What happens when sodium permeability increases?

Nernst equation for a flow battery

The cell potential given by Eq. (10) or (11) is applicable only for standard conditions, i.e., at operating temperature of 25 °C, pressure of 1 bar and electrolyte concentrations of 1 M. The cell potential may change if any of these is changed. In a redox flow battery, even if it is operating at standard pressure and temperature conditions, we can expect the concentrations of electro-active species to change as the battery gets charged or discharged. The variation of cell potential with variation in concentrations can be determined using the Nernst equation (O’Hayre and Cha, 2016) which can be derived as follows.

Consider a reversible chemical reaction given by

(12)pA+qB↔rC+sD

where p, q, r & s are the stoichiometric coefficients, A and B are the reacting molecules and C and D are the product molecules. The rates of the forward and the reverse reactions are related to the activities, ai, of the participating species, and the reaction rate is proportional to the product of the activities of species raised to the power of their stoichiometric coefficients. The activity of a species is often written in terms of the mole fraction of the species in the solution, i.e., ai = γi xi where γi is the activity coefficient of species i and xi is the mole fraction of the species. Thus, if the forward reaction rate is initially high, then the concentration of the reactants will decrease and that of the products will increase leading to increase in the rate of the reverse reaction. A thermodynamic equilibrium will eventually be reached when the activities are such that the forward and reverse reaction rates are equal. At this point, the activities are related by the equilibrium constant, K, defined as

(13)K=aCraD s/aApaBq

For very dilute solutions (< 0.01 M), the activity coefficient tends to unity and it becomes synonymous with mole fraction. Typically, in flow batteries, the molarity of the electro-active species is much higher so as to have high energy densities. In such cases, activity of a species is often expressed in terms of concentration on a molarity scale as

(14)ai=γcici/c0i

where γci is the activity coefficient of species i in a molarity scale, ci and c0i are the concentration and standard concentration of species i on a molarity scale. Usually, c0i is taken to be 1 M. The equilibrium constant can in that case be written in terms of molar concentrations of the active species as

(15)K=cCrcDs/cA pcBqγcCr γcDs/γcA pγcBq

Relatively minor error is incurred in neglecting the second curly-bracketted term on the right hand side of Eq. (15) involving ratios of the activity coefficients (Blanc, 2009; Hall et al., 2020). Neglecting these, we can write the equilibrium constant in terms of concentrations of the species participating in the reaction as

(16)K=cC rcDs/cApcB q

Now, the Gibbs free energy △ G change for the reaction can be expressed as a sum of △ Go which represents the free energy change for the reaction when the activity of each species is unity, and a variable term representing the effect of temperature and pressure on the equilibrium constant K:

(17)△G=△G0+RTlnK=△G0+RTlncCrcDs /cApcBqγcCrγcDs/γcApγcBq

The cell potential at non-standard concentrations can now be determined using Eq. (10) as

(18)E=E0+RT/nF lncCrcD s/cApcBqγcCrγcDs/γcApγcBq

In the case of the vanadium redox flow battery for which the overall cell reaction is given by Eq. (7), the cell potential during charging is given as

(19)E=E0+RT/FlncV5cV2cH+2/cV4cV3γcV5 γcV2γcH+2/γcV4γcV3

where the vanadium species have been identified by their oxidation number in the solution. Neglecting the contribution of the term involving activity coefficients in Eq. (19) will lead to the following equation that is often used in modeling studies of VRFBs:

(20)E=E0+RT/FlncV5cV2cH+2/cV4cV3

The above equation can also be re-arranged in terms of the relative concentrations of the electro-active species in the catholyte and the anolyte:

(21)E=E0+RT/FlncV5cH+2/cV4cath cV2/cV3anol

In a flow battery in which energy is stored and retrieved, the composition of the electrolytes does not remain constant but varies in the process of charging and discharging. State of charge (SoC) represents the fractional charge remaining in the battery to be converted. Taking the example of VRFB, if we start initially with equi-molar volumes of VO2+ in the catholyte and V3+ in the anolyte and conduct charge-discharge operations such that there are no side reactions and no cross-over effects, then both sides will have the same charge or discharge capacity. In such a case, the state of charge can be written as

(22)SoC=cV2/cV2+ cV3=cV5/cV4+c V5

If the two sides are not balanced, then the lower of the two SoCs will be the effective SoC of the battery. Assuming that we have a balanced SoC, the cell voltage can be written in terms of SoC of the battery as follows:

(23)E=E0 +2RT/FlncH+S/1−S

where S denotes the state of charge. Fig. 4 shows the variation of cell potential as a function of SoC for a VRFB operating at 25 °C.

