Review Article | Open Access
Christopher A. Shaw, Stephanie Seneff, Stephen D. Kette, Lucija Tomljenovic, John W. Oller, Robert M. Davidson, "Aluminum-Induced Entropy in Biological Systems: Implications for Neurological Disease", Journal of Toxicology, vol. 2014, Article ID 491316, 27 pages, 2014. https://doi.org/10.1155/2014/491316
Aluminum-Induced Entropy in Biological Systems: Implications for Neurological Disease
Over the last 200 years, mining, smelting, and refining of aluminum (Al) in various forms have increasingly exposed living species to this naturally abundant metal. Because of its prevalence in the earth’s crust, prior to its recent uses it was regarded as inert and therefore harmless. However, Al is invariably toxic to living systems and has no known beneficial role in any biological systems. Humans are increasingly exposed to Al from food, water, medicinals, vaccines, and cosmetics, as well as from industrial occupational exposure. Al disrupts biological self-ordering, energy transduction, and signaling systems, thus increasing biosemiotic entropy. Beginning with the biophysics of water, disruption progresses through the macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It injures cells, circuits, and subsystems and can cause catastrophic failures ending in death. Al forms toxic complexes with other elements, such as fluorine, and interacts negatively with mercury, lead, and glyphosate. Al negatively impacts the central nervous system in all species that have been studied, including humans. Because of the global impacts of Al on water dynamics and biosemiotic systems, CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed.
Aluminum (Al) is the most common metal and the third most abundant element in the earth’s crust [1–3]. However, it seems to have no beneficial role in the biochemistry of any biota . Until the 1820s when the industrial extraction of Al, primarily from bauxite ore , made it possible to bring Al into food processing, manufacturing, medicines, cosmetics, vaccines, and other applications, Al was almost completely absent from the biosphere . Concerns about the toxicity of ingesting Al were expressed over 100 years ago . Today, biologically ingested or injected forms include salts of Al in processed foods  and medicinal products  such as antacids, glossy coatings for pills, and vaccine adjuvants. The last use, which portrays Al compounds as “helpers”—the English translation of the Latin root of adjuvants—is supposed to shock the recipient’s immune defenses into action, ostensibly to enhance the immunogenicity of the pathogen(s) in the vaccine(s) . Al salts are also found in dyes , cosmetics , antiperspirants [11–14], sunscreens [15, 16], and thousands of material products including foils, food containers, and utensils.
In this paper, we will show that Al is harmful to the CNS, acting in a number of deleterious ways and across multiple levels, to induce biosemiotic entropy . A countervailing view exists [18–20], but the assertions of safety are invariably based on weak epidemiological designs, ones that overwhelm significant negative signals with irrelevant noise factors. Such studies that fail to detect significant negative outcomes neither stand up to rigorous scrutiny nor outweigh better designed research, in a vast and growing literature, showing significant negative impacts sustaining the central hypothesis of this paper. Irrefutable research evidence shows that Al exposure is harmful. Further, results discussed in this paper show that it is counterfactual for researchers to argue that Al is universally safe or beneficial even in trace amounts.
Al is used extensively in food processing, for example, in Al-mordanted dye lakes for food coloring, in coatings for pharmaceutical tablets and vitamin capsules, for emulsifying, as a rising agent, to thicken gravies, and in meat-binders, stabilizing agents and texturizers . Even drinking water is a source of Al exposure, although the amount contained in drinking water is typically far below concentrations in common antacids . However, there is concern that the Al in drinking water may be more easily absorbed than at mealtime, due to the fact that an empty stomach promotes absorption . Alum (Al sulfate or Al potassium sulfate) is commonly used in water treatment plants as a coagulant to allow negatively charged colloidal particles to clump together for easy removal. Epidemiological studies have shown that people living in districts with higher Al burden in drinking water are more likely to be diagnosed with Alzheimer’s disease .
Because tea plants contain a higher concentration of Al than many other plants, and, because tea beverages are consumed in large quantities worldwide, a high incidence of Al exposure comes through drinking tea . Al content in tea ranges from 2 to 6 mg/L . Tea infusions have been analyzed for the speciation of Al content, and it has been determined that it is typically bound to large organic molecules such as polyphenols or to citrate [24, 25]. Tea typically contains much more Al than water, and so tea becomes a significant source of Al for heavy tea drinkers. An experiment to estimate oral Al bioavailability from tea involving 8 rats was conducted by injecting Al citrate into tea leaves, delivering approximately the same amount of Al as is inherently found in tea leaves (0.5 to 1 mg/gm) . The brewed tea was administered through intragastric infusion. Following infusion, peak serum levels of Al were up to 1500-fold above mean pretreatment values.
In a substantial and recent review of research, Walton  concludes that Alzheimer’s disease is a manifestation of chronic Al neurotoxicity in humans. Because Al is similar to iron, it gains access to iron-dependent cells involved in memory. As it accumulates over time in such cells, it causes microtubule depletion and disables neuronal afferents and efferents resulting in the multiregion atrophy characteristic of Alzheimer’s pathology . Table 1 highlights some of the Al compounds to which humans are commonly exposed which are known to have deleterious effects on the central nervous systems (CNS) of both animals and humans , whereas Tables 2 and 3, respectively, present Al intake data, and its physical properties compared to other metals. Table 1 also shows dosage and known effects of each source on animals and/or humans.
|PTWI (provisional tolerable weekly intake) is based on orally ingested Al, generally only 0.1–0.4% of Al is absorbed from the GI tract, however, Al may form complexes with citrate, fluoride, carbohydrates, phosphates, and dietary acids (malic, oxalic, tartaric, succinic, aspartic, and glutamic), which may increase its GI absorption (0.5–5% [70, 82]). Coexposure to acidic beverages (lemon juice, tomato juice, and coffee) also increases Al absorption as well as conditions of Ca2+, Mg2+, Cu2+, and Zn2+ deficiency [70, 83–85].|
‡A single dose of vaccine delivers the equivalent of 204–1284 mg orally ingested Al (0.51−5.56 mg), all of which is absorbed into systemic circulation [86, 91]. Al hydroxide, a common vaccine adjuvant has been linked to a host of neurodegenerative diseases; it also induces hyperphosphorylation of MAP tau in vivo [44, 45, 87].
The risk of antiperspirants is both from dermal exposure and inhalation of acrosols. Al is absorbed from the nasal epithelia into olfactory nerves and distributed directly into the brain [88, 91].
Al in all of the forms studied, as Table 1 shows, produces harmful effects in living organisms: it especially harms the CNS. In studies involving in vitro cultures of neuronal-glial cells, the ROS-generating capabilities of several physiologically relevant neurotoxic factors were compared [29, 30]. It was found that Al-sulfate was the most potent single metal sulfate inducer of ROS, as well as the most potent combinatorial inducer in conjunction with Fe. Nanomolar concentrations of Al were sufficient to induce ROS and proinflammatory gene expression. Nanomolar concentrations of Al-sulfate upregulated the expression of several genes implicated in Alzheimer’s disease, including proinflammatory and proapoptotic gene expression .
Given the fact that there are no known biochemical reactions that require Al, should it be surprising that introducing it into living organisms commonly leads to pathological outcomes [31–46]? Because of its +3 charge, Al attracts negatively charged ions and electrons, but because it cannot transition to other oxidation states besides +3, it is not a component in any redox reactions. Oxygen, carbon, hydrogen, nitrogen, calcium, and phosphorous constitute 99% of human body mass, with the remaining 1% consisting of potassium, sulfur, sodium, chlorine, and magnesium, as well as trace elements such as fluorine, selenium, and zinc, and xenobiotic (biologically foreign and usually toxic) elements such as titanium, mercury, and lead . Thus, Al can end up in many biochemical contexts in theory, but in fact some atoms and molecules are far more likely to react with Al compounds . Among the most vulnerable molecules are those most directly involved in self-ordering, self-assembling systems of biosemiotics that work like multilayered, interrelated languages. The best known macromolecules that are susceptible to minute but often disabling injuries by Al compounds are DNA molecules that must be translated via the assistance of a growing multitude of RNA molecules into proteins. The latter in turn are essential to the structure and functions of the whole society of cells , tissues, and organ systems. Formerly, it was thought, following the Crick dogma , that communications were essentially a one-way street from DNA to RNA to protein, but it has more recently been argued [17, 51, 52] that communications involve more complex bidirectional interactions among those macromolecules, such that the genome is informed concerning what is going on in the environment. The dynamical matrix of negative charge densities in heparan sulfate proteoglycans (HSPGs), as modulated in time and space by interfacial water, exchanging between the first few solvation layers and bulk, might prove to be the supramolecular physical basis for informing the genome over distance .
There are estimated to be 20,000–25,000 protein coding genes in the human genome  and even more variant proteins possible through posttranslational modifications estimated to be upwards of 100,000. Thus there are many macromolecules with which Al3+ species can interact, either directly or indirectly. Eukaryotic proteins are polymers of various combinations and lengths consisting of an array of 23 amino acids joined by peptide bonds. Each of the 23 amino acids has a unique side chain consisting of various organic substituents. Al can interact with the side chains , some of which—serine, threonine, and tyrosine—are phosphorylated, enabling phosphoregulation of enzyme activity and binding with other proteins. Al can disrupt all of these side chains and the processes dependent on them . Cysteine, methionine, homocysteine, and glutathione contain sulfur, and they are intermediaries instrumental in methylation and transsulfuration pathways, as well as in heavy metal detoxification. These processes can be disrupted by Al  because of the strong binding affinity of Al with sulfur oxyanions. Glutamic and aspartic acids have negatively charged carboxylate side chains. Al has a much stronger binding affinity to these side chains, for instance, than the nontoxic cation, magnesium .
Therefore, Al is ineffective in redox reactions, though its +3 charge makes it likely to adsorb to suspended colloids (e.g., complex proteinaceous polymeric molecular structures or clusters suspended in fluid) in nonliving systems, resulting in its kosmotropic character (see Table 4), which enables the salting-out known as “flocculation.” This useful tendency, for example in public water systems, can, however, be catastrophic in the blood and fluids of living organisms, where building blocks of necessary proteins are apt to be turned into useless debris linked to Al salts [59, p. 1410] and . According to its Lewis acidity classification , Al3+ belongs in Class A, a small (hard) metal ion with low polarizability (deformability), preferentially forming ionic complexes with similar nonpolarizable ligands, particularly oxygen donors such as oxyanions of carbon, phosphorus, and sulfur—all of which are plentiful in living organisms—giving Al the potential to wreak havoc in living systems. For these reasons, Al is certainly not “inert,” nor is it biologically harmless [29–48]. As Table 1 shows, Al is causally linked to disorders in plants, animals, and humans [9, 28, 57], especially in the CNS of animals and humans.
Among the CNS problems in humans attributed to Al are dialysis associated encephalopathy (DAE) [32, 62], autism spectrum disorders [9, 63, 64], Alzheimer’s disease, Parkinson’s disease, and related dementias [28, 36] including those typical in Down syndrome . Experimental and clinical data show the CNS as the most sensitive organ system negatively impacted by Al. Toxic effects manifest in impaired psychomotor control, altered behavior (i.e., confusion, anxiety, repetitive behaviors, sleep disturbances, deficits of speech, concentration, learning, and memory), and in potentially fatal seizures [18, 28, 38]. Al has been identified as the efficient cause of a whole class of immune dysfunctions directly involving the CNS and known as “autoimmune-inflammatory syndrome induced by adjuvants” (ASIA) [65–68]. As will be seen in this paper, the disorders with which Al has been associated as a causal factor are pervasive because they begin with the disruption of fluid structures involving water. Also, although Al negatively affects every layer of the body’s biosemiotic systems, on which health depends, the symptoms of Al poisoning are often noticed when they inevitably reach and impact the CNS.
1.1. Aluminum in the Nervous System
As Table 2 shows, humans get about 95% of their Al burden from food  though estimates vary between 2 and 25 mg per day amounting to 14–175 mg per week [70–73]. In urban societies, the intake can exceed 100 mg per day, between 4 and 50 times the averages shown in Table 2. Because of increasing consumption of Al-containing convenience foods , in 2006, the Food and Agriculture World Health Organization Joint Expert Committee on Food Additives (FAO/WHO-JECFA) amended their provisional tolerable weekly intake (PTWI) for Al from 7 mg per kilogram of body weight (amounting to 490 mg per week for an average 70 kg human) to 1/7 of that amount. The Committee concluded that “aluminum compounds have the potential to affect the reproductive system and developing nervous system at doses lower than those” previously supposed . Interpreting the averages in Table 2, using the estimated intake in urban settings as the higher end of the actual range, referring to the supposedly tolerable weekly intake based on the post-2006 numbers, average consumers weighing 70 kilograms are consuming between 2 to 100 times the provisionally estimated safe amounts of Al.
Given that severe toxic effects of Al occur in animal models at a concentration of 1.5 to 5 mg/kg of wet weight, independent of the mode of administration , it may be inferred that lethal poisoning of humans can occur at about 3–10 times the average amounts estimated to be absorbed by adult consumers studied. This leaves a narrow margin between the estimated average uptake and the lethal threshold of Al in the human CNS. Experiments on cats involved injecting Al into the brain and monitoring the response both behaviorally and physiologically . Measured tissue levels of Al averaging 14 micrograms/gram were associated with extensive neurofibrillary tangles, which are a common feature of AD. This level is only marginally higher than the 9–11 micrograms/gram that have been detected in some regions of AD brains postmortem. This physiological effect was associated with observed impairment in short-term memory and acquisition of a conditioned avoidance response . Al also causes a condensation of brain chromatin disrupting DNA transcription . Animal models of neurological disease plainly suggest that the ubiquitous presence of Al in human beings implicates Al toxicants as causally involved in Lou Gehrig’s disease (ALS) [44, 45], Alzheimer’s disease [20, 21, 28] and autism spectrum disorders [9, 63].
1.2. The Toxic Effects of Aluminum as a Vaccine Adjuvant
Al salts (hydroxide and phosphate) are the most commonly used vaccine adjuvants and, until recently, the only adjuvants licensed for use in the USA [79–89]. In the absence of Al, according to their manufacturers, antigenic components of most vaccines (with the exception of live attenuated vaccines) fail to elicit the desired level of immune response [66, 80]. Although Al is neurotoxic, it is claimed by proponents that the concentrations at which Al is used in the vaccines do not represent a health hazard . For that reason, vaccine trials often treat an Al adjuvant-containing injection as a harmless “placebo” (a comparison benchmark or control treatment) or they use another Al-containing vaccine to treat a “control group,” despite evidence that Al in vaccine-relevant exposures is universally toxic to humans and animals [9, 90, 91]. Its use in a supposed “placebo” or in any “control” treatment in vaccine trials is indefensible . It is precisely analogous to comparing fire A against fire B, to make the argument that since A is no hotter than B, A is therefore not a fire.
During the last decade, studies on animal models and humans have shown that Al adjuvants by themselves cause autoimmune and inflammatory conditions [19, 79–81, 90, 95–103]. The animal models show that subcutaneous injections of Al hydroxide induced apoptotic neuronal death and decreased motor function in mice [2, 37–39] and sheep . In newborn mice they were associated with weight increases, behavioral changes, and increased anxiety . All these findings plausibly implicate Al adjuvants in pediatric vaccines as causal factors contributing to increased rates of autism spectrum disorders in countries where multiple doses are almost universally administered . Also, as shown by Goldman and Miller in studies published in 2011 and 2012, strong correlations between infant mortality rates and the number of doses of vaccines administered also suggest deleterious impact of multiple exposures to their components [104, 105].
