Rigorous treatment of pairwise and many-body electrostatic interactions among dielectric spheres at the Debye-Hückel level.

Electrostatic interactions among colloidal particles are often described using the venerable (two-particle) Derjaguin-Landau-Verwey-Overbeek (DLVO) approximation and its various modifications. However, until the recent development of a many-body theory exact at the Debye-Hückel level (Yu in Phys Rev E 102:052404, 2020), it was difficult to assess the errors of such approximations and impossible to assess the role of many-body effects. By applying the exact Debye-Hückel level theory, we quantify the errors inherent to DLVO and the additional errors associated with replacing many-particle interactions by the sum of pairwise interactions (even when the latter are calculated exactly). In particular, we show that: (1) the DLVO approximation does not provide sufficient accuracy at shorter distances, especially when there is an asymmetry in charges and/or sizes of interacting dielectric spheres; (2) the pairwise approximation leads to significant errors at shorter distances and at large and moderate Debye lengths and also gets worse with increasing asymmetry in the size of the spheres or magnitude or placement of the charges. We also demonstrate that asymmetric dielectric screening, i.e., the enhanced repulsion between charged dielectric bodies immersed in media with high dielectric constant, is preserved in the presence of free ions in the medium.

Improving series convergence: the simple pendulum and beyond.

A simple and easy to implement method for improving the convergence of a power series is presented. We observe that the most obvious or analytically convenient point about which to make a series expansion is not always the most computationally efficient. Series convergence can be dramatically improved by choosing the center of the series expansion to be at or near the average value at which the series is to be evaluated. For illustration, we apply this method to the well-known simple pendulum and to the Mexican hat type of potential. Large performance gains are demonstrated. While the method is not always the most computationally efficient on its own, it is effective, straightforward, quite general, and can be used in combination with other methods.

Extending electrostatics of dielectric spheres to arbitrary charge distributions with applications to biosystems.

A previously developed classical model of electrostatic interactions, based on a formalism of dielectric spheres, which has been found to have surprising accuracy for S state atoms, is extended by allowing higher-order moments of the intrinsic charge distribution. Two methods to introduce the charge distribution (point moments at the center vs surface charge) are shown to be equivalent and are compared with another common model for polarizable atoms that utilizes polarizable point dipoles. Unlike the polarizable point dipole model, the polarizable spheres models do not suffer from a divergence at small separation of atoms and are easily generalized to higher multipoles.

Can dielectric spheres accurately model atomic-scale interactions?

We calculate the polarization portion of electrostatic interactions at the atomic scale using quantum mechanical methods such as density functional theories (DFT) and the coupled cluster approach, and using classical methods such as a surface charge method and a polarizable force field. The agreement among various methods is investigated. Using the coupled clusters method CCSD(T) with large basis sets as the reference, we find that for systems comprising two to six atoms and ions in S-states the classical surface charge method performs much better than commonly used DFT methods with moderate basis sets such as B3LYP/6-31G(d,p). The remarkable performance of the classical approach comes as a surprise. The present results indicate that the use of a rigorous formalism of classical electrostatics can be better justified for determining molecular interactions at intermediate distances than some of the widely used methods of quantum chemistry. PACS numbers: 41.20.Cv,32.10.Dk, 87.10.Tf.

Electrical interactions in the cell: Asymmetric screening in a watery antiverse.

The problem of electrostatics in biomolecular systems presents an excellent opportunity for cross-disciplinary science and a context in which fundamental physics is called for to answer complex questions. Due to the large density in biological cells of charged biomacromolecules such as protein factors and DNA, it is challenging to understand quantitatively the electric forces in these systems. Two questions are especially puzzling. First, how is it that such a dense system of charged molecules does not simply aggregate in random and non-functional ways? Second, since some mechanism apparently prevents such aggregation, how is it that binding of biomolecules still occurs so reliably? Recognizing the role of water as a universal solvent in living systems is key to understanding these questions. We present a simplified physical model in which water is regarded as a medium of high dielectric constant that nevertheless exhibits the key features essential for answering the two questions presented. The answer to the first question lies in the strong screening ability of water, which reduces the energy scale of the electrostatic interactions. Furthermore, our model reveals the existence of asymmetric screening, a pronounced asymmetry between the screening for a system with like charges and that for a system with opposite charges, and this provides an answer to the second question.

Simple electrostatic model applicable to biomolecular recognition.

