Bichannel Design Inspired by Membrane Pump: A Rate Booster for Conversion-type Anode of Sodium Ion Battery

The sluggish kinetic of Na+ in anode limits the rate capability of sodium ion batteries (SIBs). Herein, pyrophosphate, as a Na+ pump in cell membrane, is integrated with cobalt redox...

Transport Dynamics of MtrD: an RND multidrug efflux pump from Neisseria gonorrhoeae

Antibiotic-resistant gonorrheal infections are an urgent health concern. The MtrCDE system confers multidrug resistance to Neisseria gonorrhoeae, an obligate human pathogen, and the causative agent of the sexually-transmitted infection gonorrhea. The inner membrane pump MtrD effluxes a variety of hydrophobic and amphiphilic substrates and thereby confers resistance to a multitude of antibiotics. Using a combination of free and directed Molecular Dynamics (MD) simulations, we analyzed the interactions of MtrD with Azithromycin, an MtrD substrate and one of the last remaining courses of treatment for multidrug resistant gonorrhea. We also simulated the interactions between MtrD and Streptomycin, a non-substrate of MtrD. Using targeted MD (TMD) techniques and known conformations of MtrD homologues, we guided MtrD through the conformational changes of a putative transport cycle by applying small forces to α-carbons of the protein backbone; forces were not applied to Azithromycin or to Streptomycin. In our TMD experiments, we observed the transport of Azithromycin (in three possible protonation states) and the rejection of Streptomycin. To supplement our findings, we then demonstrate the spontaneous diffusion of Azithromycin through the periplasmic cleft in long time-scale, unbiased MD simulations. Our findings support the hypothesis that the transition from ‘Binding’ to ‘Extrusion’ is an energy requiring step in the transport process. Our data also suggest that multiple binding modes, and potentially multiple residue contact pathways, exist within the periplasmic cleft of MtrD, even for bulky substrates. To our knowledge, this is the first computational demonstration of substrate transport, and non- substrate rejection, by MtrD.

David Christopher Gadsby. 26 March 1947—9 March 2019

Over nearly five decades, David Christopher Gadsby pioneered biophysical research that advanced our mechanistic understanding of ion-transporting proteins in biological membranes. His passion for hands-on do-it-yourself electrophysiology, his depth of analytical rigor, and his idiosyncratic scientific aesthetic expanded the edge of discovery in two areas: the electrical character of the Na + pump, and the molecular workings of ‘cystic fibrosis transmembrane regulator’ (CFTR), the chloride ion channel whose mutations cause cystic fibrosis. His approach was flavoured by an appreciation for common underlying features between these ostensibly distinct types of membrane-transport systems. While David's focus was first on the basic molecular biophysics of a problem, he was always attuned to implications of his discoveries for human health. Based in New York at The Rockefeller University throughout his independent scientific career, and at the Marine Biological Laboratory in Woods Hole, Massachusetts, as a squid-season research-scientist, he was proficient in wrestling with problems spanning a wide swath of membrane biology: from determinants of the cardiac electrical waveform, to microsecond-timescale ionic currents in squid axons, to details of structure–mechanism relations in membrane pump and ion-channel proteins. He wore his eminence lightly and never distanced himself from the laboratory, where he often performed experiments with his own hands right up to his retirement. His reserved scientific personality, which demanded equally from his colleagues and himself immaculate data, unclouded logic, and substantive pertinence to the issues at hand, contrasted with his palpable joy in a good experiment and in his sea-loving life outside the lab.