Follow-up experiments focusing on Al adjuvants in mice by Khan et al.  have shown that the adjuvants do not stay localized in the muscle tissue upon intramuscular injection. The particles can travel to the spleen and brain where they can be detected up to a year after the injection. Such findings refute the notion that adjuvant nanoparticles remain localized and act through a “depot effect.” On the contrary, the Al from vaccine adjuvants does cross the blood-brain and blood-cerebrospinal fluid barriers and incites deleterious immunoinflammatory responses in neural tissues [1–3, 9]. Tracking experiments in mice reveal that some Al hydroxide nanoparticles escape the injected muscle inside immune system cells such as macrophages, which travel to regional draining lymph nodes, where it can exit to the bloodstream gaining access to all organ systems, including the brain. As Khan et al.  have warned, repeated doses of Al hydroxide are “insidiously unsafe,” especially in closely spaced challenges presented to an infant or a person with damaged or immature blood brain or cerebrospinal fluid barriers . Given macrophages acting as highly mobile “Trojan horses” , the Khan et al. warning suggests that cumulative Al from repeated doses in vaccines can produce the cognitive deficits associated with long-term encephalopathies and degenerative dementias in humans [40, 99].
The latest research by Luján et al.  described a severe neurodegenerative syndrome in commercial sheep linked to the repetitive inoculation of Al-containing vaccines. In particular, the “sheep adjuvant syndrome” mimics in many aspects human neurological diseases linked to Al adjuvants. Moreover, the outcomes in sheep were first identified following a mass-vaccination campaign against blue tongue and have now been successfully reproduced under experimental conditions following administration of Al-containing vaccines. Notably, the adverse chronic phase of this syndrome affects 50–70% of the treated flocks and up to 100% of the animals within a given flock. The disorder is made worse by cold weather conditions, suggesting synergy with other stress producing factors. The disorder is characterized by severe neurobehavioral outcomes—restlessness, compulsive wool biting, generalized weakness, muscle tremors, loss of response to stimuli, ataxia, tetraplegia, stupor, inflammatory lesions in the brain and the presence of Al in the CNS tissues, coma, and death . These findings confirm and extend those of Khan et al.  who demonstrated the ability of Al adjuvants to cross the BBB, and they show that Al in the brain can trigger severe long-term neurological damage. The findings by Luján et al.  and Khan et al.  also show how and why reported adverse reactions following vaccinations are most commonly neurological and neuropsychiatric [6, 7].
1.3. Aluminum Disrupts Biosemiosis
The nervous system utterly depends on coherent signaling from the genome upward to psychological and social behaviors and is suited to induce entropy at these and the levels in between them. The long-term consequences involve many minute injuries, leading to inflammation, disorders, diseases, and the ultimate death of certain neuronal elements and possibly of the whole organism. As documented by Gryder et al.  in reference to cancer, disruptions in gene signaling and/or RNA transcription mechanisms induce a range of deleterious outcomes on protein formation. In turn, altered proteins impact cellular function. As Al moves in the body and CNA, it can create dysfunctional cells that foul signaling systems and neural circuits leading to additional dysfunctions and even behavioral aberrations. Immediately and cumulatively, Al-induced injuries tend to be expressed as abnormalities in the CNS trending toward ultimate fatality .
2. Biophysics of Aluminum Toxicity and Impact on Cellular Processes
The concepts of kosmotropic and chaotropic solutes (water structure makers and breakers), introduced by Collins and Washabaugh in 1985, have been used extensively by the biochemical and biophysical communities . These concepts are highly relevant to this section. The reader is referred to Table 4 (above) for a summary of the concepts. According to Marcus (2012), when “the structural entropy according to [Barthel and] Krestov (1991) was compared by Collins (1997) to the entropy of pure water...for the alkali metal and halide ions, and (H2O). Those with have large surface charge densities and are called kosmotropes (water structure making) whereas those with have small surface charge densities and are chaotropes (water structure breaking)” [111–113].
2.1. Al3+ Disrupts Water Dynamics of Biological Exclusion Zones
Al is a reactive element existing abundantly in nature but almost exclusively bound as mineral salts. Al salts are relatively insoluble except under acidic conditions, which are created by organic acids in vivo and adjacent to the exclusion zones (EZs) of biomembranes . Concerning EZs, as argued by Ling  (also see his references), “under an ideal condition, an idealized checkerboard of alternatingly positively, and negatively charged sites of the correct size and distribution could polarize and orient deep layers of water molecules ad infinitum. Based on the quantitative data thus obtained and a relevant simple statistical mechanical law, the new theory predicts that a thin layer of water held between two juxtaposed ideals or near-ideal nanoprotoplasm (NP) surfaces will not freeze at any (attainable) temperature. On the other hand, water polarized and oriented by an ideal or near-ideal NP-NP system may also not evaporate at temperature hundreds of degrees higher than the normal boiling temperature of water” (p. 91). However, as Ling has also shown, Al has the power to alter these crucial EZs, disrupting their unique biophysical properties . Or, as argued more recently by Davidson and colleagues, toxicants such as Al are invariably disposed to contribute to exogenous interfacial water stress (EIWS) in the critical EZs precipitating in vast numbers of minute toxic injuries, and leading to disorders, diseases, and sometimes catastrophic changes ending in fatalities [57, 59, 68, 117–119]. Concerning the many ways that toxicants in both their near and distant effects can increase biosemiotic entropy also (see arguments developed by Oller [17, 51], Gryder et al. , and Ho ). Shaw et al. (2013) have also presented data showing that biological water dynamics crucially enable quantum coherence across all biosemiotic systems .
2.2. Al3+ Speciation, Solubility, and Adsorption Are pH-Dependent
Conventional beliefs about Al safety  are rooted in the knowledge that, in the absence of citrate, insoluble Al compounds are poorly absorbed even if ingested . However, the fact that Al hydroxide and phosphate solutions remain nearly saturated at neutral pH and standard temperature in pure water suggests that their poor solubility does not make them benign in living systems. Many other ligands besides water molecules can interact with Al when it is inhaled, ingested, topically absorbed, or parenterally injected. Acidic beverages such as soft drinks have a ; most fruit drinks have a . Al in drinking water in concert with chemical agents that literally pull it out like claws—as suggested by the term chelation—can increase gastrointestinal absorption  and thus the biosemiotic entropy-inducing tendency of Al. Moreover, precipitates of Al need not be soluble to be toxic, especially in low pH compartments, in vivo, which favor more mobile hydrated Al3+ aqua ion, [Al(H2O)6]3+, as opposed to inner sphere contact ion pairs. According to Martin, the octahedral hexahydrate [Al(H2O)6]3+ dominates at , and the tetrahedral [Al(OH)4]− at , while there is a mixture of species from [120, p. 12]. Adsorption and desorption of Al3+ species have long been known to demonstrate pH dependence [121, 122]. The aluminum aqua ion, [Al(H2O)6]3+, is well characterized in solution and the solid state . In 1994, Marcus provided data indicating that, while [Al(H2O)6]3+ behaved like a typical strong kosmotrope, with a negative structural entropy value and enhancement of the H-bond structure of water, [Al(OH)4]− demonstrated the properties of a chaotrope, with a positive structural entropy value and lessening of the H-bond structure of water . Thus, it is clear from these data that pH has a major influence in determining the speciation, solubility, adsorption, and Hofmeister behavior [58, 59] of Al in vivo.
2.3. Glyphosate—A Ubiquitous Al3+ Chelating Agent
Being a modified form of glycine with both phosphonyl and carbonyl groups, glyphosate is already known to chelate metal cations . Moreover, Al caged by glyphosate dimers and trimmers  bears a certain resemblance to chelation complexes of Al citrate. Given its biocidal effects on gut biota [126, 127], leading to inflammatory intestinal disorders commonly treated by Al-containing antacids , Al interacting with glyphosate is likely to increase its crossing of the endogenous intestinal biofilm barrier into the blood stream [129, 130]. Such Al-induced leaking of the endogenous biofilms of the gut and blood brain barrier could increase Al accumulation in the CNS. Glyphosate impairs the bioavailability of both tryptophan and methionine , and significantly reduced plasma concentrations of these amino acids have been found in Alzheimer’s disease patients [131, 132].
Given the escalating use of glyphosate worldwide and the increasing incidence of inflammatory bowel disease  and gastroesophageal reflux disease , studies with animal models  are needed to assess the potential of glyphosate to specifically chelate and distribute Al compounds in vivo. High precision adsorption calorimetry may prove to be useful means of studying the thermodynamics of Al biosequestration, generally, and glyphosate Al chelation complexation, in vitro [136–138], specifically as suggested in Figure 2 from Guo and Friedman  which shows how Gadolinium (Gd3+) serves in biological cation sequestration. CNS delivery is known to occur, at least in part, via adsorptive transcytosis of cationized proteins and peptides . This empiric observation, therefore, begs the questions: does glyphosate promote adsorptive transcytosis of Al, and vice versa; does Al promote adsorptive transcytosis of glyphosate, across the protective biofilms of the gut and blood brain barrier?
2.4. Al3+ Induces Oxidative, Genotoxic, and Interfacial Water Stress—A Triple Threat
A well-recognized effect of Al3+ is the induction of oxidative stress  and though it has prooxidant  effects through its impact on water dynamics as Ling has shown [143–145], it disrupts enzymes involved in the methylation pathway, increasing EIWS . As a consequence, Al impacts epigenetic interactions and everything dependent upon them. As early as 1968, Riddick showed that Al3+ generally promotes agglomeration and precipitation even of anionic colloidal finely ground silica (minusil) . Evidently, it does so in the same way that, in living organisms, Al3+ disrupts interfacial hydrogen bond (H-bond) cooperativity and the quantum coherence of water essential for cellular homeostasis.
2.5. Al3+ Disrupts H-Bond Cooperativity of Biological Water
The disruption induced by Al3+can be seen as a “red shift” of the stretching bands in the absorption spectra of water to longer wavelengths—thus a “bathochromic” shift—on both infrared and Raman spectroscopy. In 1985, Newton and Friedman employed a neutron diffraction method  to show that the dominant isotope effect of +3 ions is associated with the O–H stretch of the water. The shift to lower frequencies is proportional to the square of the ionic charge in Na+, Mg2+, Al3+ (or, resp., 1, 4, and 9), while the oscillatory motion—the “libration” frequency—increases linearly with z in the same series (or, resp., 1, 2, and 3). More recent confirmation of this expectation has been produced in a series of papers by Probst and Hermansson (1992), Desiraju and Steiner (2001), Joseph and Jemmis (2007), and Jemmis and Parameswaran (2007) [148–151].
Light and electron microscopy also show that cell morphology is sensitive to EIWS . Tielrooij et al. (2010)  employed both terahertz and femtosecond infrared spectroscopy showing that the effects of ions and counterions on water can be strongly interdependent and nonadditive, and, in certain cases, extend well beyond the first solvation shell of water molecules directly surrounding the ion . They also found that, “if strongly hydrated cations and anions are combined, the dynamics of water molecules are affected, wherein the hydrogen bond network is locked in multiple directions (italics, ours)” as shown in Figure 1.
2.6. Al3+ Disrupts the Critical Metastable State of Neurolemmal Membranes
Al3+ dangerously shifts the intracellular balance that normally keeps macromolecules of DNA, RNA, and proteins from breaking up and disintegrating into an incoherent, disordered chaotropic mixture. This can lead to the disintegration of blood cells for example in hemolysis or, with equal harm, bioactive molecules combining in biologically useless ways into kosmotropic precipitates, forming dysfunctional molecular debris deposited on the walls of blood vessels (as in atherosclerosis, e.g.) or disabling neurons (as seen in the beta amyloid and/or hyperphosphorylated tau deposits characteristic of Alzheimer’s plaques and tangles). To the extent that the membranous (plasmalemmal) material of all cells, along with the material linings of mitochondria, neurons, and neurofibrils, can be depolarized by Al3+; the loss of cytoskeletal conduction, much like an electrical circuit that “shorts-out” and burns, is certain to be injurious to macromolecules and to cells.
Some molecular damage can result in the orderly, and usually safe, disassembly of cells by apoptosis  or, with Al3+ toxicity, the disorderly disintegration which may release formerly contained pathogens and/or additional toxic debris, leading to necrosis and disease-enabling conditions. The noted effects of Al3+ can graduate from destroying macromolecules, plasmalemmal membranes, and whole cells to the destruction of tissues, organs, and even the death of the whole organism . Studies on plant seedlings have shown an immediate effect on the cytoskeleton in which Al3+ causes a calcium channel blockade by its depolarization of membrane potential . In both plants and animals, Al3+ blocks voltage-gated calcium channels and interferes with normal metabolism [157–162]. It also disrupts the stable water clusters found in highly structured multilayered EZs that serve as vehicles for storing incident radiant energy, as Chai et al. have shown .
Platt et al. (1993) demonstrated that extracellular pH modulates the Al blockade of mammalian voltage-activated calcium channel currents  at concentration range <200 μM. Platt and Büsselberg (1994) then investigated the extracellular and intracellular effects of Al on voltage-activated calcium channel currents (VACCCs) in rat dorsal root ganglion neurons  and found that (a) Al applied extracellularly reduces VACCCs in a concentration-dependent manner, (b) the effect of Al was highly pH dependent in the investigated range (pH 6.4 to 7.8), and (c) there was evidence of intracellular as well as extracellular binding. They concluded that irreversibility, use dependence, and pH dependence, as well as binding sites for Al inside cells, contribute to its neurotoxicity. Platt and Busselberg also examined the combined actions of Pb2+, Zn2+, and Al3+ on VACCCs  showing that each of these metals reduced VACCCs, for all possible combinations, independent of the order of application. The impacts were additive and consistent with two metals acting at the same site as well as independent actions at different locations of the ion channel. Trombley (1998) demonstrated selective disruption of class A gamma-aminobutyric acid, the ligand gated ion channels () receptors, by Al occurred with a minuscule concentration of <100 μM in a culture of rat olfactory bulb neurons .
At the same time, and for some of the same reasons, ultrafast electron crystallography of’ interfacial water by Pal and Zewail (2004) as followed by Oliveira et al. (2010) showed that recognition at the macromolecular levels of DNA, RNA, and protein is dependent on biological water dynamics in the 20–40 picosecond range [159, 160]. Based on the biosemiotic functions of such macromolecules, loss of such recognition would invariably lead to molecular mimicry, immune dysfunction, and the onset of autoimmune disease. Neuropathological states involving immune disorders can thus be conceptualized to arise from the breakdown of, or deviation from, the metastable critical state of biological water dynamics at the interphase of neuronal membranes. Similarly, with respect to neurological damage, Al has been shown to induce neuronal apoptosis in vivo as well as in vitro .
Sadiq et al. (2012) found that metal ions such as Al3+ tend invariably to target signaling pathways and may interact with various targets simultaneously. The long-range consequences show that ions interacting with any given molecular target can disrupt all of the processes dependent on it . With respect to developmental neurological and other communication disorders, Oller and colleagues (2010a, 2014) have described this phenomenon as a domino or cascading effect [167–169] and Seneff et al. produced the same sort of argument for the biophysical level . Likewise, Shaw et al. (2013) show how minimally stable states of interphase water at neurolemmal membranes can be upset by “noise” from Al3+ producing a “domino” effect  inducing long-wavelength perturbations leading to a cascade of energy dissipation on all scales .
