Transport In Biological Systems Research Articles

Evaluation of the Lipophilicity of Angularly Condensed Diquino- and Quinonaphthothiazines as Potential Candidates for New Drugs.

Lipophilicity is one of the most important properties of compounds required to estimate the absorption, distribution, and transport in biological systems, in addition to solubility, stability, and acid-base nature. It is crucial in predicting the ADME profile of bioactive compounds. The study assessed the usefulness of computational and chromatographic methods (thin-layer chromatography in a reversed-phase system, RP-TLC) for estimating the lipophilicity of 21 newly synthesized compounds belonging to diquinothiazines and quinonaphthiazines. In order to obtain reliable values of the relative lipophilicities of diquinothiazines and quinonaphthiazines, the partition coefficients obtained using different algorithms such as AlogPs, AClogP, AlogP, MLOGP, XLOGP2, XLOGP3, logP, and ClogP were compared with the chromatographic RM0 values of all the tested compounds measured by the experimental RP-TLC method (logPTLC). Additionally, logPTLC values were also correlated with other descriptors, as well as the predicted ADME and drug safety profiling parameters. The linear correlations of logPTLC values of the tested compounds with other calculated molecular descriptors such as molar refractivity, as well as ADME parameters (Caco-2 substrates, P-gp inhibitors, CYP2C19, and CYP3A4) generally show poor predictive power. Therefore, in silico ADME profiling can only be helpful at the initial step of designing these new candidates for drugs. The compliance of all discussed diquinothiazines and naphthoquinothiazines with the rules of Lipiński, Veber, and Egan suggests that the tested pentacyclic phenothiazine analogs have a chance to become therapeutic drugs, especially orally active drugs.

Nanoparticle transport in biomimetic polymer‐linked emulsions

AbstractThe ability of nanoparticles to penetrate and transport through soft tissues is essential to delivering therapeutics to treat diseases or signaling agents for advanced imaging and sensing. Nanoparticle transport in biological systems, however, is challenging to predict and control due to the physicochemical complexity of tissues and biological fluids. Here, we demonstrate that nanoparticles suspended in a novel class of soft matter—polymer‐linked emulsions (PLEs)—exhibit characteristics essential for mimicking transport in biological systems, including subdiffusive dynamics, non‐Gaussian displacement distributions, and decoupling of dynamics from material viscoelasticity. Using multiple particle tracking, we identify the physical mechanisms underlying this behavior, which we attribute to a coupling of nanoparticle dynamics to fluctuations in the local network of polymer‐linked droplets. Our findings demonstrate the potential of PLEs to serve as fully synthetic mimics of biological transport.

Tuning Charge Transport of Oligopeptide Junctions via Interfacial Amino Acids†

Comprehensive SummaryThe charge transport through peptides can imitate the corresponding processes in more complicated proteins, enabling us to develop high‐performance bioelectronic devices and to understand the mechanisms of biomolecular recognition and information transfer. While charge transport modulation through individual peptides has been achieved via various covalent strategies, the intermolecular modulation is still very challenging, which may capture the charge transport between proteins. To tackle this challenge, we used well‐defined self‐assembled monolayers (SAMs) of oligopeptides as a model to imitate the interface of proteins and explored an interfacial amino acid strategy for charge transport modulation. We showed that non‐covalently interfaced charged amino acids (e.g., arginine) effectively attenuated the charge transport of glutamic acid terminated polyglycine peptide SAMs. By analyzing the relationship of the charge transport with the molecular frontier orbital relative to the Fermi energy level of the electrode, the molecule‐electrodes coupling (Γ), and the trends in skewness and kurtosis with voltage and the dielectric constant (εr), we showed that the attenuation was from the decreased Γ and the reduced polarizability. We present an efficient strategy to modulate the charge transport of oligopeptide‐SAM junctions by intermolecular interactions, which will advance our understanding of charge transport in biological systems and facilitate developing future electronics.

Electrically conductive [Fe4S4]-based organometallic polymers.

Tailoring the molecular components of hybrid organic-inorganic materials enables precise control over their electronic properties. Designing electrically conductive coordination materials, e.g. metal-organic frameworks (MOFs), has relied on single-metal nodes because the metal-oxo clusters present in the vast majority of MOFs are not suitable for electrical conduction due to their localized electron orbitals. Therefore, the development of metal-cluster nodes with delocalized bonding would greatly expand the structural and electrochemical tunability of conductive materials. Whereas the cuboidal [Fe4S4] cluster is a ubiquitous cofactor for electron transport in biological systems, few electrically conductive artificial materials employ the [Fe4S4] cluster as a building unit due to the lack of suitable bridging linkers. In this work, we bridge the [Fe4S4] clusters with ditopic N-heterocyclic carbene (NHC) linkers through charge-delocalized Fe-C bonds that enhance electronic communication between the clusters. [Fe4S4Cl2(ditopic NHC)] exhibits a high electrical conductivity of 1 mS cm-1 at 25 °C, surpassing the conductivity of related but less covalent materials. These results highlight that synthetic control over individual bonds is critical to the design of long-range behavior in semiconductors.

Stable potassium isotopes (41K/39K) track transcellular and paracellular potassium transport in biological systems.

As the most abundant cation in archaeal, bacterial, and eukaryotic cells, potassium (K+) is an essential element for life. While much is known about the machinery of transcellular and paracellular K transport-channels, pumps, co-transporters, and tight-junction proteins-many quantitative aspects of K homeostasis in biological systems remain poorly constrained. Here we present measurements of the stable isotope ratios of potassium (41K/39K) in three biological systems (algae, fish, and mammals). When considered in the context of our current understanding of plausible mechanisms of K isotope fractionation and K+ transport in these biological systems, our results provide evidence that the fractionation of K isotopes depends on transport pathway and transmembrane transport machinery. Specifically, we find that passive transport of K+ down its electrochemical potential through channels and pores in tight-junctions at favors 39K, a result which we attribute to a kinetic isotope effect associated with dehydration and/or size selectivity at the channel/pore entrance. In contrast, we find that transport of K+ against its electrochemical gradient via pumps and co-transporters is associated with less/no isotopic fractionation, a result that we attribute to small equilibrium isotope effects that are expressed in pumps/co-transporters due to their slower turnover rate and the relatively long residence time of K+ in the ion pocket. These results indicate that stable K isotopes may be able to provide quantitative constraints on transporter-specific K+ fluxes (e.g., the fraction of K efflux from a tissue by channels vs. co-transporters) and how these fluxes change in different physiological states. In addition, precise determination of K isotope effects associated with K+ transport via channels, pumps, and co-transporters may provide unique constraints on the mechanisms of K transport that could be tested with steered molecular dynamic simulations.

Lamellar water induced quantized interlayer spacing of nanochannels walls

The nanoscale confinement is of great important for the industrial applications of molecular sieve, desalination, and also essential in biological transport systems. Massive efforts have been devoted to the influence of restricted spaces on the properties of confined fluids. However, the situation of channel-wall is crucial but attracts less attention and remains unknown. To fundamentally understand the mechanism of channel-walls in nanoconfinement, we investigated the interaction between the counter-force of the liquid and interlamellar spacing of nanochannel walls by considering the effect of both spatial confinement and surface wettability. The results reveal that the nanochannel stables at only a few discrete spacing states when its confinement is within 1.4 nm. The quantized interlayer spacing is attributed to water molecules becoming laminated structures, and the stable states are corresponding to the monolayer, bilayer and trilayer water configurations, respectively. The results can potentially help to understand the characterized interlayers spacing of graphene oxide membrane in water. Our findings are hold great promise in design of ion filtration membrane and artificial water/ion channels.

Infrared fingerprints of water collective dynamics indicate proton transport in biological systems.

Recent publications on spectroscopy of water layers in water bridge structures revealed a significant enhancement of the proton mobility and the dielectric contribution of translational vibrations of water molecules in the interfacial layers compared to bulk water. Herewith, the results of long-term studies of proton dynamics in solid-state acids have shown that proton mobility increases significantly with the predominance of hydronium, but not Zundel, cations in the aqueous phase. In the present work, in the light of these data, we reanalyzed our previously published results on broadband dielectric spectroscopy of bovine heart cytochrome c, bovine serum albumin, and the extracellular matrix and filaments of Shewanella oneidensis MR-1. We revealed that, just as in water bridges, an increase in electrical conductivity in these systems correlates with an increase in the dielectric contribution of water molecular translational vibrations. In addition, the appearance of spectral signatures of the hydronium cations was observed only in those cases when the system revealed noticeable electrical conductivity due to delocalized charge carriers.

A General DNA-Gated Hydrogel Strategy for Selective Transport of Chemical and Biological Cargos

The selective transport of molecular cargo is critical in many biological and chemical/materials processes and applications. Although nature has evolved highly efficient in vivo biological transport systems, synthetic transport systems are often limited by the challenges associated with fine-tuning interactions between cargo and synthetic or natural transport barriers. Herein, deliberately designed DNA-DNA interactions are explored as a new modality for selective DNA-modified cargo transport through DNA-grafted hydrogel supports. The chemical and physical characteristics of the cargo and hydrogel barrier, including the number of nucleic acid strands on the cargo (i.e., the cargo valency) and DNA-DNA binding strength, can be used to regulate the efficiency of cargo transport. Regimes exist where a cargo-barrier interaction is attractive enough to yield high selectivity yet high mobility, while there are others where the attractive interactions are too strong to allow mobility. These observations led to the design of a DNA-dendron transport tag, which can be used to universally modify macromolecular cargo so that the barrier can differentiate specific species to be transported. These novel transport systems that leverage DNA-DNA interactions provide new chemical insights into the factors that control selective cargo mobility in hydrogels and open the door to designing a wide variety of drug/probe-delivery systems.

Fast and Selective Ionic Transport: From Ion-Conducting Channels to Ion Exchange Membranes for Flow Batteries

This review discusses selective and fast transport of ionic species (ions and their associates) through systems as diverse as ion-conducting transmembrane proteins and ion exchange membranes (IEMs) in aqueous environments, with special emphasis on the role of electrostatics, specific chemical interactions, and morphology (steric effects). Contrary to the current doctrine, we suggest that properly balanced ion-coordinating interactions are more important than steric effects for selective ion transport in biological systems. Steric effects are more relevant to the selectivity of ionic transport through IEMs. As a general rule, decreased hydration leads to higher selectivity but also to lower transport rate. Near-perfect selectivity is achieved by ion-conducting channels in which unhydrated ions transfer through extremely short hydrophobic passages separating aqueous environments. In IEMs, ionic species practically keep their hydration shell and their transport is sterically constrained by the width of aqueous pathways. We discuss the trade-off between selectivity and transport rates and make suggestions for choosing, optimizing, or developing membranes for technological applications such as vanadium-redox-flow batteries.

Modulating the charge transport in metal│molecule│metal junctions via electrochemical gating

This review introduces the concept of electrochemical gating, in conjunction with its working principle, and demonstrates its applicability and prospects towards fabricating functional molecular devices. In this vein, various redox-active and -inactive molecular systems of relevance have been discussed. In terms of the electrochemical environment for gating, the significance of ionic liquids over aqueous electrolytes has been highlighted in multiple examples. As a means of investigating the electrochemically gated molecular junctions, experimental testbeds based on scanning probe microscopy and break junction techniques—in terms of their setups and advantages—have been described. The manifestation of quantum interference effects and the approach for tuning these via electrochemical gating have been stressed. The relevance of electrochemically gated charge transport in biological systems has also been covered. A few miscellaneous systems—deploying indirect approaches involving chemical and environmental gating—have been exemplified. The review finally concludes by outlining the future research directions of the field. In essence, this review is aimed towards conveying the status of the conceptual understanding of electrochemical gating—which would further the development of emerging molecular device technologies.