Amitriptyline Induced Alterations in Liver and Kidney Functions and Structures in Male Rats

Aims: Depression is a mental health issue that starts most often in early adulthood and it is a common and recurrent disorder causing significant morbidity and mortality worldwide. Amitriptyline is a tricyclic antidepressant that is known to inhibit the presynaptic reuptake of serotonin, norepinephrine, and inhibitor of mitochondrial functions and induces apoptosis in several tissues. This study aims to identify the changes in liver and kidney structure and functions after treatment of male rats with Amitriptyline drugs. Materials and Methods: A total of 20 male albino rats were randomly and equally divided into 2 groups (G1, control group that included animals that did not receive any treatment during the experimental period. G2, Amitriptyline (Tryptizol; El Kahira Pharm And Chem Ind Co) group in which rats were injected intraperitoneally with Amitriptyline (100 mg/kg body weight/daily) for four weeks). Results: The current results revealed that; Amitriptyline treatments significantly (P <0.05) increased the levels of serum ALT, AST, ALP, urea, creatinine, sodium ions, chloride ions and liver and kidney damages as compared to control. In contrast; a significant (P <0.05) decrease in albumin, and total protein, potassium ions and calcium ions in Amitriptyline group was reported when compared with control group. Conclusion: Amitriptyline has many side effects on rat liver and kidney, it induced liver and kidney toxicity and tissue injury were it metabolized to nortriptyline which inhibits the reuptake of norepinephrine and serotonin almost equally. Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons.

Proton uptake mechanism in bacteriorhodopsin captured by serial synchrotron crystallography

Conformational dynamics are essential for proteins to function. We adapted time-resolved serial crystallography developed at x-ray lasers to visualize protein motions using synchrotrons. We recorded the structural changes in the light-driven proton-pump bacteriorhodopsin over 200 milliseconds in time. The snapshot from the first 5 milliseconds after photoactivation shows structural changes associated with proton release at a quality comparable to that of previous x-ray laser experiments. From 10 to 15 milliseconds onwards, we observe large additional structural rearrangements up to 9 angstroms on the cytoplasmic side. Rotation of leucine-93 and phenylalanine-219 opens a hydrophobic barrier, leading to the formation of a water chain connecting the intracellular aspartic acid–96 with the retinal Schiff base. The formation of this proton wire recharges the membrane pump with a proton for the next cycle.

Proton uptake mechanism in bacteriorhodopsin captured by serial synchrotron crystallography

Conformational dynamics are essential for proteins to function. Here we describe how we adapted time-resolved serial crystallography developed at X-ray lasers to visualize protein motions using synchrotrons. We recorded the structural changes upon proton pumping in bacteriorhodopsin over 200 ms in time. The snapshot from the first 5 ms after photoactivation shows structural changes associated with proton release at comparable quality to previous X-ray laser experiments. From 10-15 ms onwards we observe large additional structural rearrangements up to 9 Å on the cytoplasmic side. Rotation of Leu93 and Phe219 opens a hydrophobic barrier leading to the formation of a water chain connecting the intracellular Asp96 with the retinal Schiff base. The formation of this proton wire recharges the membrane pump with a proton for the next cycle.

Flow field velocity measurement of liquid interaction with rigid and flexible wall

The motivation of this research was to determine the flow interactions on the pulsation and to express the influence on the flow character in the rigid and flexible tube. The character of Newtonian liquid was measured with the Particle Image Velocimetry method (PIV). Here, we used glass tube and Tygon tube for our comparison. We build the circuit equipped with membrane pump for generating pulsatile flow. The results were analysed over the pulse period sampled in 10 time steps. The fluid flow varied from Re 560 to Re 8800. The velocity profiles uncovered backward revers flows closed to the wall. These structures are prevailing close to flexible wall. The effect of interaction between pulsatile liquid flow and flexible wall was experimentally proved.

Membrane Pump Operation Synchronicity (Criticality) in Epidermal Cells: The Possibility of Quantifying the Level of Synchronization

The authors analyze the results of atomic emission spectrometry of hair samples for Al, Cd, Fe, Cr, Cu, Li, Pb, V, and Zn in 952 healthy subjects and 952 liquidators of the Chernobyl nuclear power plant accident. Using correlation analysis (Pearson) of the obtained data, the authors have found pair correlations between metal concentration values. According to the authors, criticality or synchronization (as a particular case of the critical state of the system) can be inherent in all ATP-dependent membrane pumps (P-type) controlling metal-ligand homeostasis in epidermal cells. A quantitative criterion (synchronization index) is proposed to measure the level of criticality (synchronization) in the functioning of membrane ATPases.