the observed endpoint error distributions. Furthermore, the model was found to be nearly consistent with Fitts' law. Further analysis revealed that the coefficients of Fitts' law could be expressed by arm dynamics and signal-dependent noise parameters. Consequently, our answer to the question above is: Fitts' law for reaching movements can be expressed based on human arm dynamics; thus, Fitts' law closely fits human's behavioural data under various conditions.

Lower urinary tract symptoms in patients with Niigata Minamata disease: a case-control study 50 years after methyl mercury pollution.

OBJECTIVES: To clarify the prevalence of lower urinary tract symptoms and overactive bladder in patients with chronic methyl mercury poisoning. METHODS: A total of 151 patients (61 men and 90 women; mean age 72.1 years) with Niigata Minamata disease were enrolled. An age- and sex-matched group of 150 participants was used as control. Patients reported their International Prostate Symptom Score and overactive bladder symptom score. RESULTS: In men, the total, storage and voiding International Prostate Symptom Score scores were higher in the Niigata Minamata disease group than in the control group (10.6 ± 7.8 vs 5.0 ± 5.0, 4.5 ± 3.3 vs 2.4 ± 2.4 and 6.1 ± 5.1 vs 2.7 ± 3.1, respectively, P < 0.001 in all). In women, these scores were also higher in the Niigata Minamata disease group than in the control group (8.9 ± 7.3 vs 4.0 ± 4.0, 4.4 ± 3.2 vs 2.8 ± 2.4 and 4.5 ± 5.0 vs 1.3 ± 2.0, respectively, P < 0.001 in all). The prevalence of overactive bladder was more frequent in the Niigata Minamata disease group compared with that in the control group (51.7% vs 26.7%, P < 0.001). In both men and women, the overactive bladder symptom score was higher in the Niigata Minamata disease group than in the control group (4.1 ± 3.0 vs 2.4 ± 2.9, P = 0.002 and 4.6 ± 3.6 vs 2.7 ± 2.9, P < 0.001, respectively). The International Prostate Symptom Score and overactive bladder symptom score in the Niigata Minamata disease group were highest in patients aged 60-69 years (P < 0.001 in both), whereas these increased in an age-dependent manner in the control group. CONCLUSIONS: Lower urinary tract symptoms and overactive bladder are severe and highly prevalent conditions among patients with methyl mercury poisoning. The higher prevalence of lower urinary tract symptoms among patients aged 60-69 years might be related to the fact that they were exposed to methyl mercury during their childhood/development.

Methyl mercury exposure at Niigata, Japan: results of neurological examinations of 103 adults.

BACKGROUND: Large-scale poisonings caused by methyl mercury (MeHg) have occurred in Japan (Minamata in the 1950s and Niigata in the 1960s) and Iraq (in the 1970s). The current WHO neurological risk standard for adult exposure (hair level: 50 µg/g) was based partly on evidence from Niigata which did not consider any cases who were diagnosed later and/or exposed to low level of MeHg (hair mercury level less than 50 µg/g). METHODS: Early in the Niigata epidemic in June 1965 there were two extensive surveys. From these two surveys, we examined 103 adults with hair mercury measurement who consulted two medical institutions. We compared the prevalence and the distribution of neurological signs related to MeHg poisoning between exposure categories. RESULT: We found 48 subjects with neurological signs related to MeHg poisoning who had hair mercury concentration less than 50 µg/g. Among the neurological signs, sensory disturbance of the bilateral distal extremities was observed more frequently, followed by disequilibrium, hearing impairment, and ataxia, in groups with hair MeHg concentration both below 50 µg/g and over 50 µg/g. CONCLUSION: The present study suggests the possibility that exposure to MeHg at levels below the current WHO limits could cause neurologic signs, in particular, sensory disturbance.

Regular alcohol consumption improves insulin resistance in healthy Japanese men independent of obesity.

BACKGROUND: There is a great deal of controversy surrounding the relationship between alcohol consumption and insulin resistance. This association may be further confounded by the presence of obesity. We aimed to clarify whether regular alcohol consumption improves insulin resistance in healthy Japanese men and whether obesity affects this relationship. METHODS: We examined 1029 men (ages 24 to 87 y) who had undergone medical checkups. They were divided into non-obese (body mass index (BMI) <25 kg/m(2)) or obese subjects (BMI > or =25 kg/m(2)) and further classified into non-regular drinkers (NRD), moderate drinkers (MD; 1-6 days/week), and daily drinkers (DD; 7 days/week). The homeostasis model assessment of insulin resistance (HOMA-IR) and other cardiac risk factors were compared between the groups. RESULTS: In both non-obese and obese men, alcohol consumption decreased HOMA-IR in a dose-dependent manner, although HOMA-IR was about 2 times greater in obese men compared to non-obese men in any category (p<0.001). Stepwise logistic regression analysis revealed that alcohol consumption was the independent negative risk factor for HOMA-IR [OR, 0.576 (95% C.I. 0.402-0.824), p=0.003] after adjusting for age, BMI, systolic blood pressure, smoking status, LDL-cholesterol, HDL-cholesterol, and liver dysfunction. CONCLUSIONS: Regular alcohol consumption improves insulin resistance in healthy Japanese men independent of obesity.

Movement time planning in human movement with via-points.

In previous research, even though various models that reproduce movement trajectory have already been proposed, a movement time planning criterion has never been proposed. However, a possible computational model that can estimate via-point time in complex trajectories has been proposed that suggests that the via-point time average of the integration of the square of the smoothness of the motor commands between each via-point is equal. In this report, we measured three kinds of via-point reaching movements and then performed statistical tests to investigate the computational theory. Results suggest that their computational theory is valid.

Can human isochrony be explained by a computational theory?

Previous studies on human motor control reported a phenomenon called isochrony, which is the compensatory increase of movement speed with increasing movement distance. On the other hand, in complex via-points trajectory formation, a possible computational model that can estimate via-point time has been proposed. This model is optimized on the condition that the Duration average of the Commanded Torque Change (DCTC) between each via-point is equal. In this paper, we consider the possibility that human isochrony can be explained by the computational theory and investigate the human drawing movement of a set of figure eight and double elliptical patterns. Results show that isochrony was observed in both duration and DCTC and that relative variance with an increasing movement perimeter ratio of DCTC was significantly less than duration. The possibility is suggested that human isochrony is a phenomenon observed as a result of movement time planning to equalize DCTC.

Simple and precision design of porous gel as a visible indicator for ionic species and concentration.

Here we report the design and synthesis of a novel porous gel for an ionic visible indicator. The rapid-responsive porous gel which reveals color changes depending on a potassium ion concentration was prepared using a templating technique.