Modeling Antiretrovial Treatment to Mitigate HIV in the Brain: Impact of the Blood-Brain Barrier.

Current research in Human Immunodeficiency Virus (HIV) focuses on eradicating virus reservoirs that prevent or dampen the effectiveness of antiretroviral treatment (ART). One such reservoir, the brain, reduces treatment efficacy via the blood-brain barrier (BBB), causing an obstacle to drug penetration into the brain. In this study, we develop a mathematical model to examine the impact of the BBB on ART effectiveness for mitigating brain HIV. A thorough analysis of the model allowed us to fully characterize the global threshold dynamics with the viral clearance and persistence in the brain for the basic reproduction number less than unity and greater than unity, respectively. Our model showed that the BBB has a significant role in inhibiting the effect of ART within the brain despite the effective viral load suppression in the plasma. The level of impact, however, depends on factors such as the CNS Penetration Effectiveness (CPE) score, the slope of the drug dose-response curves, the ART initiation timing, and the number of drugs in the ART protocol. These results suggest that reducing the plasma viral load to undetectable levels due to some drug regimen may not necessarily indicate undetectable levels of HIV in the brain. Thus, the effect of the BBB on viral suppression in the brain must be considered for developing proper treatment protocols against HIV infection.

A diffusive virus model with a fixed intracellular delay and combined drug treatments.

The method of administration of an effective drug treatment to eradicate viruses within a host is an important issue in studying viral dynamics. Overuse of a drug can lead to deleterious side effects, and overestimating the efficacy of a drug can result in failure to treat infection. In this study, we proposed a reaction-diffusion within-host virus model which incorporated information regarding spatial heterogeneity, drug treatment, and the intracellular delay to produce productively infected cells and viruses. We also calculated the basic reproduction number [Formula: see text] under the assumptions of spatial heterogeneity. We have shown that the infection-free periodic solution is globally asymptotically stable when [Formula: see text], whereas when [Formula: see text] there is an infected periodic solution and the infection is uniformly persistent. By conducting numerical simulations, we also revealed the effects of various parameters on the value of [Formula: see text]. First, we showed that the dependence of [Formula: see text] on the intracellular delay could be monotone or non-monotone, depending on the death rate of infected cells in the immature stage. Second, we found that the mobility of infected cells or virions could facilitate the virus clearance. Third, we found that the spatial fragmentation of the virus environment enhanced viral infection. Finally, we showed that the combination of spatial heterogeneity and different sets of diffusion rates resulted in complicated viral dynamic outcomes.

Oriented Self-Assembled Monolayer of Zn(II)-Tetraphenylporphyrin on TiO2 Electrode for Photoelectrochemical Analysis.

The photoelectrochemical performance of a zinc porphyrin sensitized TiO2 photoelectrode fabricated through the axial-coordination strategy has been studied. Zinc(II) tetraphenylporphyrin (TPPZn) was immobilized on the TiO2 electrode through the axial coordination reaction with surface premodified methyl 4-(1 H-imidazol-1-yl)benzoate (PhImMe). Spectral characterizations were carried out to confirm the robust interaction between TPPZn and PhImMe, while the chemical bonding of PhImMe on TiO2 surface has been evidenced by XPS measurement. The modified TiO2 electrode produces a stable and enhanced photocurrent signal under 410 nm irradiation at a bias of 0.2 V in phosphate buffer solution, compared with pristine TiO2. A sensitive increment of the photocurrent is observed with the addition of l-glutathione. A possible mechanism for this photoelectrochemical process includes the photoexcitation of the porphyrin, electron injection from porphyrin toward the TiO2, and the hole-scavenging process by the reductants. The "lying-low" surface conformation of the porphyrin plane might facilitate the PEC process owing to the enhanced electronic coupling between the porphyrin plane and the TiO2 substrate. A PEC analysis on l-glutathione has been carried out to evaluate the photoelectrochemical performance of the modified TiO2 electrode, which presents the wide linear ranges of 5-80 µM and 80-5000 µM, with a lower detection limit of 3.21 µM at an S/N ratio of 3. This work reports for the first time on the PEC performance of metalloporphyrin axially coordinated on a semiconductor surface and could lead to the designing of more efficient photoelectrochemical sensors and devices based on similar electrode structures.

