Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling.

BACKGROUND: Cardiac contractile function requires high energy from mitochondria, and Ca2+ from the sarcoplasmic reticulum (SR). Via local Ca2+ transfer at close mitochondria-SR contacts, cardiac excitation feedforward regulates mitochondrial ATP production to match surges in demand (excitation-bioenergetics coupling). However, pathological stresses may cause mitochondrial Ca2+ overload, excessive reactive oxygen species production and permeability transition, risking homeostatic collapse and myocyte loss. Excitation-bioenergetics coupling involves mitochondria-SR tethers but the role of tethering in cardiac physiology/pathology is debated. Endogenous tether proteins are multifunctional; therefore, nonselective targets to scrutinize interorganelle linkage. Here, we assessed the physiological/pathological relevance of selective chronic enhancement of cardiac mitochondria-SR tethering. METHODS: We introduced to mice a cardiac muscle-specific engineered tether (linker) transgene with a fluorescent protein core and deployed 2D/3D electron microscopy, biochemical approaches, fluorescence imaging, in vivo and ex vivo cardiac performance monitoring and stress challenges to characterize the linker phenotype. RESULTS: Expressed in the mature cardiomyocytes, the linker expanded and tightened individual mitochondria-junctional SR contacts; but also evoked a marked remodeling with large dense mitochondrial clusters that excluded dyads. Yet, excitation-bioenergetics coupling remained well-preserved, likely due to more longitudinal mitochondria-dyad contacts and nanotunnelling between mitochondria exposed to junctional SR and those sealed away from junctional SR. Remarkably, the linker decreased female vulnerability to acute massive ß-adrenergic stress. It also reduced myocyte death and mitochondrial calcium-overload-associated myocardial impairment in ex vivo ischemia/reperfusion injury. CONCLUSIONS: We propose that mitochondria-SR/endoplasmic reticulum contacts operate at a structural optimum. Although acute changes in tethering may cause dysfunction, upon chronic enhancement of contacts from early life, adaptive remodeling of the organelles shifts the system to a new, stable structural optimum. This remodeling balances the individually enhanced mitochondrion-junctional SR crosstalk and excitation-bioenergetics coupling, by increasing the connected mitochondrial pool and, presumably, Ca2+/reactive oxygen species capacity, which then improves the resilience to stresses associated with dysregulated hyperactive Ca2+ signaling.

The Relationship Between Colles' Fractures and Leukocytosis in the Emergency Department.

In Taiwan, emergency physicians often perform wrist joint reduction and cast immobilization before orthopedic surgeons arrange for surgical management. Prophylactic antibiotics can decrease the risk of wound infection and have been routinely employed in orthopedic surgery. In Taiwan, emergency physicians also regularly perform blood investigations and administer prophylactic antibiotics to prevent infection if the patient exhibits leukocytosis. However, pain and pressure also cause leukocytosis, making it difficult to discern if the cause is infection or injury. Therefore, we explored the relationship between Colles' fractures and leukocytosis to determine if antibiotic treatment is necessary for this type of injury.

Spin-Polarized Photocatalytic CO2 Reduction of Mn-Doped Perovskite Nanoplates.

"Spin" has been recently reported as an important degree of electronic freedom to improve the performance of electrocatalysts and photocatalysts. This work demonstrates the manipulations of spin-polarized electrons in CsPbBr3 halide perovskite nanoplates (NPLs) to boost the photocatalytic CO2 reduction reaction (CO2RR) efficiencies by doping manganese cations (Mn2+) and applying an external magnetic field. Mn-doped CsPbBr3 (Mn-CsPbBr3) NPLs exhibit an outstanding photocatalytic CO2RR compared to pristine CsPbBr3 NPLs due to creating spin-polarized electrons after Mn doping. Notably, the photocatalytic CO2RR of Mn-CsPbBr3 NPLs is significantly enhanced by applying an external magnetic field. Mn-CsPbBr3 NPLs exhibit 5.7 times improved performance of photocatalytic CO2RR under a magnetic field of 300 mT with a permanent magnet compared to pristine CsPbBr3 NPLs. The corresponding mechanism is systematically investigated by magnetic circular dichroism spectroscopy, ultrafast transient absorption spectroscopy, and density functional theory simulation. The origin of enhanced photocatalytic CO2RR efficiencies of Mn-CsPbBr3 NPLs is due to the increased number of spin-polarized photoexcited carriers by synergistic doping of the magnetic elements and applying a magnetic field, resulting in prolonged carrier lifetime and suppressed charge recombination. Our result shows that manipulating spin-polarized electrons in photocatalytic semiconductors provides an effective strategy to boost photocatalytic CO2RR efficiencies.

Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction.