2.7. Biological Water Modulates Biosemiotic Entropy at Multiple Levels Concurrently
Underlying all of the foregoing evidence, there is sound theory and a growing body of research (partially summed up in Figure 1) showing that water, rather than being a passive medium in which biological reactions take place, is an active participant [59, 60, 171]. With that in mind, it is plain that Al3+ must disrupt long-range, dynamical, interfacial H-bond cooperativity and that it must interfere with the quantum coherence of water, both of which are essential for cellular homeostasis. The geometry proposed by Tielrooij et al. (Figure 1), in which the water dynamics are locked in two directions, shows how the cation and anion produce the polarized-oriented multilayer (PML), confirming the theory of Ling (2003) , the exclusion zones (EZs) of water reported by Zheng and Pollack (2003) [114, 172, 173], and the H-bond cooperativity implicit in the EIWS theory . Because of their chemical properties and affinities, Al3+ species tend to disrupt the hydrophobic surfaces of water based biofilms of all kinds. Al3+ disrupts such films by breaking down the complex hydrophobic forces binding the liquid. This kind of breakdown can be seen in its impact on the liquid films containing the peculiar colloids known as “coacervates” studied for the last 150 years by Lillie , Oparin and Synge , and numerous others, the recounting of which is found in Ling’s work as cited. It also has the same disintegrative effect on the neurolemmal membranes throughout the body, showing how protoplasmic poisoning is invariably induced at many levels by the Al3+ species. The barriers between the blood and the brain and blood and the spinal cord, as well as the barriers protecting the blood and the rest of the body’s tissues from the contents of the gut can be thought of as analogous to “exclusion zones” or differentiated “coherence domains” [172, 176], consisting in part or in whole of polarized-oriented multilayers of biological water as described by Ling  (and see his references).
Because of stretching and reorientation of H–O bonds, generalized from the dynamics illustrated in Figure 1, the local “unwetting,” “stretching,” and hydrophobic “collapse” of interfacial water can also disrupt signaling systems, leading to immune dysfunctions and autoimmune diseases, all beginning with EIWS [59, 68]. Also, for reasons already partially explained, the CNS is particularly susceptible to Al toxic damage, especially considering the critical role of biosulfates, both the HSPGs and, especially, the sulfoglycolipids such as sulfatide [57, 117, 118, 177] in the CNS. The latter are crucially involved in the formation of myelin, which is essential for healthy neural tissue and functions of the CNS and peripheral systems. Myelin, in turn, depends on HSPGs, which are essential in generating current and separating charge. But because myelin lipids and proteins demonstrate surface fractality over many scales [170, 178], toxic impact from Al and its compounds can do far-reaching harm. Also, it is known that Al3+, F1−, Hg2+, and Pb2+ are synergistically toxic and particularly so because of their affinity for biosulfates, such as the HSPGs.
The anion in Figure 2 may be generalized conceptually to include the biosulfates, or , fluoride (1−), carboxylates, oxyanions of nitrogen, and the biophosphates. The cation in this figure may also be generalized conceptually to include high charge density polycationic metals, such as Al3+, Hg2+, and Pb2+, as well as oxycations. If vectors (arrows with direction and magnitude) are employed, as in Figure 1 , the dynamical reorientation of the OD-stretch transition dipole moment vectors and permanent dipole vectors will result in polarization and orientation of multiple layers of water along the lines explained by Ling in 2003 .
2.8. Protoplasmic Poisoning via Cooperative Adsorption of Polycationic Metal Toxicants
In 2008, Harrison et al. found that certain heavy metal cations exert synergistic bactericidal and antibiofilm activity against Pseudomonas aeruginosa . In May 28, 2008, Harrison et al. filed patent (U.S. 2008/0118573 A1) for use of heavy metals in the treatment of biofilms, including metal cations such as Mn2+, Co2+, Ni2+, Cu2+, Zn2+, Al3+, Ag+, Hg2+, Pb2+, Cd2+, Sn4+, and metalloid oxyanions. In 2010, Renslow et al. employed pulsed-field gradient nuclear magnetic resonance to study in situ effective diffusion coefficient () profiles in live biofilms  and observed distinctive spatial and temporal variation in for various locations in the biofilm. In 2013, Davidson et al. reviewed literature showing that, in several neurodegenerative and neuroimmune diseases, loss of anisotropy, loss of curvature, increase in diffusion magnitude, and loss of stiffness (softening), may be directly attributed to destructuring of interfacial water, which precedes overt signs and symptoms of oncologic, neurologic, and infectious disease [119, pp. 3851-3852].
Ling (1991) has argued as follows.
In autocooperative adsorption, the adsorption of an th solute favors the adsorption of more ith solute; in a heterocooperative adsorption, the adsorption of an th solute favors the adsorption of the alternative th solute. Autocooperative behaviors, like those of a school of swimming fish and the sentinels guarding the Great Wall of China, tend to be all-or-none. … autocooperative adsorption is the backbone of coherent behavior in living cells including the maintenance of the living state [181, pp. 135–58].
Heterocooperative adsorption of Hg2+ solute would favor the adsorption of an alternative solute, such as Al3+ and vice versa, in a manner which tends to be all-or-none. Cumulative heterocooperative adsorption of cationic neurotoxicant metals, for example, Hg2+, Al3+, and Pb2+ explains their neurotoxic synergy and biosequestration.
2.9. EIWS Promotes Both Structural and Biosemiotic Entropy
The fact that Al3+ species are potent exogenous interfacial water stressors per the EIWS theory was elaborated by Davidson et al. [57, 59, 68, 117, 119, 177]; Marcus (2013) found, in his study of the incremental surface tensions of various elements, that Al3+ has one of the largest individual ionic surface tension increments (second only to La3+) . This finding explains why Al3+ along with Hg2+ and Pb2+, as well as various cationic and nonionic surfactants, are potent factors in producing EIWS. Such observed facts explain how aluminum/phosphate and aluminum/sulfate species, either as the Al3+ aqua ion form at low pH or the inner sphere contact ion pairs at higher pH, by exceeding the incremental surface tension threshold of exclusion zones, can disrupt H-bond cooperativity . In doing so they must augment biosemiotic entropy in vivo, tending toward dehydration as described by Sharma and Debenedetti (2012) .
In 1966 and 1967, Selye had already provided a comprehensive exposition of the toxicity of polyvalent metal ion salts [183, 184], particularly those with high charge density, leading to serial sensitization, resulting in both local and systemic thrombohemorrhagic phenomena, with microvascular ischemic and immune sequelae, in a highly stereotyped, pluricausal manner. The earliest events in the toxicity of Al3+ are biophysical, mediated by water, through disrupted interfacial H-bond cooperativity and quantum coherence [185–190]. Consistent with the red shift in Raman vibrational absorption frequencies discussed earlier and demonstrating it, in part, Falk (1984) had already found that a lowering of the bending frequency of water is associated with increasing cation charge and decreasing cation size . Much more recently, Imoto et al. (2013) studied the origin of the difference in the H–O–H bend of the infrared spectra between liquid water and ice . Furthermore, as suggested by Exley (2004)  and Mujika et al. (2011) , Al3+ may be predisposed to react in vivo with toxic impact on endogenous reactive oxygen species, such as the superoxide radical anion to form an Al-superoxide semireduced radical cation complex 2+.
2.10. Distinctive Physical Properties of Al Species Determine Their Toxicity
Another unique property of Al ions is their high charge density. Ionic charge densities are reported in Table 3 using the methodology described by Rayner-Canham and Overton (2010) . Also reported in the table are the crystal atomic radii as published by Shannon (1976) for the various ions . The charge density of Al3+ is 372.6 C·mm−1 as compared to that of Gd3+ (91.5 C·mm−1), F1− (16.2 C·mm−1), Na+ (24.5 C·mm−1), and Ca2+ (51.6 C·mm−1).
The high charge density of Al is a consequence of its relatively small radius and its fixed 3+ charge. These factors impact the solubility of the individual Al salts and their incremental impact on the surface tension of water [94, 195, 196]. With respect to biological impact, the vast array of enzymes and signaling proteins inhibited by Al species shows that Al toxicity is not limited merely to diffusion. The interaction of the various Al species with long-range, dynamical H-bond networks and the coherence domains of interfacial water suggests the involvement of nonthermal, magnetic , and quantum effects that are no doubt generalizable to many toxicants, particularly those with polycationic surfactants of high charge density (see Table 3).
Inorganic ions can be ranked on a chaotropic (disintegrative) to kosmotropic (colloid forming) gradient according to their enthalpy of hydration [197, 198] presented in Table 5 (above). The more negative the enthalpy of hydration, the more kosmotropic the solute. The opposite would indicate a chaotropic tendency. A formula that aids in understanding the relationship between charge density, radius, and enthalpy of hydration is given as follows: where = Hydration enthalpy, = Charge of the ion, = Ionic radius, and = Dielectric constant of the solvent.
A smaller atomic radius and higher charge correlate with a more negative hydration enthalpy and greater kosmotropism—defined biologically as the tendency to cause macromolecular complexes in bodily fluids to form useless colloidal precipitates that are effectively sequestered from the water in organelles, cells, blood, lymph, protoplasm, or any bodily fluid. In biological systems, protein folding and unfolding (DNA also) depend on a delicate balance of chaotropic and kosmotropic forces on water . Solutes sorted according to a chaotropic to kosmotropic gradient define the Hofmeister series . In agreement with hydration enthalpies found in Table 5, Al3+ normally acting as a powerful kosmotrope plays havoc with the biological balance. In particular, the more kosmotropic a substance is, the more capable it is of salting-out proteins from an aqueous medium. Table 4 presents a comparison of the properties of chaotropic and kosmotropic ions.
The oxyphilic behavior of Al acting as a kosmotrope is shown in its avid binding to oxyanions of carbon, sulfur, and phosphorus . Its lipophilicity, dose-dependence, time-dependence, and glial versus neuronal specificity have been studied by Campbell et al. (2001)  and as early as 1996, Bondy and Kirstein had already shown how Al species can promote iron-induced generation of harmful reactive oxygen species . Cations such as Al can bind to π electrons within biomolecules  in vivo, inciting lipid peroxidation, DNA damage, and disruption of essentially all the biosemiotic systems deploying molecules containing calcium and sulfur . A prima facie indicator of its toxicity is inflammation shown in cerebral markers elicited by chronic exposure to Al in drinking water . Kiss (2013) has reviewed the coordination chemistry of Al3+ with small and large biomolecules, including serum components, and also the role of time in the distribution of this “sluggish” metal ion in a biological environment . The results agreed with the computer model of Beardmore and Exley (2008), showing that Al has kosmotropic effects at a greater distance and more quickly than the “depot” theories could possibly explain .
The magnitude of the kosmotropic property of Al3+ can be seen in bold relief by comparing the degree of H-bond strengthening required to cause Al3+ to behave as a chaotrope . If the H-bond energy of water increases, then various kosmotropic ions behave as chaotropes and vice versa. The required change in strength of H-bonds to cause Na+ to behave as a chaotrope is 11% strengthening and for K+ to behave as a kosmotrope is 11% weakening. The gradient between Na+ and K+ is almost two orders of magnitude smaller in comparison with the hydration enthalpy of Al3+ (−4690 kJ mol−1), in theory, the amount of energy released (as heat) when a mole of Al3+ dissolves into an infinitely diluted solution. The change of H-bond strength required for Al3+, a kosmotrope, to behave as a chaotrope is 1260.75% H-bond strengthening. The required H-bond strengthening is calculated by dividing the hydration enthalpy of the solute by the estimated isotropic point (−372 kJ mol−1). Table 5 shows selected hydration enthalpies of several common biologically relevant ions.
2.11. Molecular and Cellular Biosemiotic Disruption by Al3+ Is Concomitant
The foregoing facts and findings in this section help to show why and how Al3+ interacts synergistically with certain other toxic molecules and how it acts in producing or augmenting auto- and neuroimmune diseases. Kamalov et al. (2011) demonstrated the cytotoxicity on immune cells of environmentally common concentrations of Al (10–40 μM) in murine thymocytes and lymphocytes . Nearly all thymocytes showed evidence of damage at 30 μM AlCl3 after only 5 minutes of incubation. A 60-minute exposure to 10 μM AlCl3 caused damage of about 5% of thymocytes, while 50% were injured after 10 minutes at 20 μM. In lymphocytes, injury was observed at 15 μM AlCl3, and less than 50% of cells were injured after a 60-minute exposure to 20 μM. Injury only rarely proceeded to rapid cell death and was associated with cell swelling. These results demonstrated a rapid dose-dependent injury in murine thymocytes and lymphocytes resulting from exposure to Al, as indicated by an increase in the entry into the cell of the DNA-binding dye, propidium iodide. The data suggest direct damage to the plasma membrane, manifested as an increase in membrane permeability, consistent with the EIWS theory.
Likewise, with respect to the synergistic interaction of Al3+ with Hg2+ species, Kern et al. (2013) examined the action of low levels, 1,000 nM, of thimerosal (49.55% Hg2+ by weight) on immortalized B-cells taken, respectively, from autism spectrum disorder subjects, their fraternal twins, a sibling, and an age/sex matched control. Observed contrasts showed impaired sulfation chemistry owed to the thimerosal exposure [209, 210]. In 2009, Pogue et al. presented data which underscores the potential of nanomolar concentrations of Al to drive genotoxic mechanisms characteristic of neurodegenerative disease processes [211, 212]. These data, combined with results reported earlier by Haley (2005), suggest toxic synergy between μM Al3+ levels and nM thimerosal levels, in vivo .
While Al3+ can undoubtedly form complexes with proteins, nucleotides, nucleosides, RNAs, and DNAs, so too can stable nanoclusters of water, some of which are helical . The presence of Al3+ could only create difficulties in such delicately balanced systems . Also, given the growing body of empirical data suggesting that both gene structure and protein structure are dependent in part on interfacial water dynamics, it follows that the best known biological macromolecules depend in part on supramolecular systems [216, 217].
3. Corrupted Processes and Pathways Induced by Aluminum
3.1. Effect of Al on Iron Toxicity and Interference with BH4 and Calmodulin Function
Al is primarily transported in serum by transferrins . Al may interact with transferrins at multiple candidate binding sites, including the transferrin receptors, thus influencing iron metabolism and transport. The fastest subunit of transferrins to react with iron is the tyrosinate complex . Other amino acid residues with which Al may interact are aspartic acid, glutamic acid, and glutamine . Al readily binds to apo-transferrin binding sites but does not compete with iron for binding with halo-transferrins. Al causes small conformational changes in transferrins without significant structural consequence , thus enabling transferrin receptors to actively transport Al across the blood brain barrier as if it were iron . Once in the brain, displacement of iron from transferrins by Al results in iron toxicity and overproduction of reactive oxygen species by Fenton reactions [203, 223].
Six interactive cycles within the methylation pathway include (1) the urea cycle, (2) the tetrahydrobiopterin (BH4) cycle, (3) the folate cycle, (4) the methionine cycle (5) the S-Adenosyl methionine (SAM) cycle, and (6) the transsulfuration pathway. Dihydrobiopterin reductase (DHPR) is a critically important enzyme in the BH4 cycle that is inhibited by Al, and calmodulin (CaM) is critically inhibited in the urea cycle.
DHPR inhibition is implicated in Al induced encephalopathy . Many accounts of Al toxicity are reported in the context of renal insufficiency. Al intoxication associated with pediatric renal insufficiency causes progressive encephalopathy in children . Furthermore, Al intoxication by any cause such as occupational exposures will have the same inhibitory effect on DHPR . BH4/BH2 ratios are decreased as a result of DHPR inactivation. BH4/BH2 ratios are reported to be decreased in Alzheimer’s disease  and in autism . About 60% of children on the autism spectrum are reported to experience clinical improvement after BH4 replacement therapy .