Vagal baro- and chemoreceptors in middle internal carotid artery and carotid body in rat.

The glossopharyngeal nerve, via the carotid sinus nerve (CSN), presents baroreceptors from the internal carotid artery (ICA) and chemoreceptors from the carotid body. Although neurons in the nodose ganglion were labelled after injecting tracer into the carotid body, the vagal pathway to these baro- and chemoreceptors has not been identified. Neither has the glossopharyngeal intracranial afferent/sensory pathway that connects to the brainstem been defined. We investigated both of these issues in male Sprague-Dawley rats (n = 40) by injecting neural tracer wheat germ agglutinin-horseradish peroxidase into: (i) the peripheral glossopharyngeal or vagal nerve trunk with or without the intracranial glossopharyngeal rootlet being rhizotomized; or (ii) the nucleus of the solitary tract right after dorsal and ventral intracranial glossopharyngeal rootlets were dissected. By examining whole-mount tissues and brainstem sections, we verified that only the most rostral rootlet connects to the glossopharyngeal nerve and usually four caudal rootlets connect to the vagus nerve. Furthermore, vagal branches may: (i) join the CSN originating from the pharyngeal nerve base, caudal nodose ganglion, and rostral or caudal superior laryngeal nerve; or (ii) connect directly to nerve endings in the middle segment of the ICA or to chemoreceptors in the carotid body. The aortic depressor nerve always presents and bifurcates from either the rostral or the caudal part of the superior laryngeal nerve. The vagus nerve seemingly provides redundant carotid baro- and chemoreceptors to work with the glossopharyngeal nerve. These innervations confer more extensive roles on the vagus nerve in regulating body energy that is supplied by the cardiovascular, pulmonary and digestive systems.

Exploring the Confinement Effect of Carbon Nanotubes on the Electrochemical Properties of Prussian Blue Nanoparticles.

A novel and efficient photochemical method has been proposed for the encapsulation of Prussian blue nanoparticles (PBNPs) inside the channels of carbon nanotubes (PB-in-CNTs) in an acidic ferrocyanide solution under UV/vis illumination, and the confinement effect of CNTs on the electrochemical properties of PBNPs is systematically explored. PB-in-CNTs show a faster electron-transfer process, an enhanced electrocatalytic activity toward the reduction of H2O2, and an increased anti-base ability compared to PBNPs loaded outside of CNTs (PB-out-CNTs). In addition, PB-in-CNTs show an increased electrochemical reversibility and an unexpected diameter-independent catalytic activity with the decrease of CNT diameters. The improved electrochemical properties of PB-in-CNTs are attributed to the modified electronic properties and dimensions of PBNPs induced by the confinement effect of CNTs. This work provides further insights into the confinement effect on the properties of nanomaterials and will inspire extensive relevant investigations in the development of novel composites or excellent catalysts.

Energy Level Engineering of MoS2 by Transition-Metal Doping for Accelerating Hydrogen Evolution Reaction.

Water-splitting devices for hydrogen generation through electrolysis (hydrogen evolution reaction, HER) hold great promise for clean energy. However, their practical application relies on the development of inexpensive and efficient catalysts to replace precious platinum catalysts. We previously reported that HER can be largely enhanced through finely tuning the energy level of molybdenum sulfide (MoS2) by hot electron injection from plasmonic gold nanoparticles. Under this inspiration, herein, we propose a strategy to improve the HER performance of MoS2 by engineering its energy level via direct transition-metal doping. We find that zinc-doped MoS2 (Zn-MoS2) exhibits superior electrochemical activity toward HER as evidenced by the positively shifted onset potential to -0.13 V vs RHE. A turnover of 15.44 s-1 at 300 mV overpotential is achieved, which by far exceeds the activity of MoS2 catalysts reported. The large enhancement can be attributed to the synergistic effect of electronic effect (energy level matching) and morphological effect (rich active sites) via thermodynamic and kinetic acceleration, respectively. This design opens up further opportunities for improving electrocatalysts by incorporating promoters, which broadens the understanding toward the optimization of electrocatalytic activity of these unique materials.

Copper-Nitrogen-Doped Graphene Hybrid as an Electrochemical Sensing Platform for Distinguishing DNA Bases.

