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Structural diversity of ABC transporters
No full text<p>ATP-binding cassette (ABC) transporters form a large superfamily of ATP-dependent protein complexes that mediate transport of a vast array of substrates across membranes. The 14 currently available structures of ABC transporters have greatly advanced insight into the transport mechanism and revealed a tremendous structural diversity. Whereas the domains that hydrolyze ATP are structurally related in all ABC transporters, the membrane-embedded domains, where the substrates are translocated, adopt four different unrelated folds. Here, we review the structural characteristics of ABC transporters and discuss the implications of this structural diversity for mechanistic diversity.</p>
Tau phosphorylation: In Hibernation and Alzheimer’s
No full textTau is a MAP found in neurons. Tau hyperphosphorylation, which detaches tau from microtubules is one of the hallmarks of PHF’s observed in AD but is also observed in torpor where it is reversed after arousal without lasting neuronal damage. This review focusses on tau phosphorylation. We seek to understand the differences between tau phosphorylation in AD patients and tau phosphorylation in torpid animals in order to asses if reversal of tau phosphorylation, like during arousals, can treat tau pathology in AD. Human tau has an essential role in microtubule stability, intracellular transport and the release of neurotransmitters. When phosphorylated, tau detaches from microtubules. Phosphorylation is done by GSK3B, CDK5, CK1, PKA and many more kinases. PP2A is mostly responsible for the dephosphorylation of tau. AD is characterized by synaptic degeneration and extracellular SP’s, consisting of AB and intracellular tangles consisting of hyperphosphorylated tau. Tau phosphorylation but also deficiency of glucose metabolism correlates with disease progression. In AD increased GSK3B, CDK5, CK1, PSK1 activity and decreased PP2A activity is found. In vitro they can cause the phosphorylation of all residues found in AD tau. Due to its complexity the process of tau phosphorylation is still not completely understood and it remains to be proven if these kinases are solely responsible in vivo. During torpor tau is hyperphosphorylated by increased PKA and GSK3B activity and decreased PP2A activity. This is likely caused by temperature dependent activity shifts. During arousals animals quickly rewarm to euthermic state. Neuronal connections reappear and phosphorylation sites within tau’s MDB are rapidly dephosphorylated. Sites implicated in microtubule binding are phosphorylated in AD as well as during torpor. GSK3B activity is increased during AD and torpor possibly due to hypometabolism. Also PKA, CDK5, CK1 and PSK1 activity is increased in AD while in torpor only GSK3B and PKA are reported. Furthermore in AD the amount of phosphorylated tau slowly increases and is deposited into PHF’s while in hibernators tau is dephosphorylated during arousals. During torpor metabolic challenge and decreased temperature cause hyperphosphorylated tau which protects neurons from damage. The neurons of torpid animals do not have AB deposition and clear phosphorylated tau before irreversible damage occurs. Removing AB has failed to show significant efficacy in AD but GSK3B inhibition with lithium was found to partially reverse tau pathology. Mimicking what we learned from torpid animal decreasing kinase activity and increasing phosphatase activity could reverse tau phosphorylation partially or even fully and stop disease progression. This could ultimately restore the natural balance between kinase and phosphatase activity and lead to normal functioning tau but will unfortunately not be able to reverse the existing damage.
Flagellar hydrodynamics of biological and biomimetic micro-swimmers
No full textSandeep Namdeo deed onderzoek aan ‘autonome micro-zwemmers’. Dat zijn micro-organismen die zich met haarachtige structuren voortbewegen. Namdeo verwacht dat deze methode van voortstuwing wellicht gebruikt kan worden voor biomedische toepassingen in therapeutische, diagnostische en chirurgische procedures. Namdeo ontwierp kunstmatige micro-zwemmers die op afstand bestuurd kunnen worden.
‘Een noodzakelijke stap voor dit idealistisch doel is het realiseren van een systeem dat nauwkeurige controle over de richting en snelheid van de microzwemmers geeft via externe stimuli zoals licht en elektrische en magnetische velden,’ zegt hij in de samenvatting van zijn proefschrift. ‘Het is aantrekkelijk om een bio-geïnspireerde benadering te volgen en de evolutionaire voordelen van de natuur te benutten, met als doel innovatieve oplossingen mogelijk te maken voor complexe problemen.’
Veel micro-organismen gebruiken haarachtige structuren, bekend als flagella, om voortstuwing te genereren. Het proefschrift van Namdeo bevat een numerieke analyse van de flagellaire hydrodynamica van zowel biologische als biomimetische microzwemmers. Op basis van de inzichten uit de studie van biologische flagella werden autonome biomimetische microzwemmers ontworpen die op afstand aangedreven en bestuurd kunnen worden door een uniform magnetisch veld bij lage Reynoldsgetallen.
Biomimetic designs and actuation strategies of magnetic micro-swimmers are suggested by exploiting the swimming principles of various flagellated micro-organisms. Controlled and bi-directional propulsion - through narrow channels via external stimuli - of such a micro-swimmer makes it a potential candidate for biomedical applications involving therapeutic, diagnostic, and surgical procedures.
To study the propulsive hydrodynamics of flagellated systems, finite element based computational models are developed in which the solid mechanics, fluid dynamics, and magneto-static equations are solved simultaneously. The key dimensionless parameters are identified to explore the design space for biomimetic systems and to study the propulsive hydrodynamics of natural flagella. The thesis provides fundamental physical insights on flagellar hydrodynamics of biological and biomimetic micro-swimmers.