An exact, analytic solution for a simple electrostatic model applicable to biomolecular recognition is presented. In the model, a layer of high-dielectric constant material (representative of the solvent, water), whose thickness may vary separates two regions of low-dielectric constant material (representative of proteins, DNA, RNA, or similar materials), in each of which is embedded a point charge. For identical charges, the presence of the screening layer always lowers the energy compared to the case of point charges in an infinite medium of low-dielectric constant. Somewhat surprisingly, the presence of a sufficiently thick screening layer also lowers the energy compared to the case of point charges in an infinite medium of high-dielectric constant. For charges of opposite sign, the screening layer always lowers the energy compared to the case of point charges in an infinite medium of either high or low dielectric constant. The behavior of the energy leads to a substantially increased repulsive force between charges of the same sign. The attractive force between charges of opposite signs is weaker than in an infinite medium of low dielectric constant material but stronger than in an infinite medium of high dielectric constant material. The presence of this behavior, which we name asymmetric screening, in the simple system presented here confirms the generality of the behavior that was established in a more complicated system of an arbitrary number of charged dielectric spheres in an infinite solvent.

Rigorous treatment of electrostatics for spatially varying dielectrics based on energy minimization.

An energy minimization formulation of electrostatics that allows computation of the electrostatic energy and forces to any desired accuracy in a system with arbitrary dielectric properties is presented. An integral equation for the scalar charge density is derived from an energy functional of the polarization vector field. This energy functional represents the true energy of the system even in nonequilibrium states. Arbitrary accuracy is achieved by solving the integral equation for the charge density via a series expansion in terms of the equation's kernel, which depends only on the geometry of the dielectrics. The streamlined formalism operates with volume charge distributions only, not resorting to introducing surface charges by hand. Therefore, it can be applied to any spatial variation of the dielectric susceptibility, which is of particular importance in applications to biomolecular systems. The simplicity of application of the formalism to real problems is shown with analytical and numerical examples.

Electrostatics of charged dielectric spheres with application to biological systems.

Because electrostatic forces are crucial in biological systems, molecular dynamics simulations of biological systems require a method of computing electrostatic forces that is accurate and rapid. We propose a surface charge method, apply it to a system of arbitrary number of charged dielectric spheres, and obtain an exact solution for an arbitrary configuration of the spheres. The precision depends only on the number of terms kept in a series expansion and can therefore be controlled at will. It appears that the first few terms are usually adequate. The exact result exhibits a phenomenon that we call asymmetric screening. Namely, the magnitude of attractive interactions is decreased (relative to point charges in an infinite solvent) while the magnitude of repulsive interactions is increased (again, relative to point charges in an infinite solvent). This effect might aid in the adoption of correct conformations and in intermolecular recognition. Evaluation of the energy involves only matrix inversion. The surface charge method can be transformed easily to a numerical method for use with arbitrary surfaces. With modest additions, the model also describes an electrorheological fluid. Such a system provides the cleanest opportunity to apply the model.

Structure and functional connections of presynaptic terminals in the vertebrate retina revealed by activity-dependent dyes and confocal microscopy.

The fluorescent dyes sulforhodamine 101 (SR 101) and FM1-43 were used as activity-dependent dyes (ADDs) to label presynaptic terminals in the retinas of a broad range of animals, including amphibians, mammals, fish, and turtles. The pattern of dye uptake was studied in live retinal preparations by using brightfield, fluorescence, and confocal microscopy. When bath-applied to the retina-eyecup, these dyes were avidly sequestered by the presynaptic terminals of virtually all rods, cones, and bipolar and amacrine cells; ganglion cell dendrites and horizontal cells lacked significant dye accumulation. Other structures stained with these dyes included pigment epithelial cells, cone outer segments, and Müller cell end-feet. Studies of dye uptake in dark- and light-adapted preparations showed significant differences in the dye accumulation pattern in the inner plexiform layer (IPL), suggesting a dynamic, light-modulated control of endocytotic activity. Presynaptic terminals in the IPL could be segregated on the basis of volume: bipolar varicosities in the IPL were typically larger than those of amacrine cells. The combination of retrograde labeling of ganglion cells and presynaptic terminal labeling with ADDs served as the experimental preparation for three-dimensional reconstruction of both structures, based on dual detector, confocal microscopy. Our results demonstrate a new approach for studying synaptic interactions in retinal function. These findings provide new insights into the likely number and position of functional connections from amacrine and bipolar cell terminals onto ganglion cell dendrites.

Calcium channel immunoreactivity in the salamander retina.

This study reports the distribution of the alpha1D and alpha1E calcium channel subunits in the neotenous tiger salamander retina based on immunohistochemical techniques. Confocal and light microscopy were used to localize staining with fluorescently tagged antibodies to alpha1D and alpha1E in cross-sectional and flatmount preparations of retina. Alpha1D-immunoreactivity (alpha1D-IR) was localized to the inner and outer plexiform layers (IPL and OPL, respectively), ganglion cell layer (GCL), and optic fiber layer. Alpha1E-IR was found predominantly in the IPL, with scattered, weak representation in the OPL. Alpha1E-IR was not detected in the GCL or fiber layer. These findings suggest that different alpha1 calcium channel proteins have distinctive distributions in retina, which may reflect their unique and different roles in retinal processing and homeostasis.