The folate cycle  enables components of urea, BH4, and methionine cycles to adapt to varying oxidative conditions. The dihydrofolate reductase (DHFR) system is a means of BH4 supply in cases of dysfunctional or inactive DHPR . In this process, DHPR becomes more active in recycling BH4 from BH2 instead of acting on dihydrofolate to synthesize tetrahydrofolate when DHPR is functional. Congenital DHPR deficiency, such as in phenylketonuria (PKU) is associated with folate depletion  and treatment for PKU includes dietary folate replacement .
In addition, BH4 is cofactor for production of dopamine from tyrosine. Dopamine, cyanocobalamin, and 5-methyl tetrahydrofolate are required for synthesis of methionine from homocysteine [233, 234]. In Al toxicity, as in autism , dopamine becomes depleted because BH4 is depleted, further limiting remethylation of DNAs, RNAs, lipids, and proteins . Furthermore, methionine is required to methylate DNA. The brain malformations seen in autopsies of autistic subjects  suggest failure of DNA methylation during brain development and growth.
In the urea cycle, BH4 is a cofactor with arginine in the synthesis of nitric oxide (NO) under endothelial nitric oxide synthase (eNOS). Not only does Al inhibit DHPR and production of BH4, but it also out-competes calcium for binding sites on calmodulin (CaM) causing conformational changes . Properly bound with calcium, CaM is an essential cofactor in coupled eNOS mediated production of citrulline and NO from arginine. If BH4 is depleted or Al binds to calmodulin, eNOS follows an uncoupled pathway that favors production of peroxynitrite and superoxide. NO levels are paradoxically high in BH4 depletion, because it continues to be produced by alternate pathways, and its release from endothelial cells is inhibited by the high level of accumulated homocysteine .
High NO levels are associated with increased vascular permeability. NO stimulates mast cells and macrophages to release proinflammatory cytokines including IL-1, IL-6 tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) . This is the inflammatory profile found in autistic encephalopathy . Accumulation of both reactive oxygen and nitrogen species results in severe oxidative and nitrosative stress [241–243].
3.2. Effects of Distinct Formulations of Aluminum Adjuvants: A Role for the Zeta Potential
As already noted, Al adjuvants are predominant modulators used in vaccines, although relatively little is known about how they work . It was formerly claimed that Al adjuvants directly stimulate antigen-presenting cells by forming an antigen depot at the injection site . Given the evidence that Al species used in adjuvants are readily transported throughout the body, the depot theory must be rejected. Others have proposed that Al stimulates dendritic cells, activates the immune complement system, and induces the release of chemokines . It is generally agreed that Al hydroxide induces a Th2 type immune response [247, 248], whereas Al phosphate has been shown to induce a Th1 type response .
However, based on data from the CDC’s Vaccine Adverse Event Reporting System (VAERS) database it is possible to compare the three distinct Al adjuvants used in the DTaP vaccine in particular (see Table 6): they consist of a hydroxide, a potassium sulfate, and a phosphate. The fact that all are used in the same multivalent vaccine minimizes the degree to which other factors, including the several antigens in the vaccine, might be influencing adverse reactions. Assuming only that all other factors excepting the Al adjuvants are held constant, an experimentally orthogonal comparison is possible among the three adjuvants. The method of comparison was a standard ratio of an expected value to the one obtained in each instance as susceptible to a standard chi-square distribution (the log-likelihood ratio) as described in .
The statistic in question expresses the likelihood that a given ratio of expected adverse reactions to actually observed adverse reactions could be attributed to chance. The critical probability for our tests was conservatively set at . The VAERS database for DTaP adverse reactions for the several formulations were compared with subsamples matched for age and number of cases. The comparison enabled the testing of experimental predictions concerning the relative mobility of charged particles in an electric field based on the Zeta potential (ZP) of the various Al adjuvants at issue. In blood—the most abundant fluid involved in transporting adjuvants from an injection site—the ZP reflects the negative charge of molecules attached to the membranes of suspended particles, such as red blood cells (RBCs) or lipid particles, which the Al3+ compound in any given case would be likely to link up with. A less negative ZP is associated with an increased tendency for RBCs to aggregate  that is, to form clots, whereas an even more negative ZP reduces that tendency.
The three DTaP formulations (Table 6) differ chemically only in their Al adjuvant component, as detailed by Caulfield et al. , and to that extent the vaccines differ in zeta potential (ZP). As those researchers found, ZP measured at pH 7.0 closely matching the value for blood, yielded a ZP value for hydroxide at +30 mV, for sulfate at 0 mV, and for phosphate at −20 mV: the sulfate formulation, therefore, should have the least impact. Using its ZP value at 0 mV as the baseline, it provided a reasonable estimate of the “expected value” for the ratio comparisons with the other two adjuvants to assess the impact of ZP on the adverse reactions reported. Results shown in Tables 7 and 8 show the outcomes for phosphate and hydroxide adjuvants. Compared to phosphate, local adverse events are reported more often for hydroxide, which, as expected, should migrate less from the injection site owing to a higher positive ZP, while phosphate should show the opposite effect owing to its negatively displaced ZP value.
The negative charge induces mobility owing to the electrical field induced by the voltage difference between arteries and veins [99, 100] while the positive charge tends to prevent mobility through the blood. The voltage difference is partly because the veins have a lower pH because CO2 is more acidic than O2. The lymphatic system, of course, as noted by Gherardi and colleagues [98–100], affords a bypass route that white blood cells (e.g., immune cells) can take (having penetrated the endothelial wall into the tissues) [252, 253]. However, this pathway also has the same voltage drop that would propel movement of negatively charged particles, as the lymph system returns to the venous system at the subclavian vein. On the other hand, positively charged particles would be stalled in the tissues as shown by Davidson and Seneff .
Thus, with the Al hydroxide adjuvant, we expect and find relatively more edema (swelling) at the injection site accompanied by “injection site reaction” and cellulitis because both plasma and lymphatic transit are stalled. Al phosphate, in contrast, with higher mobility and easier migration through the lymphatic system into the venous system, is more likely to reach distant areas including the brain, resulting, as observed, in a greater likelihood of systemic responses such as throat irritation, nausea, diarrhea, abdominal pain, and seizures. As expected, Al potassium sulfate did not produce any reactions with a value under 0.05, when compared against either of the other formulations.
Observed syndromes associated with Al hydroxide include “macrophagic myofasciitis” (MMF) characterized by diffuse myalgia, chronic fatigue, and cognitive dysfunction, termed “mild cognitive impairment” [38, 40]. In a relevant study of that disorder, it was determined that the Al hydroxide adjuvant led to an accumulation of Al-loaded macrophages at the site of a previous intramuscular immunization . Given the results reported in Table 7, it must be inferred that macrophages lingering at the injection site on account of the elevated ZP associated with the hydroxide formulation are responsible for this observed syndrome. Likewise, the autoimmune syndrome recently identified by Shoenfeld and colleagues [65–67] is consistent with the generalized toxicity of the Al adjuvants.
3.3. Aluminum Interactions with Fluorine
Fluorine is the most chemically reactive nonmetal and the most electronegative element . According to Martin (1996) , Al3+ binds F- more strongly than 60 other metal ions tested. Even with micromolar concentrations of Al3+, these two atoms react to form , a molecule whose shape and physical properties closely resemble those of the phosphate anion, . This feature has been exploited to help researchers understand phosphate-dependent reactions in signaling cascades [255–258]. For example, it has been shown, by exploiting , that melatonin’s widespread signaling effects are mediated by G-proteins . However, if forms whenever these two elements are both present, it is known to interfere with regulatory GTP hydrolases which play an initiating role in phosphate-based signaling cascades [260, 261]. Should the mimetic, which is not responsive to the GTPase, stick in the “on” position, an overresponsive cascade of transcription, motility, and contractility, as well as apoptosis would proliferate. If this were to happen, such interference, for which Al toxicity affords many alternative routes remaining to be explored, is certain in all cases to augment biosemiotic entropy.
Strunecká and Patocka proposed that the toxic role of Al in Alzheimer’s disease may be predominantly due to the formation of . The formation of that complex, according to experimental evidence, in quantities as little as 1 ppm of fluoride contamination of water supplied to rats led to greater uptake of Al into the kidney and brain along with the formation of amyloid deposits like those in Alzheimer’s disease . As proteins, RNAs, and DNAs become damaged through oxidation [264–267], if they cannot be repaired, failure of the lysosomal and mitochondrial organelles will lead to apoptosis [268–270] or, in worse cases, to necrosis. Al compounds can only contribute to such outcomes in a negative way.
Prior research has also shown that insufficient sulfate in the extracellular matrix of all the tissues, particularly the endothelial wall, plays a significant role in disorders and disease conditions [59, 117, 177, 199]. Heparan sulfate populates the glycocalyx in the capillaries [118, 271–273] and enables a low-resistance capillary wall permitting smooth blood flow [57, 59, 68, 117, 177, 199]. Sphingosine-1-phosphate-induced Rac activation, chemotaxis, and angiogenesis associated with endothelial cell migration are mediated by G-proteins .
With all of the above considered it may be notable that postmortem examination of Alzheimer’s brains reveals severe deficiency in sulfatide, a myelin-specific sulfated sphingolipid, which normally makes up 6% of the lipid content and is especially concentrated in the myelin sheath . Twenty-two subjects in the early stage of Alzheimer’s disease showed a depletion of 93% in gray matter and up to 58% in white matter in all brain regions examined. Aside from an overabundance of ceramide, the precursor to sulfatide (ceramide was elevated threefold in white matter), all other lipid parameters appeared normal. This outcome was not associated with a defect in sulfatide synthesis, so the pathology appears to involve breakdown of sulfatide to provide sulfate to the vasculature, critical for maintenance of an adequate supply of oxygen and nutrients to the brain.
Seneff et al. previously suggested that endothelial nitric oxide synthase (eNOS), an enzyme present in endothelial cells, RBCs, and platelets, among other cell types, is a “moonlighting” enzyme, which synthesizes sulfate when it is attached to caveolin in the plasma membrane and synthesizes NO (which is converted to nitrate within a few seconds) when it is phosphorylated and bound by a calcium-CaM complex in the cytoplasm . These findings suggest that eNOS plays the dual-purpose of regulating the balance between kosmotropes and chaotropes in the cytoplasm of the cell and also enabling the proper folding and functions of cellular proteins , as detailed in Figure 3.
Considering all the ways Al3+ is known to impact biological systems negatively, as summed up in Table 1, exposure to that cation generally disrupts biosemiotic cascades. Its effects lead to minute cumulative injuries to DNAs, RNAs, cellular proteins, and lipids through glycation and oxidation damage, as well as impaired lysosomal recycling of debris, and, ultimately, in some cases, leads to cell death by necrosis. Death by apoptosis, the preferred alternative, may also follow Al-induced injuries and changes in DNAs, RNAs, proteins, and any downstream mediators. For example, MMF has been shown to manifest with Al retention at the injection site of vaccines containing Al hydroxide [38, 39] and far-reaching negative effects on the body’s immune systems can be seen in ASIA owed to eventual migration of Al adjuvants away from the injection site [65–67]. Given its positive differential impact on ZP, Al hydroxide has been shown to linger at the injection site for many months, although it eventually is transported into brain by macrophages . In that particular case, the normal apoptosis of injured cells is disrupted by the high electrostatic attraction of the Al3+ ion towards the negatively charged sulfates in the glycocalyx actually forcing the Al3+ cation to penetrate and traverse the viscous water of the exclusion zone. The result is disruption of the structured water in the exclusion zone, compromising the glycocalyx barrier and allowing signaling molecules to gain access and launch a G-protein mediated cascade reaction.
This cascade is intensified by the effects of AlFx on G-protein signaling, and the subsequent disruption of cellular metabolism follows. When the cell becomes necrotic, having skipped over any possibility of normally regulated and orderly apoptosis, it virtually disintegrates, releasing DNA and other cellular debris into the interstitial spaces to degenerate or to be carried away by the lymphatic system. In the case of the other less confined Al adjuvants that can more readily migrate away from the injection site, the confusion induced in biosemiotic systems is the predictable source of a confused and self-destructive autoimmune response as seen in ASIA. The downstream result is an immune attack on cells, tissues, and organs throughout the body but especially in the CNS, as seen in diseases such as multiple sclerosis and other demyelinating conditions.
It is clear that Al3+ toxicity, interacting synergistically with other toxicants such as solvated species of Hg2+, Pb2+, F−, AlFx (aluminofluoride), SiFx (silicofluoride), glyphosate, and including chelation complexes, must directly increase biosemiotic entropy on multiple levels simultaneously by disrupting long-range, dynamical, interfacial hydrogen bond cooperativity and the quantum coherence of water. The outcome is widespread (systemic) and involves virtually simultaneous inhibition of many different enzyme systems. It is therefore unsurprising that Al3+ is associated with anaphylaxis and sudden death . The data from the studies reviewed here show that the complex coacervate protoplasm, studied now for about 150 years [145, 174, 175], is susceptible to poisoning by high charge density polyvalent cations, for example, Al3+, Hg2+, and Pb2+. Empirical studies [93, 94] of ion solvation suggest that local order induction can result in loss of long-range, systemic coherence and cooperativity . On a supramolecular biosemiotic level, EIWS induced by Al3+ disrupts interfacial hydrogen bond cooperativity and quantum coherence of biointerfacial water. At a critical threshold, the self-ordered criticality of biointerfacial water collapses. The most notable effects of this sort occur in the CNS [68, 276].
In the larger context, however, Al toxicants can themselves, or by synergistically interacting with other toxicants, destroy cells in any organ system, although none are more vulnerable than the CNS and the peripheral systems attached to it. While significant everywhere in the body, the impact of biosemiotic entropy in the CNS is critical because of the nested and highly interdependent systems connected to it. For example, the loss of neural cells (neurons or glia) in the CNS tends to disrupt circuits that depend on such cells. In turn, groups of neurons in functional nuclei can be rendered dysfunctional through the loss of individual neuronal elements. In the same way, the loss of functional nuclei can lead to catastrophic stress on the CNS itself and/or on dependent organ systems. Fatality may be preceded by a cascading series of failures resembling the collapse of complex interdependent networks .
An additional factor that makes the nervous system uniquely vulnerable is the highly specified differentiation of neuronal activities due to sequenced developmental programs. These programs, acting in response to both genetic and environmental instructions, ensure that the loss of functional circuits cannot be easily replaced, since the very milieu into which they might be integrated (e.g., stem cells) differs from one stage of development to the next during which some window, or “critical period,” for neuroplasticity may have passed. While it is true that critical periods vary between neuronal regions (human association versus primary cortex, e.g.), younger nervous systems appear to have a greater capacity for recovery following injuries to organ systems provided stem cells remain intact. However, damage to the DNA of stem cells is apt to be irreparable even in early stages of development, and Al3+ can cause both injuries to organs and DNA damage directly impacting stem cells.
A third reason for the notable toxicity of Al3+ is that neurogenesis—that is, the birth of new neurons—is relatively rare in the adult CNS in most regions. Compared to the ability of other organs to regenerate, for example, the skin or liver, the CNS has limited capacity to do so, which renders it more vulnerable to irreversible damage at fairly early stages of development. Thus, Al and its compounds have remarkable power to harm neurons and to produce systemic damage. The observed impact may, in some instances, be sudden, as in anaphylaxis and sudden death syndrome, but in other instances, it may build slowly to a crisis level through chronic doses leading to systemic autoimmune responses as in the vaccine-induced disorders. The variable range of toxic effects in ASIA, for example, can best be explained in terms of the biodistribution and pharmacokinetics of the particular Al adjuvant used. Some of the observed differences depend predictably on ZP and its impact on interfacial water tension.