The threshold cell membrane potential

The threshold cell membrane potential is reached when sodium permeability increases to the point that sodium entry exceeds potassium exit, depolarization becomes self-perpetuating, and an action potential develops. The ability of specialized cells to develop an action potential is crucial to normal cardiac conduction, muscle contraction, and nerve impulse transmission. The excitability of a tissue is determined by the difference between the resting and threshold potentials (the smaller the difference, the greater the excitability).

Hypokalemia increases the resting potential (i.e., makes it more negative) and hyperpolarizes the cell, whereas hyperkalemia decreases the resting potential (i.e., makes it less negative) and initially makes the cell hyperexcitable (Fig. 5-2). If the resting potential decreases to less than the threshold potential, depolarization results, repolarization cannot occur, and the cell is no longer excitable. Translocation of potassium between body compartments results in a greater change in the ratio of intracellular to extracellular potassium concentrations ([K+]I/[K+]O) than does a change in total body potassium. In the former instance, the potassium concentrations of the two compartments change in opposite directions, whereas in the latter instance, they change in the same direction.

Membrane excitability also is affected by ionized calcium concentration and acid-base balance. Calcium affects the threshold potential rather than the resting potential. Ionized hypocalcemia increases membrane excitability by allowing self-perpetuating sodium permeability to be reached with a lesser degree of depolarization, whereas ionized hypercalcemia requires greater than normal depolarization for this threshold to be reached (see Fig. 5-2). Thus, hypercalcemia counteracts hyperkalemia by normalizing the difference between the resting and threshold potentials, whereas hypocalcemia exacerbates the effect of hyperkalemia on membrane excitability. This principle is the basis for treating hyperkalemia with calcium salts (see the Treatment of Hyperkalemia section). Membrane excitability is increased by alkalemia and decreased by acidemia. As a result of these factors, clinical signs are not necessarily correlated with serum potassium concentrations. Electrocardiographic findings and muscle strength reflect the functional consequences of abnormalities in serum potassium concentration.

Abstract

Dental stem cells are potential cells for use in tissue engineering, including dental tissue, nerve, and bone regeneration. Multifactorial potential including high proliferation rate, multidifferentiation ability, easy accessibility, high viability, and ease to be induced to distinct cell lineages, make the dental stem cells an attractive cell source. Several types of dental stem cells are described: dental pulp stem cells, stem cells from human exfoliated deciduous teeth, stem cells from apical papilla, dental follicle progenitor cells, and periodontal ligament stem cells. An overview and biological properties of these cell populations are provided in this article.

5.5 CD44

CD133 is a reported potential CSC marker of liver cancer. Zhu et al. demonstrated that both CD133- and CD44-positive HCC cells possessed properties similar to CSCs, including extensive proliferation, self-renewal, and the ability to give rise to differentiated progeny, as well as initiated tumor growth in immunodeficient mice at very low cell numbers, when their CD133+ CD44− counterparts did not. They concluded that CSCs in HCC were characterized by coexpression of CD133 and CD44 [151]. Mima et al. reported that overexpression of the standard isoform of CD44 (CD44s) promoted tumor invasiveness, increased the expression of a mesenchymal marker vimentin, and regulated the transforming growth factor (TGF)-β–mediated mesenchymal phenotype in HCC cells. Clinically, overexpression of CD44s was associated with low expression of E-cadherin, high expression of vimentin, and poor prognosis in HCC patients. The findings suggested that CD44s plays a critical role in the TGF-β–mediated mesenchymal phenotype and therefore represents a potential therapeutic target for HCC [152]. In GBCs, CD44+ CD133+ cells demonstrated a high degree of chemoresistance, possibly due to upregulation of ABCG2 and the transcription factor Gli1-like CD133 [121].

Cell source

Step 2: There are numerous potential cell sources available for cellularizing the synthetic or naturally derived scaffolds. The strategy that we are currently pursuing is to isolate progenitor cells from circulating blood, and expand them to obtain the EC and SMC that are required for TEBV. The overall concept is to utilize cell-selective markers to isolate and expand the progenitor cells, prior to differentiation and further proliferation for seeding purposes. This process is well characterized with respect to differentiation of endothelial cells from endothelial progenitor cells, but further research is required in order to obtain similar procedures for derivation of smooth muscle cells from circulating muscle progenitor cells. The latter work is ongoing in our group.

Introduction

A full appreciation of the concept of the cell membrane potential and the factors that control it is often difficult for students, and even some research workers, to grasp adequately. Because of this, our department has in the past endeavored to run laboratory exercises that demonstrated how the generation of the membrane potential depended on the relative permeability of different ions and on their concentrations in the adjacent solutions bathing the membrane. An ideal laboratory exercise would be to simulate an experiment in which excitable cells were impaled with microelectrodes so that both resting membrane potentials and action potentials could be measured as the external electrolyte composition was varied, following such classic experiments as those of Hodgkin and Horowicz (1), Hodgkin and Katz (2), and Nastuk and Hodgkin (3), and as depicted in a film by Adrian (4). To provide such a laboratory exercise the MEMPOT computer simulation program was recently developed [see Barry (5)]. Since then the program has been significantly upgraded, and at the time of writing it has been ordered and acquired by over 30 university departments in at least 12 countries around the world. In addition to its stand-alone value, MEMPOT could also be used as a laboratory exercise in conjunction with the somewhat complementary AXOVACS program (6), which uses the Hodgkin–Huxley equations to simulate the kinetic and pharmacological aspects of the action potential.

Molecular Mechanisms of Lineage Commitment: Loss of B Cell Potential

With its distinctive timing, loss of B cell potential is obviously mediated by a different mechanism than the losses of potential for myeloid, dendritic cell, and NK cell fates and requires a lower threshold of Notch signal intensity (Schmitt et al., 2004; Van de Walle et al., 2011).

B cell transcription factors such as EBF1 and Pax5 are not expressed in thymic immigrants, but need to be turned on de novo when CLPs enter the B cell pathway. This activation does not occur under Notch-signaling conditions. However, ETPs do express the basic helix-loop-helix transcription factor E2A (Tcf3), the forkhead box transcription factor FoxO1, and other broadly expressed transcription factors including Ikaros (Ikzf1), PU.1, and Runx1 which play roles in Ebf1 gene activation. Thus, Notch or a Notch-induced factor interferes with the ability of these factors to activate Ebf1 in the early T context. Pax5 depends on E2A, EBF1, PU.1, and probably also Stat5 transcription factors activated by IL-7R signaling. Once it is activated, it also feeds back positively to enhance Ebf1 expression, but this also fails to happen in early T cells.

The details of how Notch signaling so completely blocks B cell development are still being defined. Notch signaling activates a number of potent dedicated repressors like Hes1 and its relatives, but these do not appear to include direct repressors of B cell genes (B cell precursors themselves express Hes1). Notch signaling may antagonize B cell development by inducing the degradation of E2A protein through an MAP kinase–dependent pathway that is especially easy to trigger in B lineage cells (Nie et al., 2008), although it is not clear if this operates in the LMPP or CLP precursors which choose B versus T fate. A mechanism for direct Notch inhibition of EBF1 function has also been described (Smith et al., 2005). Importantly, though, Notch does not block B cell development by itself. One of the T cell genes upregulated early by Notch signaling in the ETP stage is Gata3, encoding the transcription factor GATA-3. This is itself a strong antagonist of the B cell fate, and its stable expression once activated may explain why thymic immigrants so rapidly lose even the potential to generate B cells when removed from Notch signals. Loss of GATA-3 does not convert thymic immigrants to B cells in the thymic microenvironment the way loss of Notch2 itself does, and Notch2 gain of function can block B cell development even from Gata3-deleted cells. Thus, Notch still plays a separate, overlapping role (Hozumi et al., 2008a). However, forced expression of GATA-3 can block B cell development from fetal liver or bone marrow precursors even in the absence of Notch signals (Taghon et al., 2007; Scripture-Adams et al., 2014), and loss of GATA-3 can restore some B cell developmental capacity of thymocytes even in the DN2 stage, although many other Notch-activated genes are turned on (García-Ojeda et al., 2013; Scripture-Adams et al., 2014). Thus, GATA-3 is a potent part of the commitment mechanism that excludes B cell potential within the ETP stage in early T cells.

Faradaic Processes

Also called oxidoreduction reactions, redox reactions or electrolysis. Faradaic processes are the best-known electrode reactions, taught in any school chemistry programme. As an example, we will take the case of a zinc electrode in a zinc sulphate solution. By making the electrode sufficiently positive, zinc atoms can be oxidized into zinc ions:

Zn→Zn++ +e−

At sufficiently negative electrode potentials, zinc ions are reduced:

Zn+++e−→Zn ↓

The metallic zinc precipitates onto the surface of the electrode.

