TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice

Excess production of reactive oxygen species (ROS) caused by hyperglycemia is a major risk factor for heart failure. We previously reported that transient receptor potential canonical 3 (TRPC3) channel mediates pressure overload-induced maladaptive cardiac fibrosis by forming stably functional complex with NADPH oxidase 2 (Nox2). Although TRPC3 has been long suggested to form hetero-multimer channels with TRPC6 and function as diacylglycerol-activated cation channels coordinately, the role of TRPC6 in heart is still obscure. We here demonstrated that deletion of TRPC6 had no impact on pressure overload-induced heart failure despite inhibiting interstitial fibrosis in mice. TRPC6-deficient mouse hearts 1 week after transverse aortic constriction showed comparable increases in fibrotic gene expressions and ROS production but promoted inductions of inflammatory cytokines, compared to wild type hearts. Treatment of TRPC6-deficient mice with streptozotocin caused severe reduction of cardiac contractility with enhancing urinary and cardiac lipid peroxide levels, compared to wild type and TRPC3-deficient mice. Knockdown of TRPC6, but not TRPC3, enhanced basal expression levels of cytokines in rat cardiomyocytes. TRPC6 could interact with Nox2, but the abundance of TRPC6 was inversely correlated with that of Nox2. These results strongly suggest that Nox2 destabilization through disrupting TRPC3-Nox2 complex underlies attenuation of hyperglycemia-induced heart failure by TRPC6.Fil: Oda, Sayaka. Okazaki Institute for Integrative Bioscience; Japón. SOKENDAI; JapónFil: Numaga Tomita, Takuro. Okazaki Institute for Integrative Bioscience; Japón. SOKENDAI; JapónFil: Kitajima, Naoyuki. Okazaki Institute for Integrative Bioscience; Japón. Kyushu University; JapónFil: Tomizaki, Takashi. Okazaki Institute for Integrative Bioscience; Japón. Kyushu University; Japón. University of Tsukuba; JapónFil: Harada, Eri. Ajinomoto Co.; Japón. EA Pharma Co.; JapónFil: Shimauchi, Tsukasa. Okazaki Institute for Integrative Bioscience; Japón. Kyushu University; JapónFil: Nishimura, Akiyuki. Okazaki Institute for Integrative Bioscience; Japón. SOKENDAI; Japón. Ajinomoto Co.; JapónFil: Ishikawa, Tatsuya. Kyushu University; Japón. Ajinomoto Co.; Japón. EA Pharma Co.; JapónFil: Kumagai, Yoshito. University of Tsukuba; JapónFil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Nishida, Motohiro. Okazaki Institute for Integrative Bioscience; Japón. SOKENDAI; Japón. Kyushu University; Japón. PRESTO; Japó

Surrogate models for the magnitude of convection in droplets levitated through EML, ADL, and ESL methods

Fluid flow and heat transfer in levitated droplets were numerically investigated. Three levitation methods: electro-magnetic levitation (EML), aerodynamic levitation (ADL), and electro-static levitation (ESL) were considered, and conservative laws of mass, momentum, and energy were applied as common models. The Marangoni effect was applied as a velocity boundary condition, whereas heat transfer and radiation heat loss were considered as thermal boundary conditions. As specific models to EML, the Lorentz force, and Joule heat were calculated based on the analytical solution of the electromagnetic field. For the ADL model, besides the Marangoni effect, the flow driven by the surface shear force was considered. For ADL and ESL models, the effect of laser heating was introduced as a boundary condition. All the equations were nondimensionalized using common scales for all three levitations. Numerical simulations were performed for several materials and droplet sizes, and the results were evaluated in terms of the Reynolds number based on the maximum velocity of the flow in the droplet. The order of magnitude of Reynolds numbers was evaluated as $\text{Re} \sim 10^4$ for EML, $\text{Re} \sim 10^3$ for ADL, and $\text{Re} \sim 10^1$ for ESL. Based on the simulation results, we proposed simple formulas for predicting the Reynolds number of droplet internal convection using combinations of nondimensional numbers determined from the physical properties of the material and the driving conditions. The proposed formulas can be used as surrogate models to predict the Reynolds numbers, even for materials other than those used in this study

Anesthetic Care of a Patient with AFE

Two types of amniotic fluid embolism (AFE) have been described : cardiopulmonary collapse type and disseminated intravascular coagulation (DIC) type, with the latter proposed as uterine type. This report describes a healthy 28-year-old woman who developed AFE during a cesarean section. Because of a previous cesarean section, the patient underwent an elective cesarean section, under combined spinal-epidural anesthesia, at 38 weeks of pregnancy. She began coughing 5 minutes after delivery of the fetus, subsequently becoming unconscious and developing glossoptosis and bradycardia. Her blood pressure decreased to 76/43 mmHg, and AFE was suspected. Her uterus was atonic, and she experienced persistent noncoagulant bleeding, with a final blood loss of 6300 ml. Considerable blood transfusion was required. The patient survived, and she and her baby were discharged without any sequelae on the eighth postoperative day. This patient met the Japanese criteria for clinical AFE, with an obstetrical DIC score of 21 meeting the criteria for obstetrical DIC. Early diagnosis and treatment likely resulted in patient survival

