This review focuses on the type A cytochrome c oxidases (CcO), which are found in all mitochondria and also in several aerobic bacteria. CcO catalyzes the respiratory reduction of dioxygen (O2) to ...water by an intriguing mechanism, the details of which are fairly well understood today as a result of research for over four decades. Perhaps even more intriguingly, the membrane-bound CcO couples the O2 reduction chemistry to translocation of protons across the membrane, thus contributing to generation of the electrochemical proton gradient that is used to drive the synthesis of ATP as catalyzed by the rotary ATP synthase in the same membrane. After reviewing the structure of the core subunits of CcO, the active site, and the transfer paths of electrons, protons, oxygen, and water, we describe the states of the catalytic cycle and point out the few remaining uncertainties. Finally, we discuss the mechanism of proton translocation and the controversies in that area that still prevail.
Delayed capillary break-up of viscoelastic filaments presents scientific and technical challenges relevant for drop formation, dispensing, and adhesion in industrial and biological applications. The ...flow kinematics are primarily dictated by the viscoelastic stresses contributed by the polymers that are stretched and oriented in a strong extensional flow field resulting from the streamwise gradients created by the capillarity-driven squeeze flow. After an initial inertiocapillary (IC) or viscocapillary (VC) regime, where elastic effects seem to play no role, the interplay of capillarity and viscoelasticity can lead to an elastocapillary (EC) response characterized by exponentially-slow thinning of neck radius (extensional relaxation time is determined from the delay constant). Less frequently, a terminal visco-elastocapillary (TVEC) response with linear decay in radius can be observed and used for measuring terminal, steady extensional viscosity. However, both IC/VC–EC and EC–TVEC transitions are inaccessible in devices that create stretched necks by applying a step strain to a liquid bridge (e.g., capillary breakup extensional rheometer). In this study, we use dripping-onto-substrate rheometry to obtain radius evolution data for unentangled polymer solutions. We deduce that the plots of transient extensional viscosity vs. Hencky strain (scaled by the respective values at the EC–TVEC transition) emulate the functional form of the birefringence–macromolecular strain relationship based on Peterlin’s theory. We quantify the duration and strain between the IC/VC–EC and the EC–TVEC transitions using measures we term elastocapillary span and elastocapillary strain increment and find both measures show values directly correlated with the corresponding variation in extensional relaxation time.
Alzheimer’s disease (AD) is a neurodegenerative disease that is of high importance to the neuroscience world, yet the complex pathogenicity is not fully understood. Inflammation is usually observed ...in AD and could implicate both beneficial or detrimental effects depending on the severity of the disease. During initial AD pathology, microglia and astrocyte activation is beneficial since they are involved in amyloid-beta clearance. However, with the progression of the disease, activated microglia elicit detrimental effects by the overexpression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) bringing forth neurodegeneration in the surrounding brain regions. This results in decline in Aβ clearance by microglia; Aβ accumulation thus increases in the brain resulting in neuroinflammation. Thus, Aβ accumulation is the effect of increased release of pro-inflammatory molecules. Reactive astrocytes acquire gain of toxic function and exhibits neurotoxic effects with loss of neurotrophic functions. Astrocyte dysfunctioning results in increased release of cytokines and inflammatory mediators, neurodegeneration, decreased glutamate uptake, loss of neuronal synapses, and ultimately cognitive deficits in AD. We discuss the role of intracellular signaling pathways in the inflammatory responses produced by astrocytes and microglial activation, including the glycogen synthase kinase-3β, nuclear factor kappa B cascade, mitogen-activated protein kinase pathways and c-Jun N-terminal kinase. In this review, we describe the role of neuroinflammation in the chronicity of AD pathogenesis and an overview of the recent research towards the development of new therapies to treat this disorder.