Figure 4 is a two-dimensional schematic showing some of the ways Al and its compounds can impact the biosemiotic systems encompassed by the CNS. The summary suggests a nested biosemiotic hierarchy of ranked systems communicating within and across levels. In ascending order, they range from molecules to genes, proteins, cells, circuits, CNS subsystems, and the CNS itself. Impacts at any level can induce changes in those above and below them. For example, Al actions at a cellular level will necessarily perturb protein structures and DNA (the levels below) and alter cell-to-cell communication at the circuit level (above). Although Figure 4 focuses on the deleterious effects of Al on the nervous system, it should be clear that its impacts are systemic.
Aluminum induces entropy in living organisms by disrupting all levels of structure from water molecules through all biosemiotic systems. Entropy-inducing cascades, feedback loops (positive and negative) within and across levels, can damage DNAs, RNAs, proteins, cells, tissues, and whole organ systems. As a result of cellular damage caused by an Al compound, injured and dying cells will release proteases, excitatory amino acids, and ions (e.g., potassium, calcium), disrupting biosemiosis at many levels. Toxic effects of Al and its compounds thus tend to proliferate. Interactive results involving immune functions, for instance, make the impact worse than if only one system were involved. Of course, the dose-response of Al and its compounds must be considered, but even at low doses, especially with repeated exposures, Al can have cumulative deleterious effects that can be extreme and even fatal. For that reason, a repeated low dose exposure may prove more damaging than a single larger dose. Al and its compounds can cross biosemiotic levels, damaging genetic systems, proteins, cells, and all systems up through the CNS. While higher doses may rapidly affect multiple levels, as in dialysis-associated encephalopathy (DAE), low doses over time, for example, from vaccines, can degrade metabolism and disrupt repair and defense systems and can spiral out of control as in ASIA. Al adjuvants in vaccines may hyperdrive the immune functions of the body but they also directly disrupt biosemiotic systems. Sound theory, empirical research, and reasonable inferences from sources cited here show that Al and its compounds damage biological systems. Such conclusions warrant considerations at a policy level to limit human exposure to Al and its compounds.
(i)Aluminum (Al3+), suspected as a toxicant for 100 years, injures the CNS and immune systems, individually and synergistically.(ii)Al3+ disrupts biological water dynamics and macromolecules: DNAs, RNAs, proteoglycans, and proteins.(iii)Al3+ disrupts H-bond cooperativity interfering with the quantum coherence of living systems.(iv)Al3+ interferes with biological signaling—biosemiosis—from the very lowest to the highest levels in the nervous system.(v)The effects are synergistic with other toxicants, including mercury, lead, fluoride, and glyphosate.
Christopher A. Shaw, Stephanie Seneff, Stephen D. Kette, Lucija Tomljenovic, John W. Oller Jr., and Robert M. Davidson are equal first authors.
Conflict of Interests
The authors declare that there is no conflict of interests.
This work was supported in part by the Dwoskin Family Foundation, the Katlyn Fox Foundation, and the Luther Allyn Shouds Dean estate (to CAS) and by Quanta Computers, Taiwan, under the auspices of the Qmulus project. This paper is dedicated to the memory of Prof. Peter Hillman, formerly of the Hebrew University and graduate supervisor and mentor of CAS. Peter was a physicist and neurobiologist whose curiosity was boundless. The authors think he would have appreciated this paper.
- C. Exley, “The coordination chemistry of aluminium in neurodegenerative disease,” Coordination Chemistry Reviews, vol. 256, no. 19-20, pp. 2142–2146, 2012.
- C. A. Shaw, Y. Li, and L. Tomljenovic, “Administration of aluminium to neonatal mice in vaccine-relevant amounts is associated with adverse long term neurological outcomes,” Journal of Inorganic Biochemistry, vol. 128, pp. 237–244, 2013.
- C. Exley, “Darwin, natural selection and the biological essentiality of aluminium and silicon,” Trends in Biochemical Sciences, vol. 34, no. 12, pp. 589–593, 2009.
- G. Power, J. S. C. Loh, and C. Vernon, “Organic compounds in the processing of lateritic bauxites to alumina part 2: effects of organics in the Bayer process,” Hydrometallurgy, vol. 127-128, pp. 125–149, 2012.
- R. A. Yokel, “Aluminium toxicokinetics: an updated minireview,” Pharmacology and Toxicology, vol. 88, no. 4, pp. 159–167, 2001.
- W. J. Gies, “Some objections to the use of alum baking-powder,” The Journal of the American Medical Association, vol. 57, no. 10, pp. 816–821, 1911.
- J. F. Struve, “Taking Aluminum out of the Diet,” http://home.earthlink.net/∼joannefstruve/_wsn/page2.html.
- “Avoid aluminum—Locate the unexpected sources of aluminum in products,” http://www.naturalnews.com/033431_aluminum_personal_care_products.html.
- L. Tomljenovic and C. A. Shaw, “Aluminum vaccine adjuvants: are they safe?” Current Medicinal Chemistry, vol. 18, no. 17, pp. 2630–2637, 2011.
- R. W. Dapson, “The history, chemistry and modes of action of carmine and related dyes,” Biotechnic & Histochemistry, vol. 82, no. 4-5, pp. 173–187, 2007.
- P. D. Darbre, “Underarm cosmetics are a cause of breast cancer,” European Journal of Cancer Prevention, vol. 10, no. 5, pp. 389–393, 2001.
- P. D. Darbre, “Aluminium, antiperspirants and breast cancer,” Journal of Inorganic Biochemistry, vol. 99, no. 9, pp. 1912–1919, 2005.
- P. D. Darbre, D. Pugazhendhi, and F. Mannello, “Aluminium and human breast diseases,” Journal of Inorganic Biochemistry, vol. 105, no. 11, pp. 1484–1488, 2011.
- A.-P. Sappino, R. Buser, L. Lesne et al., “Aluminium chloride promotes anchorage-independent growth in human mammary epithelial cells,” Journal of Applied Toxicology, vol. 32, no. 3, pp. 233–243, 2012.
- “Science News Aluminum Found in Sunscreen: Could It Cause Skin Cancer?” http://www.sciencedaily.com/releases/2007/08/070812084458.htm.
- S. Nicholson and C. Exley, “Aluminum: a potential pro-oxidant in sunscreens/sunblocks?” Free Radical Biology and Medicine, vol. 43, no. 8, pp. 1216–1217, 2007.
- J. W. Oller, “Biosemiotic entropy: concluding the series,” Entropy, vol. 16, pp. 4060–4087, 2014.
- R. J. Mitkus, D. B. King, M. A. Hess, R. A. Forshee, and M. O. Walderhaug, “Updated aluminum pharmacokinetics following infant exposures through diet and vaccination,” Vaccine, vol. 29, no. 51, pp. 9538–9543, 2011.
- P. A. Offit and R. K. Jew, “Addressing parents’ concerns: do vaccines contain harmful preservatives, adjuvants, additives, or residuals?” Pediatrics, vol. 112, no. 6, pp. 1394–1397, 2003.
- J. R. J. Sorenson, I. R. Campbell, L. B. Tepper, and R. D. Lingg, “Aluminum in the environment and human health,” Environmental Health Perspectives, vol. 8, pp. 3–95, 1974.
- T. P. Flaten, “Aluminium as a risk factor in Alzheimer's disease, with emphasis on drinking water,” Brain Research Bulletin, vol. 55, no. 2, pp. 187–196, 2001.
- D. Krewski, R. A. Yokel, E. Nieboer et al., “Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide,” Journal of Toxicology and Environmental Health B: Critical Reviews, vol. 10, no. 1, pp. 1–269, 2007.
- Z.-L. Xie, D.-M. Dong, G.-Z. Bao, S.-T. Wang, Y.-G. Du, and L.-M. Qiu, “Aluminum content of tea leaves and factors affecting the uptake of aluminum from soil into tea leaves,” Chinese Geographical Science, vol. 11, no. 1, pp. 87–91, 2001.
- T. P. Flaten and M. Ødegård, “Tea, aluminium and Alzheimer's disease,” Food and Chemical Toxicology, vol. 26, no. 11-12, pp. 959–960, 1988.
- A.-K. Flaten and W. Lund, “Speciation of aluminium in tea infusions studied by size exclusion chromatography with detection by post-column reaction,” Science of the Total Environment, vol. 207, no. 1, pp. 21–28, 1997.
- R. A. Yokel and R. L. Florence, “Aluminum bioavailability from tea infusion,” Food and Chemical Toxicology, vol. 46, no. 12, pp. 3659–3663, 2008.
- J. R. Walton, “Chronic aluminum intake causes Alzheimer's disease: applying Sir Austin Bradford Hill's causality criteria,” Journal of Alzheimer's Disease, vol. 40, pp. 765–838, 2014.
- L. Tomljenovic, “Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link?” Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 567–598, 2011.
- W. J. Lukiw, S. Bjattacharjee, Y. Zhao, A. I. Pogue, and M. E. Percy, “Generation of reactive oxygen species (ROS) and pro-inflammatory signaling in human brain cells in primary culture,” Journal of Alzheimer's Disease & Parkinsonism, supplement 2, article 001, 2012.
- W. J. Lukiw, M. E. Percy, and T. P. Kruck, “Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression in human brain cells in primary culture,” Journal of Inorganic Biochemistry, vol. 99, no. 9, pp. 1895–1898, 2005.
- N. J. Bishop, R. Morley, B. Chir, J. Philip Day, and A. Lucas, “Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions,” The New England Journal of Medicine, vol. 336, no. 22, pp. 1557–1561, 1997.
- J. A. Flendrig, H. Kruis, and H. A. Das, “Aluminium intoxication: the cause of dialysis dementia?” Proceedings of the European Dialysis and Transplant Association, vol. 13, pp. 355–368, 1976.
- E. K. Pivnick, N. C. Kerr, R. A. Kaufman, D. P. Jones, and R. W. Chesney, “Rickets secondary to phosphate depletion: a sequela of antacid use in infancy,” Clinical Pediatrics, vol. 34, no. 2, pp. 73–78, 1995.
- N. C. Bowdler, D. S. Beasley, E. C. Fritze et al., “Behavioral effects of aluminum ingestion on animal and human subjects,” Pharmacology, Biochemistry and Behavior, vol. 10, no. 4, pp. 505–512, 1979.
- C. Exley and M. M. Esiri, “Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 77, no. 7, pp. 877–879, 2006.
- J. R. Walton and M.-X. Wang, “APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer's disease,” Journal of Inorganic Biochemistry, vol. 103, no. 11, pp. 1548–1554, 2009.
- M. S. Golub, M. E. Gershwin, J. M. Donald, S. Negri, and C. L. Keen, “Maternal and developmental toxicity of chronic aluminum exposure in mice,” Toxicological Sciences, vol. 8, no. 3, pp. 346–357, 1987.
- R. K. Gherardi, M. Coquet, P. Chérin et al., “Macrophagic myofasciitis: an emerging entity,” The Lancet, vol. 352, no. 9125, pp. 347–352, 1998.
- R. K. Gherardi and F. J. Authier, “Macrophagic myofasciitis: characterization and pathophysiology,” Lupus, vol. 21, no. 2, pp. 184–189, 2012.
- E. Passeri, C. Villa, M. Couette et al., “Long-term follow-up of cognitive dysfunction in patients with aluminum hydroxide-induced macrophagic myofasciitis (MMF),” Journal of Inorganic Biochemistry, vol. 105, no. 11, pp. 1457–1463, 2011.
- M. Couette, M. F. Boisse, P. Maison et al., “Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction,” Journal of Inorganic Biochemistry, vol. 103, no. 11, pp. 1571–1578, 2009.
- A. M. Ryan, N. Bermingham, H. J. Harrington, and C. Keohane, “Atypical presentation of macrophagic myofasciitis 10 years post vaccination,” Neuromuscular Disorders, vol. 16, no. 12, pp. 867–869, 2006.
- L. Luján, M. Pérez, E. Salazar et al., “Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep,” Immunologic Research, vol. 56, no. 2-3, pp. 317–324, 2013.
- M. S. Petrik, M. C. Wong, R. C. Tabata, R. F. Garry, and C. A. Shaw, “Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice,” NeuroMolecular Medicine, vol. 9, no. 1, pp. 83–100, 2007.
- C. A. Shaw and M. S. Petrik, “Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration,” Journal of Inorganic Biochemistry, vol. 103, no. 11, pp. 1555–1562, 2009.
- H. Sińczuk-Walczak, M. Szymczak, G. Raźniewska, W. Matczak, and W. Szymczak, “Effects of occupational exposure to aluminum on nervous system: clinical and electroencephalographic findings,” International Journal of Occupational Medicine and Environmental Health, vol. 16, no. 4, pp. 301–310, 2003.
- CRC, CRC Handbook of Chemistry and Physics 2012-2013, CRC Press, New York, NY, USA, 2012.
- C. Exley, “Human exposure to aluminium,” Environmental Science: Processes & Impacts, vol. 15, pp. 1807–1816, 2013.
- C. Sonnenschein and A. M. Soto, The Society of Cells, Bios Scientific, Oxford, UK, 1999.
- F. Crick, “Central dogma of molecular biology,” Nature, vol. 227, no. 5258, pp. 561–563, 1970.
- J. W. Oller Jr., “The antithesis of entropy: biosemiotic communication from genetics to human language with special emphasis on the immune systems,” Entropy, vol. 12, no. 4, pp. 631–705, 2010.
- M.-W. Ho, “The new genetics and natural versus artificial genetic modification,” Entropy, vol. 15, no. 11, pp. 4748–4781, 2013.
- D. Grant, W. F. Long, and F. B. Williamson, “Heparin-polypeptide interaction. Near-i.r. spectroscopy in an anhydrous dispersant allows the involvement of polymer-associated water to be assessed,” Biochemical Journal, vol. 277, no. 2, pp. 569–571, 1991.
- International Human Genome Sequencing Consortium, “Initial sequencing and analysis of the human genome,” Nature, vol. 431, pp. 931–945, 2004.
- D. Bohrer, P. C. Do Nascimento, J. K. A. Mendonça, V. G. Polli, and L. M. de Carvalho, “Interaction of aluminium ions with some amino acids present in human blood,” Amino Acids, vol. 27, no. 1, pp. 75–83, 2004.
- P. J. Brothers and C. E. Ruggerio, “Coordination and solution chemistry of the metals: biological, medical, and environmental relevance,” in The Group 13 Metals Aluminium , Gallium, Indium and Thallium, Chemical Patterns and Peculiarities, S. Aldridge and A. J. Downs, Eds., p. 584, John Wiley & Sons, Chichester, UK, 2011.
- S. Seneff, R. M. Davidson, and J. Liu, “Empirical data confirm autism symptoms related to aluminum and acetaminophen exposure,” Entropy, vol. 14, no. 11, pp. 2227–2253, 2012.
- J. M. Mercero, J. E. Fowler, and J. M. Ugalde, “Aluminum(III) interactions with the acidic amino acid chains,” Journal of Physical Chemistry A, vol. 102, no. 35, pp. 7006–7012, 1998.
- R. M. Davidson and S. Seneff, “The initial common pathway of inflammation, disease, and sudden death,” Entropy, vol. 14, no. 8, pp. 1399–1442, 2012.
- V. Gatta, D. Drago, K. Fincati et al., “Microarray analysis on human neuroblastoma cells exposed to aluminum, β1-42-amyloid or the β1-42-amyloid aluminum complex,” PLoS One, vol. 6, no. 1, Article ID e15965, 2011.
- J. H. Duffus, “‘Heavy metals’ a meaningless term?” Pure and Applied Chemistry, vol. 74, no. 5, pp. 793–807, 2002.