An electrochemical sensor using ultralight and porous copper-nitrogen-doped graphene (CuNRGO) nanocomposite as the electrocatalyst has been constructed to simultaneously determine DNA bases such as guanine (G) and cytosine (C), adenine (A), and thymine (T). The nanocomposite is synthesized by thermally annealing an ice-templated structure of graphene oxide (GO) and Cu(phen)2. Because of the unique structure and the presence of Cu2+-N active sites, the CuNRGO exhibits outstanding electrocatalytic activity toward the oxidation of free DNA bases. After optimizing the experimental conditions, the CuNRGO-based electrochemical sensor shows good linear responses for the G, A, T, and C bases in the concentration ranges of 0.132-6.62 µM, 0.37-5.18 µM, 198.2-5551 µM, and 270.0-1575 µM, respectively. The results demonstrate that CuNRGO is a promising electrocatalyst for electrochemical sensing devices.

Vagal nerve endings in visceral pleura and triangular ligaments of the rat lung.

The inner thoracic cavity is lined by the parietal pleura, and the lung lobes are covered by the visceral pleura. The parietal and visceral plurae form the pleural cavity that has negative pressure within to enable normal respiration. The lung tissues are bilaterally innervated by vagal and spinal nerves, including sensory and motor components. This complicated innervation pattern has made it difficult to discern the vagal vs. spinal processes in the pulmonary visceral pleura. With and without vagotomy, we identified vagal nerve fibres and endings distributed extensively in the visceral pleura ('P'-type nerve endings) and triangular ligaments ('L'-type nerve endings) by injecting wheat germ agglutinin-horseradish peroxidase as a tracer into the nucleus of solitary tract or nodose ganglion of male Sprague-Dawley rats. We found the hilar and non-hilar vagal pulmonary pleural innervation pathways. In the hilar pathway, vagal sub-branches enter the hilum and follow the pleural sheet to give off the terminal arborizations. In the non-hilar pathway, vagal sub-branches run caudally along the oesophagus and either directly enter the ventral-middle-mediastinal left lobe or follow the triangular ligaments to enter the left and inferior lobe. Both vagi innervate: (i) the superior, middle and accessory lobes on the ventral surfaces that face the heart; (ii) the dorsal-rostral superior lobe; (iii) the dorsal-caudal left lobe; and (iv) the left triangular ligament. Innervated only by the left vagus is: (i) the ventral-rostral and dorsal-rostral left lobe via the hilar pathway; (ii) the ventral-middle-mediastinal left lobe and the dorsal accessory lobe that face the left lobe via the non-hilar pathway; and (iii) the ventral-rostral inferior lobe that faces the heart. Innervated only by the right vagus, via the non-hilar pathway, is: (i) the inferior (ventral and dorsal) and left (ventral only) lobe in the area near the triangular ligament; (ii) the dorsal-middle-mediastinal left lobe; and (iii) the right triangular ligament. Other regions innervated with unknown vagal pathways include: (i) the middle lobe that faces the superior and inferior lobe; (ii) the rostral-mediastinal inferior lobe that faces the middle lobe; and (iii) the ventral accessory lobe that faces the diaphragm. Our study demonstrated that most areas that face the dorsal thoracic cavity have no vagal innervation, whereas the interlobar and heart-facing areas are bilaterally or unilaterally innervated with a left-rostral vs. right-caudal lateralized innervation pattern. This innervation pattern may account for the fact that the respiratory regulation in rats has a lateralized right-side dominant pattern.

Single species growth consuming inorganic carbon with internal storage in a poorly mixed habitat.

This paper presents a PDE system modeling the growth of a single species population consuming inorganic carbon that is stored internally in a poorly mixed habitat. Inorganic carbon takes the forms of "CO2" (dissolved CO2 and carbonic acid) and "CARB" (bicarbonate and carbonate ions), which are substitutable in their effects on algal growth. We first establish a threshold type result on the extinction/persistence of the species in terms of the sign of a principal eigenvalue associated with a nonlinear eigenvalue problem. If the habitat is the unstirred chemostat, we add biologically relevant assumptions on the uptake functions and prove the uniqueness and global attractivity of the positive steady state when the species persists.

Double labeling of vagal preganglionic and sympathetic postganglionic fibers in celiac ganglion, superior mesenteric arteries and myenteric plexus.