PHYSIOLOGY OF ARTAVAVAHA SROTASA: A REVIEW

Ayurvedic classics proclaim Srotasa as the system of channels designed as biological transport system performing divergent functions. Indeed, it is a generic term indicating all the macro and micro channels and pathways operat- ing in the living organism. Broadly Srotasa are classified in two categories: Bahirmukha and Antarmukha. Ar- tavavaha Srotasa is enumerated as one of the Antarmukha Srotasa by Sushruta, playing an important role in transformation of Artava and Artava Chakra, and Garbhotpatti, having Garbhasaya and Artavavahi Dhamani as its Moolasthana. Keywords: Antarmukha, Artavavaha, Garbhotpatti, Moolasthana, Srotasa

Biomimetic N-Doped Graphene Membrane for Proton Exchange Membranes.

Proton exchange membranes (PEMs) with both high selectivity and high permeance are of great demand in hydrogen-based applications, especially in fuel cells. Although graphene membranes have shown high selectivity of protons over other ions and molecules, the relatively low permeance of protons through perfect pristine graphene restricts its practical applications. Inspired by the nitrogen-assisted proton transport in biological systems, we introduced N-doping to increase the proton permeance and proposed a type of N-doped graphene membranes (NGMs) for proton exchange, which have both high proton permeance and high selectivity. Compared to the state-of-the-art commercial PEMs, the NGMs show significant increases in both areal proton conductivity (2-3 orders of magnitude) and selectivity of proton to methanol (1-2 orders of magnitude). The work realized the controllable tuning of proton permeance of the graphene membrane with N-doping and developed a new type of graphene-based PEMs with high performance for practical applications.

Investigating the influence of block copolymer micelle length on cellular uptake and penetration in a multicellular tumor spheroid model.

The efficient penetration of drug nanocarriers into tumors is an important prerequisite for therapeutic and diagnostic success. The physicochemical properties of nanocarriers, including size, shape and surface chemistry have been shown to influence their transport in biological systems. Recent studies have shown that elongated nanoparticles (NPs) can exhibit advantageous properties in comparison to spherical NPs, but these experiments have involved a variety of different materials, many of which are characterized by a broad size distribution. Here we describe a series of rigid rod-like micelles of uniform width, with narrow length distributions, and common surface chemistry, and examine their cell uptake and penetration into multicellular tumor spheroids (MCTSs) formed from two human breast cancer cell lines (MDA-MB-436 and MDB-MB-231). These micelles were prepared from a polyferrocenylsilane (PFS) diblock copolymer (BCP) with a corona block consisting of a statistical polymer of aminopropyl methacrylamide and oligo(ethyleneglycol methacrylate) (PFS27-b-PAPMA3-stat-POEGMA48). The rigid rod micelles, with a common width (12 nm) and lengths ranging from 80 to 2000 nm, were prepared by seeded growth crystallization-driven self-assembly in ethanol and then transferred to water. To consider whether changing the shape of these micelles affects its uptake and penetration behavior, analogous spherical micelles were prepared by direct nanoprecipitation into water. Both micelle shape and length were found to influence cellular uptake and penetration into 500 μm MCTSs. Laser confocal fluorescence microscopy was used to examine penetration of these micelles into three-dimensional MCTS up to 90 μm depth. Micelles with an elongated shape and short length (80 nm) demonstrated the deepest penetration into the MCTSs formed by MDA-MB-436 cells. Micelles with lengths of 200 nm also showed substantial penetration into these MCTS, but the extent and depth of tumor penetration of the rod-like micelles decreased with increasing aspect ratio. MCTS of MDA-MB-231 cells had a less dense, more open structure than those formed by MDA-MB-436 cells. Here more extensive penetration was observed, particularly for the longer micelle samples.