In such a half-cell, the electrode assumes a stable equilibrium potential, virtually independent of current strength. The potential has been shown to depend on the concentration of the salt and on a theoretical property of the metal called the metal's solution pressure, or the tendency to dissolve. Nernst established the relation between these two as:

E=RTzFln(cK)

where E is the electrode potential, T is the absolute temperature, z is the valence, c is the concentration of the metal ion and K is the mentioned solution pressure. Although the latter is a hypothetical quantity, and is even criticized as to its physical meaning, the differences between metals are very real. Some metals, such as silver, gold and platinum, do not dissolve readily (i.e. oxidize), and are called “precious metals”. Others, such as aluminium, iron and zinc, are oxidized very easily. Thus, all metals can be ordered according to their relative solution pressures. Hydrogen, although not a metal in the strict sense, fits in this electrochemical series perfectly. Its use as a standard was mentioned before.

The list below shows electrode (i.e. half-cell) potentials for a number of reactions, all taken at “normal” (one equivalent per litre) concentrations of the salt. These are called “standard electrode potentials”, and are abbreviated E0.

Note that the standard hydrogen electrode half-cell has a pH of zero. Since in biochemical systems, pH values are about 7 rather that at zero, biochemists often use electrode potentials referred to a hydrogen electrode at pH = 7.0. These are indicated as E'0 and can be found by subtracting 406mV from the respective values in the table (why?). Standard potentials of other redox systems, such as metabolic systems, can be expressed in the same way, and are called standard redox potentials. These are almost always expressed as E'0 values.

As a result of Faradaic processes, these electrode half-cells conduct electric current with very little change of the potential. Therefore, a metal in a solution of one of its salts is known as a “non-polarized electrode”. The I/V characteristic of an ideal non-polarized electrode is shown in Fig. 3-3, right. The electrode voltage is constant over a large range of current strengths. In that respect, the I/V characteristic of non-polarized electrodes is the opposite of the characteristics of polarized electrodes, where the current is zero over a large voltage range.

Ectopic expression of transcription factors can reprogram differentiated cells to induce “stemness”

The powerful potential of Sox2 to maintain the stem cell potential (totipotentiality) has proven advantageous in cellular reprogramming. By overexpressing Sox2 in somatic cells in combination with other transcription factors (for instance, c-Myc, Oct3/4 and Klf4), researchers have been able to artificially reprogram already differentiated cells to obtain cells with characteristics of stem cells or “stemness.” These cells, called induced pluripotent stem (iPS) cells, harbor the potential to differentiate into virtually any cell type depending on the specificity of their exposure to environmental cues (see also Ch. 30). The first example of iPS cells was published by Shinya Yamanaka and colleagues (Takahashi et al., 2007; Takahashi & Yamanaka, 2006), who reprogrammed differentiated mouse fibroblasts into pluripotent cells. By transfecting mouse fibroblasts with expression vectors for Sox2, c-Myc, Oct3/4 and Klf4, they showed that these cells could be reprogrammed to express stem cell markers. The gold-standard test for “stemness” is the competence for producing germline chimeras, in which the cells are capable of renewing. Since this first report, several other groups have independently reported successful iPS cell production from both murine and human tissues using different sets of transcription factors.

Normally, pluripotent progenitor or embryonic stem (ES) cells are derived from embryonic tissues, and then differentiated in culture using an array of well-characterized mitogenic factors. The use of ES cells is an important reagent in basic research and drug development and potentially also in cell-replacement therapies such as cell transplantation in spinal cord injuries. Because ES cells can be differentiated into mature cells it is possible to use these for testing drugs on human material prior to clinical trials. Drug responsiveness can also be tested as a function of genetic factors or diseases using ES cells (Nishikawa et al., 2008). However, the use of ES cells presents legal and ethical issues that may be avoided by reprogramming somatic cells using the iPS cell technology. Although the iPS technology is still quite new, it holds an enormous potential as an ES-cell–free alternative to cell-based replacement therapies. Furthermore, the iPS technology is advantageous over ES cell lines, since the donor cell can be obtained from the same patient that the tissue will eventually be transplanted into, thus eliminating potential harmful and lethal immunogenic responses.