We elucidate the influence of chemical structure on macromolecular hydrodynamics, rheological response, and pinching dynamics underlying drop formation/liquid transfer using polyethylene oxide (PEO) ...and 2-hydroxyethyl cellulose (HEC) as two polymers with distinct Kuhn length and matched overlap concentrations. We contrast the filament pinching dynamics and extensional rheology response using dripping-onto-substrate rheometry protocols. Even though dilute aqueous solutions of both polymers at matched concentrations display comparable shear viscosity, the PEO solutions exhibit distinctively higher values of extensional relaxation time, extent of strain hardening, and transient extensional viscosity, as well as an overall delay in pinch-off. We critically analyze the radius evolution for a pinching filament to posit that the solutions of flexible PEO macromolecules exhibit signatures of underlying coil-stretch transition manifested as a discontinuous, nonmonotonic variation in the extensional rate. In contrast, the solutions of semiflexible HEC show a monotonic increase in extensional rate in response to rising interfacial stress in the pinching filament, implying that the macromolecules undergo progressive stretching and orientation without undergoing coil-stretch transition. We show that the chemistry-dependent contrast in macromolecular dynamics and extensional rheology response can be characterized a priori in terms of three ratios: contour length to Kuhn length (flexibility), contour length to unperturbed coil size (extensibility), and packing length to Kuhn length (a parameter we termed as segmental dissymmetry). We identify the influence of the three ratios − flexibility, extensibility, and segmental dissymmetry − on the critical minimum concentration below which elastocapillary response and extensional relaxation time cannot be measured, the critical concentration above which the influence of concentration fluctuations disappears, and also define a stretched overlap concentration below which the extensional relaxation time becomes concentration-independent.
Quantitative studies of capillarity-driven pinching and extensional rheology of aqueous solutions of polysaccharides like hydroxyethyl cellulose (HEC) are beyond the measurable range of most ...extensional rheometers, and are relatively rare, even though polysaccharides are widely used as rheology modifiers. In this study, we utilize dripping-onto-substrate (DoS) rheometry protocols that we recently developed to characterize the pinching dynamics and extensional rheology response of aqueous HEC solutions. We find that the radius evolution data from the pinching necks show an elastocapillary regime that can be fit to determine the extensional relaxation time even for unentangled HEC solutions that show neither rate-dependent regime in shear viscosity nor measurable elasticity in the shear rheology response measured using torsional rheometers. Furthermore, the radius evolution data for the entangled HEC solutions display a power law regime, previously reported only for multicomponent complex fluids containing particles, bubbles, drops, and lamellar gel networks described with the generalized Newtonian fluid models. However, the entangled HEC solutions that exhibit pronounced shear thinning and measurable elastic moduli also reveal that the power law in the radius evolution data is modulated in the late stage by viscoelastic effects, allowing the measurement of both extensional relaxation time and steady, terminal extensional viscosity. Finally, we show that the pinching dynamics underlying drop formation/liquid transfer of HEC solutions can be determined fairly accurately by measuring shear rheology response, unlike the solutions of flexible polymers that display a stark contrast in response to shear and extensional flows.
Dihydropyridine (DHP) is among the most beneficial scaffolds that have revolutionised pharmaceutical research with unprecedented biological properties. Over the years, metamorphosis of easily ...accessible 1,2- and 1,4-dihydropyridine (1,4-DHP) intermediates by synthetic chemists has generated several drug molecules and natural products such as alkaloids. The 1,4-dihydropyridine (1,4-DHP) moiety itself is the main fulcrum of several approved drugs. The present review aims to collate the literature of 1,2- and the 1,4-DHPs relevant to synthetic and medicinal chemists. We will describe various methodologies that have been used for the synthesis of this class of compounds, including the strategies which can furnish enantiopure DHPs, either by asymmetric synthesis or by chiral resolution. We will also elaborate the significance of DHPs towards the synthesis of natural products of medicinal merit.
The present review aims to describe various methodologies that have been used for the synthesis of 1,2- & 1,4-dihydropyridines (DHPs) and also highlight their medicinal significance.
Ellis–Bronnikov (EB) wormholes require violation of null energy conditions at the ‘throat’. This problem was cured by a simple modification of the ‘shape function’, which introduces a new parameter
m
...≥
2
(
m
=
2
corresponds to the EB model). This leads to a generalised (GEB) version. In this work, we consider a model where the GEB wormhole geometry is embedded in a five dimensional warped background. We studied the status of all the energy conditions in detail for both EB and GEB embedding. We present our results analytically (wherever possible) and graphically. Remarkably, the presence of decaying warp factor leads to satisfaction of weak energy conditions even for the EB geometry, while the status of all the other energy conditions are improved compared to the four dimensional scenario. Besides inventing a new way to avoid the presence of exotic matter, in order to form a wormhole passage, our work reveals yet another advantage of having a warped extra dimension.