The Concept of Cooperative Dynamics in Simulations of Soft Matter

In this review we compiled recent advances concerning the cooperative motion in crowded soft matter systems. We tried to answer the question how to perform dynamic Monte Carlo simulations of dense macromolecular systems effectively. This problem is not simple due to the fact that the movement in such systems is strictly correlated which leads to cooperative phenomena. The influence of crowding was found interesting especially for two-dimensional cases, e.g., in membranes where the presence of macromolecules, proteins and cytoskeleton often changed the mean-square displacement as a function of the lag time and anomalous diffusion appeared. Simple models are frequently used to shed a light on molecular transport in biological systems. The emphasis was given to the Dynamic Lattice Liquid model. The latter model became a basis for a parallel algorithm that takes into account coincidences of elementary molecular motion attempts resulting in local cooperative structural transformations. The emphasis is put on influence of the model of molecular transport on the diffusion. The comparison to alternative approaches like single agent model was carried out.

Diffusioosmotic and convective flows induced by a nonelectrolyte concentration gradient

Glucose is an important energy source in our bodies, and its consumption results in gradients over length scales ranging from the subcellular to entire organs. Concentration gradients can drive material transport through both diffusioosmosis and convection. Convection arises because concentration gradients are mass density gradients. Diffusioosmosis is fluid flow induced by the interaction between a solute and a solid surface. A concentration gradient parallel to a surface creates an osmotic pressure gradient near the surface, resulting in flow. Diffusioosmosis is well understood for electrolyte solutes, but is more poorly characterized for nonelectrolytes such as glucose. We measure fluid flow in glucose gradients formed in a millimeter-long thin channel and find that increasing the gradient causes a crossover from diffusioosmosis-dominated to convection-dominated flow. We cannot explain this with established theories of these phenomena which predict that both scale linearly. In our system, the convection speed is linear in the gradient, but the diffusioosmotic speed has a much weaker concentration dependence and is large even for dilute solutions. We develop existing models and show that a strong surface-solute interaction, a heterogeneous surface, and accounting for a concentration-dependent solution viscosity can explain our data. This demonstrates how sensitive nonelectrolyte diffusioosmosis is to surface and solution properties and to surface-solute interactions. A comprehensive understanding of this sensitivity is required to understand transport in biological systems on length scales from micrometers to millimeters where surfaces are invariably complex and heterogeneous.

Differential Gene Expression Responding to Low Phosphate Stress in Leaves and Roots of Maize by cDNA-SRAP.

Phosphate (Pi) deficiency in soil can have severe impacts on the growth, development, and production of maize worldwide. In this study, a cDNA-sequence-related amplified polymorphism (cDNA-SRAP) transcript profiling technique was used to evaluate the gene expression in leaves and roots of maize under Pi stress for seven days. A total of 2494 differentially expressed fragments (DEFs) were identified in response to Pi starvation with 1202 and 1292 DEFs in leaves and roots, respectively, using a total of 60 primer pairs in the cDNA-SRAP analysis. These DEFs were categorized into 13 differential gene expression patterns. Results of sequencing and functional analysis showed that 63 DEFs (33 in leaves and 30 in roots) were annotated to a total of 54 genes involved in diverse groups of biological pathways, including metabolism, photosynthesis, signal transduction, transcription, transport, cellular processes, genetic information, and organismal system. This study demonstrated that (1) the cDNA-SRAP transcriptomic profiling technique is a powerful method to analyze differential gene expression in maize showing advantageous features among several transcriptomic methods; (2) maize undergoes a complex adaptive process in response to low Pi stress; and (3) a total of seven differentially expressed genes were identified in response to low Pi stress in leaves or roots of maize and could be used in the genetic modification of maize.