Localization of neurotransmitters and calcium binding proteins to neurons of salamander and mudpuppy retinas.

We wished to identify the different types of retinal neurons on the basis of their content of neuroactive substances in both larval tiger salamander and mudpuppy retinas, favored species for electrophysiological investigation. Sections and wholemounts of retinas were labeled by immunocytochemical methods to demonstrate three calcium binding protein species and the common neurotransmitters, glycine, GABA and acetylcholine. Double immunostained sections and single labeled wholemount retinas were examined by confocal microscopy. Immunostaining patterns appeared to be the same in salamander and mudpuppy. Double and single cones, horizontal cells, some amacrine cells and ganglion cells were strongly calbindin-immunoreactive (IR). Calbindin-IR horizontal cells colocalized GABA. Many bipolar cells, horizontal cells, some amacrine cells and ganglion cells were strongly calretinin-IR. One type of horizontal cell and an infrequently occurring amacrine cell were parvalbumin-IR. Acetylcholine as visualized by ChAT-immunoreactivity was seen in a mirror-symmetric pair of amacrine cells that colocalized GABA and glycine. Glycine and GABA colocalized with calretinin, calbindin and occasionally with parvalbumin in amacrine cells.

Local vestibular blood flow and systemic vascular responses to natural vestibular stimulation in the Mongolian gerbil.

HYPOTHESIS: Natural stimulation of the vestibular end organs will produce alterations in the local vestibular microvascular blood flow. BACKGROUND: The vestibular and cardiovascular systems require a coordinated interaction to maintain organ perfusion during rapid positional and postural changes. However, the detailed relationship of these systems is not well understood. There have been no previous descriptions of local vestibular blood flow (VBF) during natural stimulation (NS) conditions. METHODS: In vivo VBF and systemic blood pressure (BP) in the Mongolian gerbil during natural stimulation. Using laser Doppler flowmetry, the authors obtained continuous measures of local VBF in both anesthetized and alert gerbils during sinusoidal rotational stimuli. Simultaneous recordings of systemic BP were collected from the contralateral common carotid artery. RESULTS: The anesthetized gerbils showed stable VBF and BP during all vestibular stimuli. By contrast, alert subjects demonstrated a significant response to natural stimulation. The VBF increased 28% over baseline, and systemic BP increased 8% during a 45-second, 0.133-Hz sinusoid. Decreases in BP of 8% and 5%, respectively, were seen with a 0.10 and 0.20 Hz, 360-second stimulus. A corresponding determination of VBF during the extended stimulus conditions was not technically possible. CONCLUSIONS: To the authors' knowledge, these are the first in vivo descriptions of vestibular blood flow during natural stimulation. In the alert animals, VBF increased in response to NS. This increase in flow does not appear to be directly dependent on systemic blood pressure changes and indicates that the vestibular microvasculature is closely regulated.

Functional outcomes of the retromaxillary-infratemporal fossa dissection for advanced head and neck/skull base lesions.

The retromaxillary-infratemporal fossa (RM-ITF) dissection, using a preauricular incision, was initially popularized for the treatment of temporomandibular joint disorders, facial fractures, and orbital tumors. This approach has been expanded for the treatment of advanced head and neck and skull base tumors extending into the infratemporal fossa. We studied prospectively eight consecutive patients requiring a RM-ITF dissection. Pre- and postoperative functional outcomes measured were mastication, speech, swallowing, cranial nerve function, pain, and cosmesis. A significant reduction in pain was noted postoperatively in all patients studied. Limited changes were identified in mastication, speech, swallowing, vision, hearing, or cosmesis postoperatively. The RM-ITF dissection should be considered when resecting advanced head and neck/skull base lesions that extend into this region. We have found minimal morbidity associated with this dissection. This procedure may have a useful place in palliation of patients with incurable pain caused by tumor invasion into the infratemporal fossa.

The effects of flunarizine and pentoxifylline on vestibular blood flow in the guinea pig.

Several authors have proposed that complications arising from vestibular disorders are the result of compromised circulation. The purpose of the current study was to assess the ability of flunarizine and pentoxifylline to increase peripheral vestibular blood flow (VBF), since flunarizine is a selective calcium-channel entry blocker that inhibits calcium-related contraction of smooth muscle, while pentoxifylline is a xanthine derivative that promotes microcirculation by affecting red blood cell malleability. Both of these treatment strategies have received considerable attention in clinics and laboratory, but their effects on blood flow are unclear. Changes in VBF were evaluated from the posterior semicircular canal ampulla in guinea pigs using a laser Doppler flowmeter. One group of animals was infused with pentoxifylline at concentrations of 10-40 mg/ml, while a second group was treated with 0.3-1.5 mg/kg flunarizine. VBF, blood pressure (BP) and heart rate (HR) were monitored continuously. Findings showed that pentoxifylline induced a concentration-dependent increase in VBF. In contrast, no increase in VBF occurred in response to flunarizine infusions. These studies suggest that the effectiveness of pentoxifylline in the clinical treatment of vestibular disorders may be the result of improved blood flow.