Liquid transfer and drop formation/deposition processes involve complex free-surface flows including the formation of columnar necks that undergo spontaneous capillary-driven instability, thinning ...and pinch-off. For simple (Newtonian and inelastic) fluids, a complex interplay of capillary, inertial and viscous stresses determines the nonlinear dynamics underlying finite-time singularity as well as self-similar capillary thinning and pinch-off dynamics. In rheologically complex fluids, extra elastic stresses as well as non-Newtonian shear and extensional viscosities dramatically alter the nonlinear dynamics. Stream-wise velocity gradients that arise within the thinning columnar neck create an extensional flow field, and many complex fluids exhibit a much larger resistance to elongational flows than Newtonian fluids with similar shear viscosity. Characterization of pinch-off dynamics and the response to both shear and extensional flows that influence drop formation/deposition in microfluidic and printing applications requires bespoke instrumentation not available, or easily replicated, in most laboratories. Here we show that dripping-onto-substrate (DoS) rheometry protocols that involve visualization and analysis of capillary-driven thinning and pinch-off dynamics of a columnar neck formed between a nozzle and a sessile drop can be used for measuring shear viscosity, power law index, extensional viscosity, relaxation time and the most relevant processing timescale for printing. We showcase the versatility of DoS rheometry by characterizing and contrasting the pinch-off dynamics of a wide spectrum of simple and complex fluids: water, printing inks, semi-dilute polymer solutions, yield stress fluids, food materials and cosmetics. We show that DoS rheometry enables characterization of low viscosity printing inks and polymer solutions that are beyond the measurable range of commercially-available capillary break-up extensional rheometer (CaBER). We show that for high viscosity fluids, DoS rheometry can be implemented relatively inexpensively using an off-the-shelf digital camera, and for many complex fluids, similar power law scaling exponent describes both neck thinning dynamics and the shear thinning response.
Researchers have created several expert systems over the years to predict heart disease early and assist cardiologists to enhance the diagnosis process. We present a diagnostic system in this paper ...that utilizes an optimized XGBoost (Extreme Gradient Boosting) classifier to predict heart disease. Proper hyper-parameter tuning is essential for any classifier’s successful application. To optimize the hyper-parameters of XGBoost, we used Bayesian optimization, which is a very efficient method for hyper-parameter optimization. We also used One-Hot (OH) encoding technique to encode categorical features in the dataset to improve prediction accuracy. The efficacy of the proposed model is evaluated on Cleveland heart disease dataset and compared it with Random Forest (RF) and Extra Tree (ET) classifiers. Five different evaluation metrics: accuracy, sensitivity, specificity, F1-score, and AUC (area under the curve) of ROC charts were used for performance evaluation. The experimental results showed its validity and efficacy in the prediction of heart disease. In addition, proposed model displays better performance compared to the previously suggested models. Moreover, our proposed method reaches the high prediction accuracy of 91.8%. Our results indicate that the proposed method could be used reliably to predict heart disease in the clinic.
Membrane bound respiratory complex I is the key enzyme in the respiratory chains of bacteria and mitochondria, and couples the reduction of quinone to the pumping of protons across the membrane. ...Recently solved crystal or electron microscopy structures of bacterial and mitochondrial complexes have provided significant insights into the electron and proton transfer pathways. However, due to large spatial separation between the electron and proton transfer routes, the molecular mechanism of coupling remains unclear. Here, based on atomistic molecular dynamics simulations performed on the entire structure of complex I from Thermus thermophilus, we studied the hydration of the quinone-binding site and the membrane-bound subunits. The data from simulations show rapid diffusion of water molecules in the protein interior, and formation of hydrated regions in the three antiporter-type subunits. An unexpected water-protein based connectivity between the middle of the Q-tunnel and the fourth proton channel is also observed. The protonation-state dependent dynamics of key acidic residues in the Nqo8 subunit suggest that the latter may be linked to redox-coupled proton pumping in complex I. We propose that in complex I the proton and electron transfer paths are not entirely separate, instead the nature of coupling may in part be 'direct'.
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