Sympathetic efferents regulate the "fight-or-flight" response and sympathetic and vagal fibers have been suggested to retrogradely and centrally spread pathogens associated with Parkinson's disease. To examine the arrangement of the vagal and sympathetic motor fibers in the celiac ganglion (CG), gastrointestinal tract, and along the superior mesenteric artery and its sub-branches, we double-labeled the vagal efferents by injecting Dextran-Texas Red into the dorsal motor nucleus of the vagus and the sympathetic postganglionics with tyrosine hydroxylase immunohistochemistry in male Sprague-Dawley rats (n = 18). The laser scanning confocal microscope was used for image analysis. Vagal nerve endings were densely distributed around the CG neurons, and the right CG received more. Vagal and sympathetic efferent endings formed various ring or string shapes that tangled closely in the myenteric plexus of the forestomach, duodenum, jejunum and ileum. Vagal and sympathetic efferents coursed within the same nerve bundles before reaching the myenteric plexus, had in-apposition varicosities, and ran parallel with the superior mesenteric artery and its sub-branches. Although a complete sympathetic tracing and an incomplete tracing and/or damage to the vagal preganglionic neurons may lead to a sampling bias, the sympathetic innervations in the blood vessels and myenteric plexus are stronger than in the vagus. The in-apposition innervation varicosities of the vagal and sympathetic efferents within the same nerve bundles and in the myenteric plexus of the gut with complex innervation patterns may offer a network to automatically control gastrointestinal functions and an infection route of the Parkinson's disease between the autonomic efferent endings.

Highly stable and luminescent layered hybrid materials for sensitive detection of TNT explosives.

Self-assembly is an effective way to fabricate optical molecular materials. However, this strategy usually changes the nanoenvironment surrounding fluorescence molecules, yielding low luminescence efficiency. Herein, we report the intercalation of a ruthenium polypyridine (Ru) complex into the interlayer galleries of layered double hydroxides (LDHs), forming a Ru/LDH hybrid. The Ru complex exists as an ordered monolayer state, and the hybrid exhibits high thermal and photo stability. Its luminescence efficiency and lifetime are increased by ∼1.7 and ∼1 times, respectively, compared to those of free molecules. We constructed a Ru/LDH sensing platform based on a fluorescence quenching effect for highly sensitive detection of TNT with a detection limit of 4.4 µM.

Graphene-Ruthenium(II) complex composites for sensitive ECL immunosensors.

Non-covalent modification method has been proven as an effective strategy for enhancing the chemical properties of graphene while the structure and electronic properties of graphene can be retained. This work describes a novel strategy to fabricate a solid-state electrochemiluminescent (ECL) immunosensor based on ruthenium(II) complex/3,4,9,10-perylenetetracarboxylic acid (PTCA)/graphene nanocomposites (Ru-PTCA/G) for sensitive detection of α-fetoprotein (AFP). It is found that immobilization of PTCA and reduction of GO can be simultaneously achieved in one-pot synthesis method under alkaline condition and moderate temperature, forming PTCA/G nanocomposites. Further covalent attachment of ruthenium(II) complex to the PTCA assembled on graphene sheets produces the functional Ru-PTCA/G nanocomposites which show good electrochemical activity and ca. 21 times higher luminescence quantum efficiency than the adsorbed derivative ruthenium(II) complex. The Ru-PTCA/G nanocomposites based solid-state ECL sensor exhibits high stability toward the determination of tripropylamine (TPA) coreactant. In addition, a new ECL immunosensor based on steric hindrance effect is fabricated by cross-linking α-fetoprotein antibody (anti-AFP) with chitosan covered on Ru-PTCA/G composites modified electrode for detection of cancer biomarker AFP. This ECL immunosensor shows an extremely sensitive response to AFP in a linear range of 5 pg·mL(-1) -10 ng·mL(-1) with a detection limit of 0.2 pg·mL(-1) . The present approach is effective for various molecules immobilization and may become a promising technique for biomolecular detection.

Donnan potential caused by polyelectrolyte monolayers.