- J. C. K. Lai and J. P. Blass, “Inhibition of brain glycolysis by aluminum,” Journal of Neurochemistry, vol. 42, no. 2, pp. 438–446, 1984.
- L. Tomljenovic and C. A. Shaw, “Do aluminum vaccine adjuvants contribute to the rising prevalence of autism?” Journal of Inorganic Biochemistry, vol. 105, no. 11, pp. 1489–1499, 2011.
- J. Lemire and V. D. Appanna, “Aluminum toxicity and astrocyte dysfunction: a metabolic link to neurological disorders,” Journal of Inorganic Biochemistry, vol. 105, no. 11, pp. 1513–1517, 2011.
- Y. Shoenfeld and N. Agmon-Levin, ““ASIA”—autoimmune/inflammatory syndrome induced by adjuvants,” Journal of Autoimmunity, vol. 36, no. 1, pp. 4–8, 2011.
- E. Israeli, N. Agmon-Levin, M. Blank, and Y. Shoenfeld, “Adjuvants and autoimmunity,” Lupus, vol. 18, no. 13, pp. 1217–1225, 2009.
- N. Agmon-Levin, G. Hughes, and Y. Shoenfeld, “The spectrum of ASIA: ‘Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants’,” Lupus, vol. 21, no. 2, pp. 118–120, 2012.
- C. A. Shaw, S. D. Kette, R. M. Davidson, and S. Seneff, “Aluminum's role in CNS-immune system interactions leading to neurological disorders,” Immunome Research, vol. 9, article 1, 2013.
- R. A. Yokel, C. L. Hicks, and R. L. Florence, “Aluminum bioavailability from basic sodium aluminum phosphate, an approved food additive emulsifying agent, incorporated in cheese,” Food and Chemical Toxicology, vol. 46, no. 6, pp. 2261–2266, 2008.
- Agency for Toxic Substances; Disease Registry (ATSDR), Toxicological Profile for Aluminum, Agency for Toxic Substances, Disease Registry (ATSDR), Atlanta, Ga, USA, 2013, http://www.atsdr.cdc.gov/toxprofiles/tp22.pdf.
- S. M. Saiyed and R. A. Yokel, “Aluminium content of some foods and food products in the USA, with aluminium food additives,” Food Additives & Contaminants, vol. 22, no. 3, pp. 234–244, 2005.
- J. A. T. Pennington and S. A. Schoen, “Estimates of dietary exposure to aluminium,” Food Additives and Contaminants, vol. 12, no. 1, pp. 119–128, 1995.
- J. L. Greger, “Aluminum metabolism,” Annual Review of Nutrition, vol. 13, pp. 43–63, 1993.
- FAO/WHO, “Summary and conclusions,” in Proceedings of the 67th Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA '06), Rome, Italy, June 2006.
- P. O. Ganrot, “Metabolism and possible health effects of aluminum,” Environmental Health Perspectives, vol. 65, pp. 363–441, 1986.
- D. R. Crapper, S. S. Krishnan, and A. J. Dalton, “Brain aluminum distribution in Alzheimer's disease and experimental neurofibrillary degeneration,” Science, vol. 180, no. 4085, pp. 511–513, 1973.
- D. R. Crapper and A. J. Dalton, “Alterations in short term retention, conditioned avoidance response acquisition and motivation following aluminum induced neurofibrillary degeneration,” Physiology and Behavior, vol. 10, no. 5, pp. 925–933, 1973.
- W. J. Lukiw, B. Krishnan, L. Wong, T. P. A. Kruck, C. Bergeron, and D. R. Crapper McLachlan, “Nuclear compartmentalization of aluminum in Alzheimer's disease (AD),” Neurobiology of Aging, vol. 13, no. 1, pp. 115–121, 1992.
- N. W. Baylor, W. Egan, and P. Richman, “Aluminum salts in vaccines—US perspective,” Vaccine, vol. 20, supplement 3, pp. S18–S23, 2002.
- J. M. Brewer, “(How) do aluminium adjuvants work?” Immunology Letters, vol. 102, no. 1, pp. 10–15, 2006.
- T. C. Eickhoff and M. Myers, “Workshop summary: aluminum in vaccines,” Vaccine, vol. 20, supplement 3, pp. S1–S4, 2002.
- B. L. Carson, Aluminum Compounds. Review of Toxicological Literature, Abridged Final Report: 84 pages. Integrated Laboratory Systems, Research Triangle Park, North Carolina, 2000, http://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/aluminum_508.pdf#search=aluminum compounds.
- M. R. Wills and J. Savory, “Water content of aluminum, dialysis dementia, and osteomalacia,” Environmental Health Perspectives, vol. 63, pp. 141–147, 1985.
- G. L. Wenk and K. L. Stemmer, “The influence of ingested aluminum upon norepinephrine and dopamine levels in the rat brain,” NeuroToxicology, vol. 2, no. 2, pp. 347–353, 1981.
- T. Moos and E. H. Morgan, “Transferrin and transferrin receptor function in brain barrier systems,” Cellular and Molecular Neurobiology, vol. 20, no. 1, pp. 77–95, 2000.
- R. E. Flarend, S. L. Hem, J. L. White et al., “In vivo absorption of aluminium-containing vaccine adjuvants using 26Al,” Vaccine, vol. 15, no. 12-13, pp. 1314–1318, 1997.
- E. Autret-Leca, L. Bensouda-Grimaldi, A. P. Jonville-Béra, and F. Beau-Salinas, “Pharmacovigilance of vaccines,” Archives de Pediatrie, vol. 13, no. 2, pp. 175–180, 2006.
- R. Flarend, T. Bin, D. Elmore, and S. L. Hem, “A preliminary study of the dermal absorption of aluminium from antiperspirants using aluminium-26,” Food and Chemical Toxicology, vol. 39, no. 2, pp. 163–168, 2001.
- M. Dayah, “Dynamic Periodic Table,” October 1997, http://www.ptable.com.
- C. A. Shaw and L. Tomljenovic, “Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity,” Immunologic Research, vol. 56, no. 2-3, pp. 304–316, 2013.
- R. A. Yokel and P. J. McNamara, “Aluminium toxicokinetics: an updated minireview,” Pharmacology and Toxicology, vol. 88, no. 4, pp. 159–167, 2001.
- R. D. Shannon, “Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides,” Acta Crystallographica A, vol. 32, pp. 751–767, 1976.
- Y. Marcus, “Viscosity B-coefficients, structural entropies and heat capacities, and the effects of ions on the structure of water,” Journal of Solution Chemistry, vol. 23, no. 7, pp. 831–848, 1994.
- Y. Marcus, “Individual ionic surface tension increments in aqueous solutions,” Langmuir, vol. 29, no. 9, pp. 2881–2888, 2013.
- C. Exley, “Aluminium-based adjuvants should not be used as placebos in clinical trials,” Vaccine, vol. 29, no. 50, 9289 pages, 2011.
- I. Zivkovic, V. Petrusic, M. Stojanovic, A. Inic -Kanada, I. Stojicevic, and L. Dimitrijevic, “Induction of decreased fecundity by tetanus toxoid hyper-immunization in C57BL/6 mice depends on the applied adjuvant,” Innate Immunity, vol. 18, no. 2, pp. 333–342, 2012.
- X.-B. Li, H. Zheng, Z.-R. Zhang et al., “Glia activation induced by peripheral administration of aluminum oxide nanoparticles in rat brains,” Nanomedicine: Nanotechnology, Biology and Medicine, vol. 5, no. 4, pp. 473–479, 2009.
- M. Couette, M.-F. Boisse, P. Maison et al., “Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction,” Journal of Inorganic Biochemistry, vol. 103, no. 11, pp. 1571–1578, 2009.
- R. K. Gherardi, M. Coquet, P. Cherin et al., “Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle,” Brain, vol. 124, no. 9, pp. 1821–1831, 2001.
- R. K. Gherardi and F.-J. Authier, “Aluminum inclusion macrophagic myofasciitis: a recently identified condition,” Immunology and Allergy Clinics of North America, vol. 23, no. 4, pp. 699–712, 2003.
- Y. Shoenfeld and N. Agmon-Levin, “'ASIA' - Autoimmune/inflammatory syndrome induced by adjuvants,” Journal of Autoimmunity, vol. 36, no. 1, pp. 4–8, 2011.
- P. L. Meroni, “Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome?” Journal of Autoimmunity, vol. 36, no. 1, pp. 1–3, 2011.
- Y. Zafrir, N. Agmon-Levin, Z. Paz, T. Shilton, and Y. Shoenfeld, “Autoimmunity following Hepatitis B vaccine as part of the spectrum of “Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants” (ASIA): analysis of 93 cases,” Lupus, vol. 21, no. 2, pp. 146–152, 2012.
- G. S. Goldman and N. Z. Miller, “Relative trends in hospitalizations and mortality among infants by the number of vaccine doses and age, based on the Vaccine Adverse Event Reporting System (VAERS), 1990–2010,” Human and Experimental Toxicology, vol. 31, no. 10, pp. 1012–1021, 2012.
- N. Z. Miller and G. S. Goldman, “Infant mortality rates regressed against number of vaccine doses routinely given: is there a biochemical or synergistic toxicity?” Human & Experimental Toxicology, vol. 30, no. 9, pp. 1420–1428, 2011.
- Z. Khan, C. Combadière, F.-J. Authier et al., “Slow CCL2-dependent translocation of biopersistent particles from muscle to brain,” BMC Medicine, vol. 11, article 99, 2013.
- E. Nieboer, B. L. Gibson, A. D. Oxman, and J. R. Kramer, “Health effects of aluminum: a critical review with emphasis on aluminum in drinking water,” Environmental Reviews, vol. 3, no. 1, pp. 29–81, 1995.
- B. E. Gryder, C. W. Nelson, and S. Shepard, “Biosemiotic entropy of the genome: mutations and epigenetic imbalances resulting in cancer,” Entropy, vol. 15, no. 1, pp. 234–261, 2013.
- T. M. Maynard, L. Sikich, J. A. Lieberman, and A.-S. LaMantia, “Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia,” Schizophrenia Bulletin, vol. 27, no. 3, pp. 457–476, 2001.
- K. D. Collins and M. W. Washabaugh, “The Hofmeister effect and the behaviour of water at interfaces.,” Quarterly Reviews of Biophysics, vol. 18, no. 4, pp. 323–422, 1985.
- Y. Marcus, Ions in Water and Biophysical Implications: From Chaos to Cosmos, Springer, Dordrecht, The Netherlands, 2012.
- J. Barthel and G. A. Krestov, Thermodynamics of Solvation: Solution and Dissolution, Ions and Solvents, Structure and Energetics, Ellis Horwood Series in Physical Chemistry, Ellis Horwood, New York, NY, USA, 1991.
- K. D. Collins, “Charge density-dependent strength of hydration and biological structure,” Biophysical Journal, vol. 72, no. 1, pp. 65–76, 1997.
- G. H. Pollack, The Fourth Phase of Water: Beyond Solid, Liquid, and Vapor, Ebner & Sons, Seattle, Wash, USA, 2013.
- G. N. Ling, “A new theoretical foundation for the polarized-oriented multilayer theory of cell water and for inanimate systems demonstrating long-range dynamic structuring of water molecules,” Physiological Chemistry and Physics and Medical NMR, vol. 35, no. 2, pp. 91–130, 2003.
- G. N. Ling, “An updated and further developed theory and evidence for the close-contact, one-on-one association of nearly all cell K+ with β- and γ-carboxyl groups of intracellular proteins,” Physiological Chemistry and Physics and Medical NMR, vol. 37, no. 1, pp. 1–63, 2005.
- S. Seneff, R. Davidson, and L. Mascitelli, “Might cholesterol sulfate deficiency contribute to the development of autistic spectrum disorder?” Medical Hypotheses, vol. 78, no. 2, pp. 213–217, 2012.
- S. Seneff, A. Lauritzen, R. Davidson, and L. Lentz-Marino, “Is endothelial nitric oxide synthase a moonlighting protein whose day job is cholesterol sulfate synthesis? Implications for cholesterol transport, diabetes and cardiovascular disease,” Entropy, vol. 14, no. 12, pp. 2492–2530, 2012.
- R. M. Davidson, A. Lauritzen, and S. Seneff, “Biological water dynamics and entropy: a biophysical origin of cancer and other diseases,” Entropy, vol. 15, no. 9, pp. 3822–3876, 2013.
- H. Sigel and A. Sigel, Eds., Metal Ions in Biological Systems, vol. 24 of Aluminum and Its Role in Biology, Marcel Dekker, New York, NY, USA, 1988.
- D. W. Piper and B. Fenton, “The adsorption of pepsin,” Digestive Diseases and Sciences, vol. 6, no. 2, pp. 134–141, 1961.
- R. J. Sepelyak, J. R. Feldkamp, T. E. Moody, J. L. White, and S. L. Hem, “Adsorption of pepsin by aluminum hydroxide I: adsorption mechanism,” Journal of Pharmaceutical Sciences, vol. 73, no. 11, pp. 1514–1517, 1984.
- “Metal ions in aqueous solution,” 2013, http://en.wikipedia.org/wiki/Metal_ions_in_aqueous_solution.
- S. O. Duke, K. C. Vaughn, and R. D. Wauchope, “Effects of glyphosate on uptake, translocation, and intracellular localization of metal cations in soybean (Glycine max) seedlings,” Pesticide Biochemistry and Physiology, vol. 24, no. 3, pp. 384–394, 1985.
- M. Purgel, Z. Takács, C. M. Jonsson et al., “Glyphosate complexation to aluminium(III). An equilibrium and structural study in solution using potentiometry, multinuclear NMR, ATR-FTIR, ESI-MS and DFT calculations,” Journal of Inorganic Biochemistry, vol. 103, no. 11, pp. 1426–1438, 2009.
- A. Samsel and S. Seneff, “Glyphosate’s suppression of cytochrome P450 enzymes and amino acid biosynthesis by the gut microbiome: pathways to modern diseases,” Entropy, vol. 15, pp. 1416–1463, 2013.
- J. A. Carman, H. R. Vlieger, L. J. Ver Steeg et al., “A long-term toxicology study on pigs fed a combined genetically modified (GM) soy and GM maize diet,” Journal of Organic Systems, vol. 8, no. 1, pp. 38–54, 2013.
- D. D. Ulmer, “Toxicity from aluminium antacids,” The New England Journal of Medicine, vol. 294, no. 4, pp. 218–219, 1976.
- J. W. Coburn, M. G. Mischel, W. G. Goodman, and I. B. Salusky, “Calcium citrate markedly enhances aluminum absorption from aluminum hydroxide,” The American Journal of Kidney Diseases, vol. 17, no. 6, pp. 708–711, 1991.
- B. B. Kirschbaum and A. C. Schoolwerth, “Acute aluminum toxicity associated with oral citrate and aluminum-containing antacids,” The American Journal of the Medical Sciences, vol. 297, no. 1, pp. 9–11, 1989.
- V. Solfrizzi, A. M. Colacicco, A. D'Introno et al., “Macronutrients, aluminium from drinking water and foods, and other metals in cognitive decline and dementia,” Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 303–330, 2006.
- D. Fekkes, T. J. M. van der Cammen, C. P. M. van Loon et al., “Abnormal amino acid metabolism in patients with early stage Alzheimer dementia,” Journal of Neural Transmission, vol. 105, no. 2-3, pp. 287–294, 1998.
- J. K. Hou, J. R. Kramer, P. Richardson, M. Mei, and H. B. El-Serag, “The incidence and prevalence of inflammatory bowel disease among U.S. veterans: a national cohort study,” Inflammatory Bowel Diseases, vol. 19, no. 5, pp. 1059–1064, 2013.