Nutritional and zinc status of head and neck cancer patients: an interpretive review.

In this review, we provide evidence based on our studies, for zinc deficiency and cell mediated immune disorders, and the effects of protein and zinc status on clinical morbidities in patients with head and neck cancer. We investigated subjects with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx. Patients with metastatic disease and with severe co-morbidity were excluded. Nutritional assessment included dietary history, body composition, and prognostic nutritional index (PNI) determination. Zinc status was determined by zinc assay in plasma, lymphocytes, and granulocytes. Pretreatment zinc status and nutritional status were correlated with clinical outcomes in 47 patients. Assessment of immune functions included production of TH1 and TH2 cytokines, T cell subpopulations and cutaneous delayed hypersensitivity reaction to common antigens. At baseline approximately 50% of our subjects were zinc-deficient based on cellular zinc criteria and had decreased production of TH1 cytokines but not TH2 cytokines, decreased NK cell lytic activity and decreased proportion of CD4+ CD45RA+ cells in the peripheral blood. The tumor size and overall stage of the disease correlated with baseline zinc status but not with PNI, alcohol intake, or smoking. Zinc deficiency was associated with increased unplanned hospitalizations. The disease-free interval was highest for the group which had both zinc sufficient and nutrition sufficient status. Zinc deficiency and cell mediated immune dysfunctions were frequently present in patients with head and neck cancer when seen initially. Zinc deficiency resulted in an imbalance of TH1 and TH2 functions. Zinc deficiency was associated with increased tumor size, overall stage of the cancer and increased unplanned hospitalizations. These observations have broad implications in the management of patients with head and neck cancer.

Effects of zinc and nutritional status on clinical outcomes in head and neck cancer.

The head and neck cancer patient often presents with both protein malnutrition and trace element deficiencies. Zinc has been found to be deficient in many head and neck cancer patients. In this study, pretreatment zinc status and nutritional status (measured by the Prognostic Nutritional Index [PNI]) were correlated with clinical outcomes in 47 patients. The patients were followed-up for a median of 52 mo from the time of enrollment. Our results showed that the tumor size and overall stage correlated significantly to zinc status whereas no such correlation was seen with PNI, alcohol intake, or smoking in our subjects. The results also showed that impaired zinc status was associated with an increased number of treatment morbidities, unplanned hospitalizations, and treatment delays (P < 0.05). Nutritional status was not associated with any studied outcome variable. The disease-free interval was highest for the group which had both zinc-sufficient and nutrition-sufficient status. Although our data do not prove conclusively, they do suggest that impaired zinc status at presentation may contribute to treatment morbidity, and that for an optimal mean disease-free interval, a sufficient zinc and nutritional status is required.

Optimizing the AV delay in DDD pacemaker patients with high degree AV block: mitral valve Doppler versus impedance cardiography.

In DDD-pacemaker patients with high degree AV block, Doppler echocardiography of transmitral blood flow can be used to find the individually optimal AV delay (AVO) for left heart AV synchronization. This study tried to validate a Doppler method (ECHO) recently proposed to optimize left ventricular filling by comparing it to stroke volume data derived from impedance cardiography (ICG). It should be further elucidated if optimizing the AV delay (AVD) by means of this method is superior to fixed AVD settings and which differential AVD (pace-sense-offset) should be programmed for atrially triggered (ATP) and AV sequential (AVP) pacing, respectively. AVO as measured in 53 patients showed a linear correlation between ECHO and ICG for both ATP (r = 0.66, P < 0.00001) and AVP (r = 0.53; P < 0.005). The mean deviation in AVO between ECHO and ICG was +/- 26 ms (ATP) and +/- 30 ms (AVP), respectively, with a tendency to longer AVDs with the Doppler method. ECHO limitations could mainly be attributed to: (1) restrictions of AVD programming options (which may be compensated for by slight modification of the proposal); and (2) to pathophysiological mechanisms that alter mitral valve dynamics. Optimization of the AVD by Doppler produced a stroke volume that was significantly higher (19%) than with a fixed AVD (150 ms in ATP; 200 ms in AVP). There was a wide scatter in pace-sense-offsets between-7 and 134 ms, which was reflected by both methods. It is concluded that AVO determinations by ECHO are valid provided that methodological pitfalls and limitations caused by the disease are recognized. Tailoring AVD with respect to diastolic filling improves systolic function and is superior to nominal AVD settings. Fixed differential AVDs as offered by some manufacturers are far from being physiological. Thus modern pulse generators should offer free programmability over a wide range of AV delays.