The Short Term Effects of Organic Matter and Ripping on Degraded Soil in Western Australia

Abstract: The effect of wheat bran and ripping application on degraded soil such as saline soil, compacted soil and low fertile soil in Western Australia was investigated from the chemical and biological points of view. Ripping decreased ECe because of leaching of water soluble cation from topsoil. Wheat bran increased soil fertility due to enhanced enzyme activity. Potassium from bran displaced exchangeable sodium in soil, and resulted in reduction of soil dispersion and was absorbed by barley grain. Wheat bran increased number of spikelet and grain yield in degraded soil

TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice

Excess production of reactive oxygen species (ROS) caused by hyperglycemia is a major risk factor for heart failure. We previously reported that transient receptor potential canonical 3 (TRPC3) channel mediates pressure overload-induced maladaptive cardiac fibrosis by forming stably functional complex with NADPH oxidase 2 (Nox2). Although TRPC3 has been long suggested to form hetero-multimer channels with TRPC6 and function as diacylglycerol-activated cation channels coordinately, the role of TRPC6 in heart is still obscure. We here demonstrated that deletion of TRPC6 had no impact on pressure overload-induced heart failure despite inhibiting interstitial fibrosis in mice. TRPC6-deficient mouse hearts 1 week after transverse aortic constriction showed comparable increases in fibrotic gene expressions and ROS production but promoted inductions of inflammatory cytokines, compared to wild type hearts. Treatment of TRPC6-deficient mice with streptozotocin caused severe reduction of cardiac contractility with enhancing urinary and cardiac lipid peroxide levels, compared to wild type and TRPC3-deficient mice. Knockdown of TRPC6, but not TRPC3, enhanced basal expression levels of cytokines in rat cardiomyocytes. TRPC6 could interact with Nox2, but the abundance of TRPC6 was inversely correlated with that of Nox2. These results strongly suggest that Nox2 destabilization through disrupting TRPC3-Nox2 complex underlies attenuation of hyperglycemia-induced heart failure by TRPC6

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Misconceptions about the safety benefit of booster seats : the ejection stereotype hypothesis

This dissertation explores whether Lakatos’ methodology of scientific research programs and Elster’s notion of causal explanations can be used to drive innovation in injury prevention research. For illustration purposes, the problem of low rates of booster seat use is applied to a case study. Contrary to popular belief, the purpose seat belts is not solely to prevent people from being ejected out of the car, but to redirect crash forces to stronger parts of the body: hips and chest. Children between the ages of 4 and 8 years are usually too small to wear the seat belt across the hips and chest, and may end up with the straps on their bellies and neck. If a child wears it in this way, the seat belt directs crash forces to the child’s internal organs or spine, potentially causing fatal injuries. For this reason, children of these ages require a booster seat; a device that raises the child and ensures the seat belt is placed correctly across the hips and chest. Unfortunately, in Canada, 50% of children aged 4 to 8 years ride in cars strapped in seat belts, but without booster seats. To address this problem, I formulate a hypothesis that explains why booster seat use is infrequent: parents are prone to see injuries to vehicle occupants as resulting from ejection. This fixation on ejection makes them more concerned about the child being thrown through the windshield, and less worried about the dangers of early use of seat belts. I term this proposition the ejection stereotype hypothesis. This dissertation spans over philosophy of science, psychology, decision science, visual arts, and injury prevention. After summarizing different views of scientific progress and discussing the philosophy of booster seat research, fuzzy-trace theory and the ejection stereotype are described. Next, a psychological study that reports a falsification test of the ejection stereotype is reported. Following, a visual arts project is described in terms of how Tufte’s principles of information design were used to develop an infographic to correct the ejection stereotype. Finally, a proof-of-concept pilot study to test the efficacy of the infographic is reported.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat

Changes in parents' risk perception following medically attended injuries

Unintentional injuries are the leading cause of death for Canadian children aged 1 to14 years and an important public health concern. Given that parental behaviour is a key determinant of these incidents, this study examines parents’ perception of injury risk and their decision to take preventive action after medically attended injuries (MAIs) to their children. The present study examined parents’ perceived risk of injury and their likelihood of engaging in safety behaviour, approximately the day of the injury, as well as one month, four months, and 12 months later. Longitudinal analysis with mixed models was performed to examine changes in parents’ judgments of injury risk and likelihood to search injury prevention information. A sample of 39 fathers and 132 mothers (total 171) were included in the study. Parents of children who had a history of MAIs before enrolling in the study reported a higher perceived risk of the same and of any injury. Further, the perceived risk of any injury for parents of children without a history of injuries decreased over time, indicating that the first MAI to a child has a transient effect on perception of injury. There was insufficient statistical power to examine if parents were more likely to engage in safety behaviour after their child sustained a MAI. Findings are discussed in light of previous research, and implications for prevention of injury recurrence are described.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat