In Gram-negative bacteria and eukaryotic organelles, β-barrel proteins of the outer membrane protein 85-two-partner secretion B (Omp85-TpsB) superfamily are essential components of protein transport ...machineries. The TpsB transporter FhaC mediates the secretion of Bordetella pertussis filamentous hemagglutinin (FHA). We report the 3.15 Å crystal structure of FhaC. The transporter comprises a 16-stranded β barrel that is occluded by an N-terminal α helix and an extracellular loop and a periplasmic module composed of two aligned polypeptide-transport-associated (POTRA) domains. Functional data reveal that FHA binds to the POTRA 1 domain via its N-terminal domain and likely translocates the adhesin-repeated motifs in an extended hairpin conformation, with folding occurring at the cell surface. General features of the mechanism obtained here are likely to apply throughout the superfamily.
Age-related loss of muscle mass and force (sarcopenia) contributes to disability and increased mortality. Ryanodine receptor 1 (RyR1) is the skeletal muscle sarcoplasmic reticulum calcium release ...channel required for muscle contraction. RyR1 from aged (24 months) rodents was oxidized, cysteine-nitrosylated, and depleted of the channel-stabilizing subunit calstabin1, compared to RyR1 from younger (3–6 months) adults. This RyR1 channel complex remodeling resulted in “leaky” channels with increased open probability, leading to intracellular calcium leak in skeletal muscle. Similarly, 6-month-old mice harboring leaky RyR1-S2844D mutant channels exhibited skeletal muscle defects comparable to 24-month-old wild-type mice. Treating aged mice with S107 stabilized binding of calstabin1 to RyR1, reduced intracellular calcium leak, decreased reactive oxygen species (ROS), and enhanced tetanic Ca
2+ release, muscle-specific force, and exercise capacity. Taken together, these data indicate that leaky RyR1 contributes to age-related loss of muscle function.
► RyR1 in skeletal muscle is oxidized, nitrosylated, and depleted of calstabin1 with age ► Maladaptation of the RyR1 channel leads to SR Ca
2+ leak and muscle weakness ► Vicious cycle: Ca
2+ leak raises mitochondrial ROS, which oxidizes RyR1-enhancing leak ► The RyR1-stabilizing drug S107 fixes Ca
2+ leak and improves exercise capacity in aging
The type 2 ryanodine receptor/calcium release channel (RyR2), required for excitation-contraction coupling in the heart, is abundant in the brain. Chronic stress induces catecholamine biosynthesis ...and release, stimulating β-adrenergic receptors and activating cAMP signaling pathways in neurons. In a murine chronic restraint stress model, neuronal RyR2 were phosphorylated by protein kinase A (PKA), oxidized, and nitrosylated, resulting in depletion of the stabilizing subunit calstabin2 (FKBP12.6) from the channel complex and intracellular calcium leak. Stress-induced cognitive dysfunction, including deficits in learning and memory, and reduced long-term potentiation (LTP) at the hippocampal CA3-CA1 connection were rescued by oral administration of S107, a compound developed in our laboratory that stabilizes RyR2-calstabin2 interaction, or by genetic ablation of the RyR2 PKA phosphorylation site at serine 2808. Thus, neuronal RyR2 remodeling contributes to stress-induced cognitive dysfunction. Leaky RyR2 could be a therapeutic target for treatment of stress-induced cognitive dysfunction.
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► Leaky hippocampal RyR2 channels contribute to stress-induced cognitive dysfunction ► RyR2 PKA hyperphosphorylation and calstabin2 depletion cause intracellular Ca2+ leak ► Pharmacologic or genetic inhibition of Ca2+ leak prevent the cognitive dysfunction
Stabilizing a leaky calcium release channel with a small molecule alleviates the detrimental effects of long-term stress on learning and memory.
The goal of this work was to study the mechanical behavior of concrete with recycled Polyethylene Therephtalate (PET), varying the water/cement ratio (0.50 and 0.60), PET content (10 and 20
vol%) and ...the particle size. Also, the influence of the thermal degradation of PET in the concrete was studied, when the blends were exposed to different temperatures (200, 400, 600
°C). Results indicate that PET-filled concrete, when volume proportion and particle size of PET increased, showed a decrease in compressive strength, splitting tensile strength, modulus of elasticity and ultrasonic pulse velocity; however, the water absorption increased. On the other hand, the flexural strength of concrete-PET when exposed to a heat source was strongly dependent on the temperature, water/cement ratio, as well as on the PET content and particle size. Moreover, the activation energy was affected by the temperature, PET particles location on the slabs and water/cement ratio.
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