- H. B. El-Serag, “Time trends of gastroesophageal reflux disease: a systematic review,” Clinical Gastroenterology and Hepatology, vol. 5, no. 1, pp. 17–26, 2007.
- J. C. Hoffmann, N. N. Pawlowski, A. A. Kühl, W. Höhne, and M. Zeitz, “Animal models of inflammatory bowel disease: an overview,” Pathobiology, vol. 70, no. 3, pp. 121–130, 2003.
- S. Keller, C. Vargas, H. Zhao, G. Piszczek, C. A. Brautigam, and P. Schuck, “High-precision isothermal titration calorimetry with automated peak-shape analysis,” Analytical Chemistry, vol. 84, no. 11, pp. 5066–5073, 2012.
- J. C. Martinez, J. Murciano-Calles, E. S. Cobos, M. Iglesias-Bexiga, I. Luque, and J. Ruiz-Sanz, “Isothermal titration calorimetry: thermodynamic analysis of the binding thermograms of molecular recognition events by using equilibrium models,” in Applications of Calorimetry in a Wide Context—Differential Scanning Calorimetry, Isothermal Titration Calorimetry and Microcalorimetry, A. A. Elkordy, Ed., chapter 4, InTech, 2013.
- C. Zhou, Y. Gao, and G. Li, “Technology of recovery effective components in wastewater from glyphosate production by dynamic adsorption method,” CIESC Journal, vol. 64, no. 4, pp. 1453–1458, 2013 (Chinese).
- F. Guo and J. M. Friedman, “Charge density-dependent modifications of hydration shell waters by hofmeister ions,” Journal of the American Chemical Society, vol. 131, no. 31, pp. 11010–11018, 2009.
- F. Hervé, N. Ghinea, and J.-M. Scherrmann, “CNS delivery via adsorptive transcytosis,” AAPS Journal, vol. 10, no. 3, pp. 455–472, 2008.
- S. Han, J. Lemire, V. P. Appanna, C. Auger, Z. Castonguay, and V. D. Appanna, “How aluminum, an intracellular ROS generator promotes hepatic and neurological diseases: the metabolic tale,” Cell Biology and Toxicology, vol. 29, no. 2, pp. 75–84, 2013.
- C. Exley, “The pro-oxidant activity of aluminum,” Free Radical Biology & Medicine, vol. 36, no. 3, pp. 380–387, 2004.
- G. N. Ling, “An updated and further developed theory and evidence for the close-contact, one-on-one association of nearly all cell K+ with β- and γ-carboxyl groups of intracellular proteins,” Physiological Chemistry and Physics and Medical, vol. 37, no. 1, pp. 1–63, 2005.
- G. Ling, “Nano-protoplasm: the ultimate unit of life,” Physiological Chemistry and Physics and Medical NMR, vol. 39, no. 2, pp. 111–234, 2007.
- G. N. Ling, Life: At the Cell and below Cell, Pacific Press, New York, NY, USA, 2001.
- T. M. Riddick, Control of Colloid Stability through Zeta Potential: With a Closing Chapter on Its Relationship to Cardiovascular Disease, Livingston, Wynnewood, Pa, USA, 1968.
- M. D. Newton and H. L. Friedman, “A proposed neutron diffraction experiment to measure hydrogen isotope fractionation in solution,” The Journal of Chemical Physics, vol. 83, no. 10, pp. 5210–5218, 1985.
- M. M. Probst and K. Hermansson, “On frequency shifts in OH stretching vibrations of hydrated cations,” The Journal of Chemical Physics, vol. 96, no. 12, pp. 8995–9004, 1992.
- G. G. R. Desiraju and T. Steiner, “The weak hydrogen bond,” in Structural Chemistry and Biology, p. 507, Oxford University Press, Oxford, UK, 2001.
- J. Joseph and E. D. Jemmis, “Red-, blue-, or no-shift in hydrogen bonds: a unified explanation,” Journal of the American Chemical Society, vol. 129, no. 15, pp. 4620–4632, 2007.
- E. D. Jemmis and P. Parameswaran, “Structure and bonding in cyclic isomers of BAl2Hnm (n = 3 − 6, m =−2 to +1): preference for planar tetracoordination, pyramidal tricoordination, and divalency,” Chemistry, vol. 13, pp. 2622–2631, 2007.
- D. Gallez and W. T. Coakley, “Interfacial instability at cell membranes,” Progress in Biophysics and Molecular Biology, vol. 48, no. 3, pp. 155–199, 1986.
- K. J. Tielrooij, N. Garcia-Araez, M. Bonn, and H. J. Bakker, “Cooperativity in ion hydration,” Science, vol. 328, no. 5981, pp. 1006–1009, 2010.
- S. L. Budd, L. Tenneti, T. Lishnak, and S. A. Lipton, “Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 11, pp. 6161–6166, 2000.
- J. J. Lemasters and V. K. Ramshesh, “Imaging of mitochondrial polarization and depolarization with cationic fluorophores,” Methods in Cell Biology, vol. 80, pp. 283–295, 2007.
- M. Sivaguru, S. Pike, W. Gassmann, and T. I. Baskin, “Aluminum rapidly depolymerizes cortical microtubules and depolarizes the plasma membrane: evidence that these responses are mediated by a glutamate receptor,” Plant and Cell Physiology, vol. 44, no. 7, pp. 667–675, 2003.
- D. Busselberg, B. Platt, D. Michael, D. O. Carpenter, and H. L. Haas, “Mammalian voltage-activated calcium channel currents are blocked by Pb2+, Zn2+, and Al3+,” Journal of Neurophysiology, vol. 71, no. 4, pp. 1491–1497, 1994.
- D. Julka and K. D. Gill, “Altered calcium homeostasis: a possible mechanism of aluminium-induced neurotoxicity,” Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1315, no. 1, pp. 47–54, 1996.
- S. K. Pal and A. H. Zewail, “Dynamics of water in biological recognition,” Chemical Reviews, vol. 104, pp. 2099–2123, 2004.
- R. G. Oliveira, E. Schneck, S. S. Funari, M. Tanaka, and B. Maggio, “Equivalent aqueous phase modulation of domain segregation in myelin monolayers and bilayer vesicles,” Biophysical Journal, vol. 99, no. 5, pp. 1500–1509, 2010.
- B. Chai, H. Yoo, and G. H. Pollack, “Effect of radiant energy on near-surface water,” Journal of Physical Chemistry B, vol. 113, no. 42, pp. 13953–13958, 2009.
- S. Sadiq, Z. Ghazala, A. Chowdhury, and D. Büsselberg, “Metal toxicity at the synapse: presynaptic, postsynaptic, and long-term effects,” Journal of Toxicology, vol. 2012, Article ID 132671, 42 pages, 2012.
- B. Platt, H. Haas, and D. Büsselberg, “Extracellular pH modulates aluminium-blockade of mammalian voltage-activated calcium channel currents,” NeuroReport, vol. 4, no. 11, pp. 1251–1254, 1993.
- B. Platt and D. Büsselberg, “Actions of aluminum on voltage-activated calcium channels currents,” Cellular and Molecular Neurobiology, vol. 14, pp. 819–829, 1994.
- P. Q. Trombley, “Selective modulation of GABA(A) receptors by aluminum,” Journal of Neurophysiology, vol. 80, no. 2, pp. 755–761, 1998.
- M. Kawahara, “Effects of aluminum on the nervous system and its possible link with neurodegenerative diseases,” Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 171–182, 2005.
- J. W. Oller Jr., S. D. Oller, and L. C. Badon, Cases: Introducing Communication Disorders Across the Life Span, Plural Publishing, San Diego, Calif, USA, 2010.
- J. W. Oller Jr. and S. D. Oller, Autism: The Diagnosis, Treatment, and Etiology of the Undeniable Autism Epidemic, Jones and Bartlett, Boston, Mass, USA, 2010.
- J. W. Oller Jr., S. D. Oller, and S. N. Oller, Milestones: Normal Speech and Language Development across the Span, Plural Publishing, San Diego, Calif, USA, 2nd edition, 2014.
- B. Johansson and S. Sukhotskaya, “Allometric scaling behavior—a quantum dissipative state implies a reduction in thermal infrared emission and fractal ordering in distilled coherent water,” Water, vol. 3, pp. 100–121, 2012.
- P. Ball, “Water as an active constituent in cell biology,” Chemical Reviews, vol. 108, no. 1, pp. 74–108, 2008.
- J. Zheng and G. H. Pollack, “Long-range forces extending from polymer-gel surfaces,” Physical Review E: Statistical, Nonlinear, and Soft Matter Physics, vol. 68, Article ID 031408, 2003.
- D. T. Nhan and G. H. Pollack, “Effect of particle diameter on exclusion-zone size,” International Journal of Design and Nature and Ecodynamics, vol. 6, no. 2, pp. 139–144, 2011.
- R. S. Lillie, Protoplasmic Action and Nervous Action, University of Chicago Press, 1923.
- A. I. Oparin and A. Synge, The Origin of Life on the Earth, Academic Press, New York, NY, USA, 3rd edition, 1957, translated by A. Synge.
- E. G. del Giudice, P. R. Spinetti, and A. Tedeschi, “Water dynamics at the root of metamorphosis in living organisms,” Water, vol. 2, pp. 566–586, 2010.
- S. Hartzell and S. Seneff, “Impaired sulfate metabolism and epigenetics: is there a link in autism?” Entropy, vol. 14, pp. 1953–1977, 2012.
- R. G. Oliveira, M. Tanaka, and B. Maggio, “Many length scales surface fractality in monomolecular films of whole myelin lipids and proteins,” Journal of Structural Biology, vol. 149, no. 2, pp. 158–169, 2005.
- J. J. Harrison, R. J. Turner, D. A. Joo et al., “Copper and quaternary ammonium cations exert synergistic bactericidal and antibiofilm activity against Pseudomonas aeruginosa,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 8, pp. 2870–2881, 2008.
- R. S. Renslow, P. D. Majors, J. S. McLean, J. K. Fredrickson, B. Ahmed, and H. Beyenal, “In situ effective diffusion coefficient profiles in live biofilms using pulsed-field gradient nuclear magnetic resonance,” Biotechnology and Bioengineering, vol. 106, no. 6, pp. 928–937, 2010.
- G. N. Ling, “Coherent behavior and control mechanisms,” in A Revolution in the Physiology of the Living Cell, pp. 135–158, Krieger, Malabar, Fla, USA, 1991.
- S. Sharma and P. G. Debenedetti, “Evaporation rate of water in hydrophobic confinement,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 12, pp. 4365–4370, 2012.
- H. Selye, Thrombohemorrhagic Phenomena, Charles C. Thomas, Springfield, Ill, USA, 1966.
- H. Selye, In Vivo: The Case for Supramolecular Biology, Liveright, New York, NY, USA, 1967.
- E. D. Giudice, A. Tedeschi, G. Vitiello, and V. Voeikov, “Coherent structures in liquid water close to hydrophilic surfaces,” Journal of Physics: Conference Series, vol. 442, no. 1, Article ID 012028, 2013.
- I. Prigogine, Thermodynamics of Irreversible Processes, John Wiley & Sons, New York, NY, USA, 1955.
- F. Günther, Self- organisation in systems far from thermodynamic equilibrium: some clues to the structure and function of biological systems [Ph.D. thesis], Department of Systems Ecology, Stockholm University, Stockholm, Sweden, 1994.
- C. N. R. Rao, P. C. Dwivedi, H. Ratajczak, and W. J. Orville-Thomas, “Relation between O-H stretching frequency and hydrogen bond energy: Re-examination of the Badger-Bauer rule,” Journal of the Chemical Society, Faraday Transactions 2: Molecular and Chemical Physics, vol. 71, pp. 955–966, 1975.
- S. Melandri, “‘Union is strength’: how weak hydrogen bonds become stronger,” Physical Chemistry Chemical Physics, vol. 13, no. 31, pp. 13901–13911, 2011.
- G. Gilli and P. Gilli, “Towards an unified hydrogen-bond theory,” Journal of Molecular Structure, vol. 552, no. 1–3, pp. 1–15, 2000.
- M. Falk, “The frequency of the HOH bending fundamental in solids and liquids,” Spectrochimica Acta A: Molecular Spectroscopy, vol. 40, no. 1, pp. 43–48, 1984.
- S. Imoto, S. S. Xantheas, and S. Saito, “Molecular origin of the difference in the HOH bend of the IR spectra between liquid water and ice,” Journal of Chemical Physics, vol. 138, no. 5, Article ID 054506, 2013.
- J. I. Mujika, F. Ruipérez, I. Infante, J. M. Ugalde, C. Exley, and X. Lopez, “Pro-oxidant activity of aluminum: stabilization of the aluminum superoxide radical ion,” Journal of Physical Chemistry A, vol. 115, no. 24, pp. 6717–6723, 2011.
- G. Rayner-Canham and T. Overton, “Polorization and covalency,” in Descriptive Inorganic Chemistry, pp. 96–97, W. H. Freeman, New York, NY, USA, 2010.
- Y. Marcus, Supercritical Water, John Wiley & Sons, Hoboken, NJ, USA, 2012.
- B. Hribar, N. T. Southall, V. Vlachy, and K. A. Dill, “How ions affect the structure of water,” Journal of the American Chemical Society, vol. 124, no. 41, pp. 12302–12311, 2002.
- J. E. House, “Inorganic chemistry,” in Inorganic Chemistry, pp. 229–237, Academic Press, Burlington, Mass, USA, 2008.
- Y. Marcus, Ion Properties, Marcel Dekker, New York, NY, USA, 1997.
- D. Russo, “The impact of kosmotropes and chaotropes on bulk and hydration shell water dynamics in a model peptide solution,” Chemical Physics, vol. 345, no. 2-3, pp. 200–211, 2008.
- A. Campbell, D. Hamai, and S. C. Bondy, “Differential toxicity of aluminum salts in human cell lines of neural origin: implications for neurodegeneration,” NeuroToxicology, vol. 22, no. 1, pp. 63–71, 2001.
- S. C. Bondy and S. Kirstein, “The promotion of iron-induced generation of reactive oxygen species in nerve tissue by aluminum,” Molecular and Chemical Neuropathology, vol. 27, no. 2, pp. 185–194, 1996.
- A. S. Mahadevi and G. N. Sastry, “Cation- interaction: its role and relevance in chemistry, biology, and material science,” Chemical Reviews, vol. 113, pp. 2100–2138, 2013.
- S. J. Stohs and D. Bagchi, “Oxidative mechanisms in the toxicity of metal ions,” Free Radical Biology and Medicine, vol. 18, no. 2, pp. 321–336, 1995.
- A. Campbell, A. Becaria, D. K. Lahiri, K. Sharman, and S. C. Bondy, “Chronic exposure to aluminum in drinking water increases inflammatory parameters selectively in the brain,” Journal of Neuroscience Research, vol. 75, no. 4, pp. 565–572, 2004.
- J. T. Kiss, “From coordination chemistry to biological chemistry of aluminium,” Journal of Inorganic Biochemistry, vol. 128, pp. 156–163, 2013.
- J. Beardmore and C. Exley, “Towards a model of non-equilibrium binding of metal ions in biological systems,” Journal of Inorganic Biochemistry, vol. 103, no. 2, pp. 205–209, 2009.
- M. F. Chaplin, “Waters hydrogen bond strength,” in Water and Life: The Unique Properties of H2O, R. M. Lynden-Bell, S. Conway Morris, J. D. Barrow, J. L. Finney, and C. L. Harper, Eds., pp. 69–86, CRC Press, Boca Raton, Fla, USA, 2010.