The Donnan potential is successfully isolated from ion pair potential on a ferrocene-labeled polyelectrolyte (DNA) monolayer. The isolated Donnan potential shifts negatively upon the increase in NaClO4 concentration with a slope of -58.8 mV/decade. With the salt concentration grown up to 1 M, the stretched DNA chains in low salt concentration are found to experience a gradual conformation relaxing process. At salt concentrations higher than 2 M, Donnan breakdown occurs where only the ion pair effect modulates the apparent potential. The apparent formal potential also shows strong dependence on solution pH, which reveals that the charge density in the polyelectrolyte monolayer plays an important role in the establishment of Donnan equilibrium.

Competition and allelopathy with resource storage: two resources.

Allelopathy is added to a familiar mathematical model of competition between two species for two essential resources in a chemostat environment. Both species store the resources, and each produces a toxin that induces mortality in the other species. The corresponding model without toxins displays outcomes of competitive exclusion independent of initial conditions, competitive exclusion that depends on initial conditions (bistability), and globally stable coexistence, depending on tradeoffs between competitors in growth requirements and consumption of the resources. Introducing toxins that act only between, and not within species, can destabilize coexistence leading to bistability or other multiple attractors. Invasibility of the missing species into a resident׳s semitrivial equilibrium is related to competitive outcomes. Mutual invasibility is necessary and sufficient for a globally stable coexistence equilibrium, but is not necessary for coexistence at a locally stable equilibrium. Invasibility of one semitrivial equilibrium but not the other is necessary but not sufficient for competitive exclusion independent of initial conditions. Mutual non-invasibility is necessary but not sufficient for bistability. Numerical analysis suggests that when competitors display bistability in the absence of toxin production, increases in the overall magnitude of resource supply cause bistability to arise over a larger range of supply ratios between the two resources. When competitors display coexistence in the absence of toxin production, increases in overall resource supply destabilize coexistence and produce bistability or other configurations of multiple attractors over large ranges of supply ratios. The emergence of multiple attractors at high resource supplies suggests that blooms of harmful algae producing allelopathic toxins could be difficult to predict under such rich conditions.

A Reaction-Diffusion Model with Spatially Inhomogeneous Delays.

Motivated by population growth in a heterogeneous environment, this manuscript builds a reaction-diffusion model with spatially dependent parameters. In particular, a term for spatially uneven maturation durations is included in the model, which puts the current investigation among the very few studies on reaction-diffusion systems with spatially dependent delays. Rigorous analysis is performed, including the well-posedness of the model, the basic reproduction ratio formulation and long-term behavior of solutions. Under mild assumptions on model parameters, extinction of the species is predicted when the basic reproduction ratio is less than one. When the birth rate is an increasing function and the basic reproduction ratio is greater than one, uniqueness and global attractivity of a positive equilibrium can be established with the help of a novel functional phase space. Permanence of the species is shown when the birth function is in a unimodal form and the basic reproduction ratio is greater than one. The synthesized approach proposed here is applicable to broader contexts of studies on the impact of spatial heterogeneity on population dynamics, in particular, when the delayed feedbacks are involved and the response time is spatially varying.

Competition between microorganisms for a single limiting resource with cell quota structure and spatial variation.

Microbial populations compete for nutrient resources, and the simplest mathematical models of competition neglect differences in the nutrient content of individuals. The simplest models also assume a spatially uniform habitat. Here both of these assumptions are relaxed. Nutrient content of individuals is assumed proportional to cell size, which varies for populations that reproduce by division, and the habitat is taken to be an unstirred chemostat where organisms and nutrients move by simple diffusion. In a spatially uniform habitat, the size-structured model predicts competitive exclusion, such that only the species with lowest break-even concentration persists. In the unstirred chemostat, coexistence of two competitors is possible, if one has a lower break-even concentration and the other can grow more rapidly. In all habitats, the calculation of competitive outcomes depends on a principal eigenvalue that summarizes relationships among cell growth, cell division, and cell size.

Threshold dynamics of an infective disease model with a fixed latent period and non-local infections.