A comprehensive approach to the mathematical modeling of mass transport in biological systems: Fundamental concepts and models

Multiscale mathematical modeling of transport phenomena across different levels of biological systems, such as cells, capillaries, tissues, and organs, has been increasingly helpful in describing how interactions among these systems lead to their function and dysfunction. The development of models across these scales is based on knowledge from various fields, such as engineering, physiology, and biophysics, and it requires significant collaboration among scientists from the relevant areas. Therefore, a unified framework to describe the fundamental principles and unite the established models could support this growing research community. In this regard, the present work deals with the essential terminology required to understand and model biological transport mechanisms, as well as to compile currently available models. An inclusive mathematical framework for models of mass transport mechanisms in different tissue compartments, including cells, capillaries, and gland ducts, is developed, with a primary focus on the mechanisms of membrane-mediated transporters such as channels, uniporters, symporters, pumps, and antiporters. The main objective of this study is to provide a comprehensive tool to facilitate the analysis of biological mass transport mechanisms and substantially decrease the time taken to find the appropriate model for a study.

A multiple-network poroelastic model for biological systems and application to subject-specific modelling of cerebral fluid transport

Biological tissue can be viewed as porous, permeable and deformable media infiltrated by fluids, such as blood and interstitial fluid. A finite element model has been developed based on the multiple-network poroelastic theory to investigate transport phenomenon in such biological systems. The governing equations and boundary conditions are adapted for the cerebral environment as an example. The numerical model is verified against analytical solutions of classical consolidation problems and validated using experimental data of infusion tests. It is then applied to three-dimensional subject-specific modelling of brain, including anatomically realistic geometry, personalised permeability map and arterial blood supply to the brain. Numerical results of smoking and non-smoking subjects show hypoperfusion in the brains of smoking subjects, which also demonstrate that the numerical model is capable of capturing spatio-temporal fluid transport in biological systems across different scales.

Engineering Smart Nanofluidic Systems for Artificial Ion Channels and Ion Pumps: From Single-Pore to Multichannel Membranes.

Biological ion channels and ion pumps with intricate ion transport functions widely exist in living organisms and play irreplaceable roles in almost all physiological functions. Nanofluidics provides exciting opportunities to mimic these working processes, which not only helps understand ion transport in biological systems but also paves the way for the applications of artificial devices in many valuable areas. Recent progress in the engineering of smart nanofluidic systems for artificial ion channels and ion pumps is summarized. The artificial systems range from chemically and structurally diverse lipid-membrane-based nanopores to robust and scalable solid-state nanopores. A generic strategy of gate location design is proposed. The single-pore-based platform concept can be rationally extended into multichannel membrane systems and shows unprecedented potential in many application areas, such as single-molecule analysis, smart mass delivery, and energy conversion. Finally, some present underpinning issues that need to be addressed are discussed.

Thermo-responsive microfibrillar graft copolymer based on carboxymethylagarose and N-isopropylacrylamide

Carboxymethylation of agarose with ClCH2COOH in 2-propanol, formamide or dimethyl sulfoxide were evaluated in order to obtain water soluble derivatives. Higher yield (86%) and degree of substitution of carboxymethylation in primary alcoholic groups (0.70) were obtained using dimethyl sulfoxide. Carboxymethylagarose-g-PNIPAAm copolymers were synthesized by free radical graft copolymerization using Ce4+ and S2O82−/TEMED as initiators via conventional or microwave-assisted methods. Carboxymethyl derivatives and graft copolymers were characterized by FT-IR and NMR spectroscopies, elemental analysis, TGA and DSC and morphology analysis by SEM and AFM. High nitrogen content (9.7%) was found with Ce4+ by conventional method and the obtained analysis allowed to confirm the NIPAAm grafting on the carboxymethylagarose chain. Thermoresponsive materials have a low critical solution temperature between 32 and 34 °C. Thermal stability increased ca. 60% with PNIPAAm grafting. Surface analysis of copolymers reveals a microfibrillar type morphology with diameter of 4–6 μm. Synthesized glycoconjugates could find applications in bioactive compounds transport in biological systems.