Maple syrup urine disease (MSUD) is an inherited error in the metabolism of branched-chain amino acids (BCAAs) caused by a severe deficiency of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which ultimately leads to neurological disorders. The limited therapies, including protein-restricted diets and liver transplants, are not as effective as they could be for the treatment of MSUD due to the current lack of molecular insights into the disease pathogenesis. To address this issue, we developed a Drosophila model of MSUD by knocking out the dDBT gene, an ortholog of the human gene encoding the dihydrolipoamide branched chain transacylase (DBT) subunit of BCKDH. The homozygous dDBT mutant larvae recapitulate an array of MSUD phenotypes, including aberrant BCAA accumulation, developmental defects, poor mobile behavior and disrupted L-glutamate homeostasis. Moreover, the dDBT mutation causes neuronal apoptosis during the developmental progression of larval brains. The genetic and functional evidence generated by in vivo depletion of dDBT expression in the eye indicates severe impairment of retinal rhabdomeres. Further, the dDBT mutant shows elevated oxidative stress and higher lipid peroxidation accumulation in the larval brain. Therefore, we conclude from in vivo evidence that the loss of dDBT results in oxidative brain damage that may lead to neuronal cell death and contribute to aspects of MSUD pathology. Importantly, when the dDBT mutants were administrated with Metformin, the aberrances in BCAA levels and motor behavior were ameliorated. This intriguing outcome strongly merits the use of the dDBT mutant as a platform for developing MSUD therapies.This article has an associated First Person interview with the joint first authors of the paper.

Continuity of care trajectories and emergency room use among patients with diabetes.

OBJECTIVES: To analyze the pattern of continuity of care (COC) using trajectory analysis for a group of patients newly diagnosed with diabetes, and determine whether various trajectories lead to distinct patient outcomes. METHODS: We used the Taiwan National Health Insurance claims database. Newly diagnosed patients with diabetes in 2005 totaling 4367 were included in this study. All patients were followed up to 2011. We identified groups of COC trajectories using trajectory analysis. We subsequently determined whether various COC trajectories were associated with the frequency of total and diabetes-related emergency room (ER) use using negative binomial models. RESULTS: We discovered five distinct COC trajectories for our newly diagnosed diabetes sample based on trajectory analysis. The early-seeker group had the lowest IRR for total ER visits (IRR = 0.56, P < 0.001), followed by the high-maintainer group (IRR = 0.67, P < 0.001). Similar results were obtained for diabetes-specific ER use. CONCLUSIONS: We identified various COC trajectories for diabetes patients. Chronic disease patients may seek a suitable physician by compromising care continuity at the onset of disease progression and exhibit favorable outcome.

Influence of sulfur concentration on bioleaching of heavy metals from industrial waste sludge.

The bioleaching process, including acidification and solubilization of heavy metals, is a promising method for removing heavy metals from industrial waste sludge. Solubilization of heavy metals in industrial waste sludge is governed by adding elemental sulfur. A sulfur concentration exceeding 0.5% (w/v) inhibits sulfate production and the activity of acidophilic bacteria. Sulfate production was described well by a substrate inhibition expression in Haldane's kinetics. After 15 days of bioleaching, 79 to 81% copper, 50 to 69% lead, and 49 to 69% nickel were solubilized from sludge with a sulfur concentration of 0.5 to 1.0% (w/v). Experimental results indicated that the optimal sulfur concentration for the maximum solubilization rate of copper and nickel was 0.5% (w/v) and 1.0% (w/v) for lead. The profiles of denaturing gradient gel electrophoresis confirmed that indigenous acidophilic Acidithiobacilli (A. thiooxidans and A. ferrooxidans) existed and were the dominant species in the bioleaching process.

Synergistic effect of endothelin-1 and cyclic AMP on glucose transport in 3T3-L1 adipocytes.

We have demonstrated previously that chronic exposure to endothlin-1 enhances glucose transport in 3T3-L1 adipocytes via augmented GLUT1 mRNA and protein accumulation. In the present study, we further examined the combined effect of endothelin-1 (ET-1) and cAMP on glucose transport. In cells pretreated with ET-1 and 8-bromo cAMP for 8 h, a synergy between these two agents on glucose uptake was found. Insulin-stimulated glucose transport, on the other hand, was only slightly affected. The synergistic effect of these two agents was suppressed in the presence of cycloheximide and actinomycin D. Immunoblot and Northern blot analyses revealed that GLUT1 protein and mRNA levels were both increased in cells pretreated with both ET-1 and 8-bromo cAMP, greater than the additive effect of each agent alone. Further examination demonstrated that the stability of GLUT1 mRNA was markedly enhanced in the presence of both ET-1 and cAMP. To investigate the transcriptional activation of Glut1 gene, transient transfection of cells with luciferase reporter construct driven by Glut1 promoter was performed. We found that Glut1 transcription was also increased by ET-1 and cAMP in a synergistic fashion. In addition, similar synergy between ET-1 and beta-adrenergic agonists on glucose transport was found. The synergistic action of ET-1 with 8-bromo cAMP to enhance glucose transport was inhibited by GF109203X, a selective protein kinase C (PKC) inhibitor, and was mimicked by 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA), a PKC activator. Furthermore, PMA was found to act synergistically with 8-bromo cAMP to induce Glut1 transcription and ET-1 was shown to activate novel PKCdelta and PKC. Taken together, these results indicate that ET-1 may act with cAMP in a synergistic way to increase glucose transport, probably through enhanced GLUT1 expression via a PKC-dependent mechanism.