In this paper, we derive and analyze an infectious disease model containing a fixed latency and non-local infection caused by the mobility of the latent individuals in a continuous bounded domain. The model is given by a spatially non-local reaction-diffusion system carrying a discrete delay associated with the zero-flux condition on the boundary. By applying some existing abstract results in dynamical systems theory, we prove the existence of a global attractor for the model system. By appealing to the theory of monotone dynamical systems and uniform persistence, we show that the model has the global threshold dynamics which can be described either by the principal eigenvalue of a linear non-local scalar reaction diffusion equation or equivalently by the basic reproduction number R0 for the model. Such threshold dynamics predicts whether the disease will die out or persist. We identify the next generation operator, the spectral radius of which defines basic reproduction number. When all model parameters are constants, we are able to find explicitly the principal eigenvalue and R0. In addition to computing the spectral radius of the next generation operator, we also discuss an alternative way to compute R0.

Measles virus infection in adults induces production of IL-10 and is associated with increased CD4+ CD25+ regulatory T cells.

Despite steady progress in elimination of measles virus globally, measles infection still causes 500,000 annual deaths, mostly in developing countries where endemic measles strains still circulate. Many adults are infected every year in China, with symptoms more severe than those observed in children. In this study, we have used blood samples from adult measles patients in Shanghai and age-matched healthy controls to gain an understanding of the immune status of adult measles patients. IFN-alpha mRNA was reduced in patient PBMC compared with healthy controls. In contrast, gene expression and plasma production of IL-2, IL-10, and IFN-gamma were elevated in patient blood. A similar cytokine profile was observed at early times when cultured PBMC were infected with a clinical isolate of measles virus. In contrast to previous studies in pediatric patients, we did not find a reduction in total CD4(+) and CD8(+) T cells in patient PBMC. Interestingly, we found that CD4(+)CD25(+)CD127(low) regulatory T cells were significantly increased in patient PBMC compared with controls. Using intracellular cytokine staining we also show that the measles virus induces IL-10-producing CD14(+) and CD4(+)CD25(+) cells in PBMC. Our results show that adult measles patients in the acute phase of the disease have a mixed Th1/Th2 type response, accompanied with severe immunosuppression of both innate and adaptive responses including suppression of type I IFN. Both regulatory T cells and plasma IL-10 may contribute to the immunosuppression.

Effects of periodic intake of drugs of abuse (morphine) on HIV dynamics: Mathematical model and analysis.

Drugs of abuse, such as opiates, have been widely associated with diminishing host-immune responses, including suppression of HIV-specific antibody responses. In particular, periodic intake of the drugs of abuse can result in time-varying periodic antibody level within HIV-infected individuals, consequently altering the HIV dynamics. In this study, we develop a mathematical model to analyze the effects of periodic intake of morphine, a widely used opiate. We consider two routes of morphine intake, namely, intravenous morphine (IVM) and slow-release oral morphine (SROM), and integrate several morphine pharmacodynamic parameters into HIV dynamics model. Using our non-autonomous model system we formulate the infection threshold, Ri, for global stability of infection-free equilibrium, which provides a condition for avoiding viral infection in a host. We demonstrate that the infection threshold highly depends on the morphine pharmacodynamic parameters. Such information can be useful in the design of antibody-based vaccines. In addition, we also thoroughly evaluate how alteration of the antibody level due to periodic intake of morphine can affect the viral load and the CD4 count in HIV infected drug abusers.

Importance of Au nanostructures in CO2 electrochemical reduction reaction.

Electrochemical conversion of CO2 into fuels is a promising means to solve greenhouse effect and recycle chemical energy. However, the CO2 reduction reaction (CO2RR) is limited by the high overpotential, slow kinetics and the accompanied side reaction of hydrogen evolution reaction. Au nanocatalysts exhibit high activity and selectivity toward the reduction of CO2 into CO. Here, we explore the Faradaic efficiency (FE) of CO2RR catalyzed by 50 nm gold colloid and trisoctahedron. It is found that the maximum FE for CO formation on Au trisoctahedron reaches 88.80% at -0.6 V, which is 1.5 times as high as that on Au colloids (59.04% at -0.7 V). The particle-size effect of Au trisoctahedron has also been investigated, showing that the FE for CO decreases almost linearly to 62.13% when the particle diameter increases to 100 nm. The X-ray diffraction characterizations together with the computational hydrogen electrode (CHE) analyses reveal that the (2 2 1) facets on Au trisoctahedron are more feasible than the (1 1 1) facets on Au colloids in stabilizing the critical intermediate COOH*, which are responsible for the higher FE and lower overpotential observed on Au trisoctahedron.