- J. Kamalov, D. O. Carpenter, and I. Birman, “Cytotoxicity of environmentally relevant concentrations of aluminum in murine thymocytes and lymphocytes,” Journal of Toxicology, vol. 2011, Article ID 796719, 7 pages, 2011.
- J. Kern, B. Haley, D. Geier, L. Sykes, P. King, and M. Geier, “Thimerosal exposure and the role of sulfation chemistry and thiol availability in autism,” International Journal of Environmental Research and Public Health, vol. 10, no. 8, pp. 3771–3800, 2013.
- S. J. James, S. Rose, S. Melnyk et al., “Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism,” The FASEB Journal, vol. 23, no. 8, pp. 2374–2383, 2009.
- A. I. Pogue, Y. Y. Li, J. G. Cui et al., “Characterization of an NF-κB-regulated, miRNA-146a-mediated down-regulation of complement factor H (CFH) in metal-sulfate-stressed human brain cells,” Journal of Inorganic Biochemistry, vol. 103, no. 11, pp. 1591–1595, 2009.
- A. I. Pogue, B. M. Jones, S. Bhattacharjee, M. E. Percy, Y. Zhao, and W. J. Lukiw, “Metal-sulfate induced generation of ROS in human brain cells: detection using an isomeric mixture of 5- and 6-carboxy-2′,7′-dichlorofluorescein diacetate (carboxy-DCFDA) as a cell permeant tracer,” International Journal of Molecular Sciences, vol. 13, no. 8, pp. 9615–9626, 2012.
- B. E. Haley, “Mercury toxicity: genetic susceptibility and synergistic effects,” Medical Veritas, vol. 2, pp. 535–542, 2005.
- S. Acosta-Gutiérrez, J. Hernández-Rojas, J. Bretón, J. M. G. Llorente, and D. J. Wales, “Physical properties of small water clusters in low and moderate electric fields,” The Journal of Chemical Physics, vol. 135, no. 12, Article ID 124303, 2011.
- S. Sabella, R. P. Carney, V. Brunetti et al., “A general mechanism for intracellular toxicity of metal-containing nanoparticles,” Nanoscale, vol. 6, pp. 7052–7061, 2014.
- H. Frauenfelder, G. Chen, J. Berendzen et al., “A unified model of protein dynamics,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 13, pp. 5129–5134, 2009.
- S. H. Chen, M. Lagi, X. Q. Chu et al., “Dynamics of a globular protein and its hydration water studied by neutron scattering and MD simulations,” Spectroscopy, vol. 24, no. 1-2, pp. 1–24, 2010.
- W. R. Harris, Z. Wang, and Y. Z. Hamada, “Competition between transferrin and the serum ligands citrate and phosphate for the binding of aluminum,” Inorganic Chemistry, vol. 42, no. 10, pp. 3262–3273, 2003.
- G. S. Waldo and E. C. Theil, “Formation of iron(III)-tyrosinate is the fastest reaction observed in ferritin,” Biochemistry, vol. 32, no. 48, pp. 13262–13269, 1993.
- X. Liu and E. C. Theil, “Ferritins: dynamic management of biological iron and oxygen chemistry,” Accounts of Chemical Research, vol. 38, no. 3, pp. 167–175, 2005.
- S. Tang, R. MacColl, and P. J. Parsons, “Spectroscopic study of the interaction of aluminum ions with human transferrin,” Journal of Inorganic Biochemistry, vol. 60, no. 3, pp. 175–185, 1995.
- R. A. Yokel, “Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration,” Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 223–253, 2006.
- H. J. H. Fenton, “LXXIII.—Oxidation of tartaric acid in presence of iron,” Journal of the Chemical Society, Transactions, vol. 65, pp. 899–910, 1894.
- I. Bone and M. Thomas, “Dialysis dementia, aluminium, and tetrahydrobiopterin metabolism,” The Lancet, vol. 313, no. 8119, p. 782, 1979.
- A. Rotundo, T. E. Nevins, M. Lipton, L. A. Lockman, S. M. Mauer, and A. F. Michael, “Progressive encephalopathy in children with chronic renal insufficiency in infancy,” Kidney International, vol. 21, no. 3, pp. 486–491, 1982.
- Z. Z. Altindag, T. Baydar, A. B. Engin, and G. Sahin, “Effects of the metals on dihydropteridine reductase activity,” Toxicology in Vitro, vol. 17, no. 5-6, pp. 533–537, 2003.
- Y. Tani, E. Fernell, Y. Watanabe, T. Kanai, and B. Langstrom, “Decrease in GR-5,6,7,8-tetrahydrobiopterin content in cerebrospinal fluid of autistic patients,” Neuroscience Letters, vol. 181, no. 1-2, pp. 169–172, 1994.
- R. E. Frye, L. C. Huffman, and G. R. Elliott, “Tetrahydrobiopterin as a novel therapeutic intervention for autism,” Neurotherapeutics, vol. 7, no. 3, pp. 241–249, 2010.
- H. F. Nijhout, M. C. Reed, P. Budu, and C. M. Ulrich, “A mathematical model of the folate cycle: new insights into folate homeostasis,” The Journal of Biological Chemistry, vol. 279, no. 53, pp. 55008–55016, 2004.
- M. J. Crabtree, A. L. Tatham, Y. Al-Wakeel et al., “Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status insights from cells with TET-regulated GTP cyclohydrolasei expression,” Journal of Biological Chemistry, vol. 284, no. 2, pp. 1136–1144, 2009.
- A. Ponzone, M. Spada, S. Ferraris, I. Dianzani, and L. De Sanctis, “Dihydropteridine reductase deficiency in man: From biology to treatment,” Medicinal Research Reviews, vol. 24, no. 2, pp. 127–150, 2004.
- I. Smith, K. Hyland, and B. Kendall, “Clinical role of pteridine therapy in tetrahydrobiopterin deficiency,” Journal of Inherited Metabolic Disease, vol. 8, no. 1, pp. 39–45, 1985.
- M. Waly, H. Olteanu, R. Banerjee et al., “Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal,” Molecular Psychiatry, vol. 9, no. 4, pp. 358–370, 2004.
- R. Carmel, S. Melnyk, and S. J. James, “Cobalamin deficiency with and without neurologic abnormalities: differences in homocysteine and methionine metabolism,” Blood, vol. 101, no. 8, pp. 3302–3308, 2003.
- H. G. Yang, B. L. Lee, Y. X. Liang, Y. X. Zheng, and C. N. Ong, “The effects of exposure to aluminium on neurobehavioural function and dopaminergic metabolism,” International Journal of Environmental Health Research, vol. 8, no. 2, pp. 101–110, 1998.
- J. Wegiel, I. Kuchna, K. Nowicki et al., “The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes,” Acta Neuropathologica, vol. 119, no. 6, pp. 755–770, 2010.
- N. Siegel and A. Haug, “Aluminum interaction with calmodulin. Evidence for altered structure and function from optical and enzymatic studies,” Biochimica et Biophysica Acta, vol. 744, no. 1, pp. 36–45, 1983.
- G. Topal, A. Brunet, E. Millanvoye et al., “Homocysteine induces oxidative stress by uncoupling of no synthase activity through reduction of tetrahydrobiopterin,” Free Radical Biology and Medicine, vol. 36, no. 12, pp. 1532–1541, 2004.
- T. J. Guzik, R. Korbut, and T. Adamek-Guzik, “Nitric oxide and superoxide in inflammation and immune regulation,” Journal of Physiology and Pharmacology, vol. 54, no. 4, pp. 469–487, 2003.
- X. Li, A. Chauhan, A. M. Sheikh et al., “Elevated immune response in the brain of autistic patients,” Journal of Neuroimmunology, vol. 207, no. 1-2, pp. 111–116, 2009.
- S. Y. Lo, X. Geng, and D. Gann, “Evidence for the existence of stable-water-clusters at room temperature and normal pressure,” Physics Letters A: General, Atomic and Solid State Physics, vol. 373, no. 42, pp. 3872–3876, 2009.
- S. Y. Lo and B. Bonavida, “Physical, chemical and biological properties of stable water IE clusters,” in Procedings of the 1st International Symposium on Physical, Chemical and Biological Properties of Stable Water (IE) Clusters, p. 212, World Scientific, Singapore, 1998.
- J. K. Kern and A. M. Jones, “Evidence of toxicity, oxidative stress, and neuronal insult in autism,” Journal of Toxicology and Environmental Health B, vol. 9, no. 6, pp. 485–499, 2006.
- M. J. Caulfield, L. Shi, S. Wang et al., “Effect of alternative aluminum adjuvants on the absorption and immunogenicity of HPV16 L1 VLPs in mice,” Human Vaccines, vol. 3, no. 4, pp. 139–145, 2007.
- E. B. Lindblad, “Aluminium adjuvants—in retrospect and prospect,” Vaccine, vol. 22, no. 27-28, pp. 3658–3668, 2004.
- H. HogenEsch, “Mechanisms of stimulation of the immune response by aluminum adjuvants,” Vaccine, vol. 20, no. 3, pp. S34–S39, 2002.
- J. M. Brewer and J. Alexander, “Cytokines and the mechanisms of action of vaccine adjuvants,” Cytokines, Cellular & Molecular Therapy, vol. 3, no. 4, pp. 233–246, 1997.
- J. M. Brewer, M. Conacher, C. A. Hunter, M. Mohrs, F. Brombacher, and J. Alexander, “Aluminium hydroxide adjuvant initiates strong antigen-specific Th2 responses in the absence of IL-4- or IL-13-mediated signaling,” Journal of Immunology, vol. 163, no. 12, pp. 6448–6454, 1999.
- S. Wang, X. Liu, K. Fisher et al., “Enhanced type I immune response to a hepatitis B DNA vaccine by formulation with calcium- or aluminum phosphate,” Vaccine, vol. 18, no. 13, pp. 1227–1235, 2000.
- T. Dunning, “Accurate methods for the statistics of surprise and coincidence,” Computational Linguistics, vol. 19, p. 6174, 1993.
- K. M. Jan and S. Chien, “Role of surface electric charge in red blood cell interactions.,” Journal of General Physiology, vol. 61, no. 5, pp. 638–654, 1973.
- G. Oliver and M. Detmar, “The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature,” Genes and Development, vol. 16, no. 7, pp. 773–783, 2002.
- M. W. Peterson, P. Stone, and D. M. Shasby, “Cationic neutrophil proteins increase transendothelial albumin movement,” Journal of Applied Physiology, vol. 62, no. 4, pp. 1521–1530, 1987.
- G. F. Liptrot, Modern Inorganic Chemistry, Mills & Boons, London, UK, 1974.
- R. B. Martin, “Ternary complexes of Al3+ and F− with a third ligand,” Coordination Chemistry Reviews, vol. 149, pp. 23–32, 1996.
- A. Strunecká and J. Patocka, “Aluminofluoride complexes: a useful tool in laboratory investigations, but a hidden danger for living organisms?” in Group 13 Chemistry: Fundamental Research, Material Science and Catalysis, P. Shapiro and D. Atwood, Eds., vol. 822 of ACS Symposium Series, chapter 19, 2002.
- A. Strunecká, R. Blaylock, and J. Patocka, “Aluminofluoride complexes: phosphate analogues and a hidden hazard for living organisms,” Current Inorganic Chemistry, vol. 2, pp. 8–18, 2012.
- A. Strunecká and J. Patocka, “Chapter 19,” in Group 13 Chemistry: Fundamental Research, Material Science and Catalysis, P. Shapiro and D. Atwood, Eds., ACS Symposium Series 822, 2002.
- M. Bubis, “Facilitation and inhibition of G-protein regulated protein secretion by melatonin,” Neurochemistry International, vol. 27, no. 2, pp. 177–183, 1995.
- H. E. Hamm, “The many faces of G protein signaling,” The Journal of Biological Chemistry, vol. 273, no. 2, pp. 669–672, 1998.
- N. Wettschureck and S. Offermanns, “Mammalian G proteins and their cell type specific functions,” Physiological Reviews, vol. 85, no. 4, pp. 1159–1204, 2005.
- A. Strunecká and J. Patocka, “Aluminofluoride complexes in the etiology of Alzheimer’s disease,” Structure and Bonding, vol. 104, pp. 139–180, 2003.
- J. A. Varner, K. F. Jensen, W. Horvath, and R. L. Isaacson, “Chronic administration of aluminum-fluoride or sodium-fluoride to rats in drinking water: alterations in neuronal and cerebrovascular integrity,” Brain Research, vol. 784, no. 1-2, pp. 284–298, 1998.
- S. Mac Neil, T. Lakey, and S. Tomlinson, “Calmodulin regulation of adenylate cyclase activity,” Cell Calcium, vol. 6, no. 3, pp. 213–226, 1985.
- L. Lyras, N. J. Cairns, A. Jenner, P. Jenner, and B. Halliwell, “An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease,” Journal of Neurochemistry, vol. 68, no. 5, pp. 2061–2069, 1997.
- D. A. Butterfield, J. Drake, C. Pocernich, and A. Castegna, “Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid β-peptide,” Trends in Molecular Medicine, vol. 7, no. 12, pp. 548–554, 2001.
- P. Mecocci, U. MacGarvey, and M. F. Beal, “Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease,” Annals of Neurology, vol. 36, no. 5, pp. 747–751, 1994.
- T. Kurz, A. Terman, B. Gustafsson, and U. T. Brunk, “Lysosomes and oxidative stress in aging and apoptosis,” Biochimica et Biophysica Acta—General Subjects, vol. 1780, no. 11, pp. 1291–1303, 2008.
- R. Castellani, K. Hirai, G. Aliev et al., “Role of mitochondrial dysfunction in Alzheimer's disease,” Journal of Neuroscience Research, vol. 70, no. 3, pp. 357–360, 2002.
- P. I. Moreira, C. Carvalho, X. Zhu, M. A. Smith, and G. Perry, “Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology,” Biochimica et Biophysica Acta: Molecular Basis of Disease, vol. 1802, no. 1, pp. 2–10, 2010.
- S. Reitsma, D. W. Slaaf, H. Vink, M. A. M. J. Van Zandvoort, and M. G. A. Oude Egbrink, “The endothelial glycocalyx: composition, functions, and visualization,” Pflugers Archiv: European Journal of Physiology, vol. 454, no. 3, pp. 345–359, 2007.
- M. Nieuwdorp, M. C. Meuwese, H. L. Mooij et al., “Measuring endothelial glycocalyx dimensions in humans: a potential novel tool to monitor vascular vulnerability,” Journal of Applied Physiology, vol. 104, no. 3, pp. 845–852, 2008.
- R. D. Rosenberg, N. W. Shworak, J. Liu, J. J. Schwartz, and L. Zhang, “Heparan sulfate proteoglycans of the cardiovascular system: specific structures emerge but how is synthesis regulated?” The Journal of Clinical Investigation, vol. 100, no. 11, pp. S67–S75, 1997.
- M. J. Lee, S. Thangada, J. H. Paik et al., “Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis,” Molecular Cell, vol. 8, no. 3, pp. 693–704, 2001.
- X. Han, D. M. Holtzman, D. W. McKeel Jr., J. Kelley, and J. C. Morris, “Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis,” Journal of Neurochemistry, vol. 82, no. 4, pp. 809–818, 2002.
- T. J. Taylor, C. Hartley, P. Simon, I. Z. Kiss, and L. Berthouze, “Identification of criticality in neuronal avalanches: I. A theoretical investigation of the non-driven case,” Journal of Mathematical Neuroscience, vol. 3, article 5, 2013.
- S. V. Buldyrev, R. Parshani, G. Paul, H. E. Stanley, and S. Havlin, “Catastrophic cascade of failures in interdependent networks,” Nature, vol. 464, no. 7291, pp. 1025–1028, 2010.
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