Multifractality in Human Heartbeat Dynamics

Recent evidence suggests that physiological signals under healthy conditions may have a fractal temporal structure. We investigate the possibility that time series generated by certain physiological control systems may be members of a special class of complex processes, termed multifractal, which require a large number of exponents to characterize their scaling properties. We report on evidence for multifractality in a biological dynamical system --- the healthy human heartbeat. Further, we show that the multifractal character and nonlinear properties of the healthy heart rate are encoded in the Fourier phases. We uncover a loss of multifractality for a life-threatening condition, congestive heart failure.Comment: 19 pages, latex2e using rotate and epsf, with 5 ps figures; to appear in Nature, 3 June, 199

Random Amino Acid Mutations and Protein Misfolding Lead to Shannon Limit in Sequence-Structure Communication

The transmission of genomic information from coding sequence to protein structure during protein synthesis is subject to stochastic errors. To analyze transmission limits in the presence of spurious errors, Shannon's noisy channel theorem is applied to a communication channel between amino acid sequences and their structures established from a large-scale statistical analysis of protein atomic coordinates. While Shannon's theorem confirms that in close to native conformations information is transmitted with limited error probability, additional random errors in sequence (amino acid substitutions) and in structure (structural defects) trigger a decrease in communication capacity toward a Shannon limit at 0.010 bits per amino acid symbol at which communication breaks down. In several controls, simulated error rates above a critical threshold and models of unfolded structures always produce capacities below this limiting value. Thus an essential biological system can be realistically modeled as a digital communication channel that is (a) sensitive to random errors and (b) restricted by a Shannon error limit. This forms a novel basis for predictions consistent with observed rates of defective ribosomal products during protein synthesis, and with the estimated excess of mutual information in protein contact potentials

Optimal In Silico Target Gene Deletion through Nonlinear Programming for Genetic Engineering

Optimal selection of multiple regulatory genes, known as targets, for deletion to enhance or suppress the activities of downstream genes or metabolites is an important problem in genetic engineering. Such problems become more feasible to address in silico due to the availability of more realistic dynamical system models of gene regulatory and metabolic networks. The goal of the computational problem is to search for a subset of genes to knock out so that the activity of a downstream gene or a metabolite is optimized.Based on discrete dynamical system modeling of gene regulatory networks, an integer programming problem is formulated for the optimal in silico target gene deletion problem. In the first result, the integer programming problem is proved to be NP-hard and equivalent to a nonlinear programming problem. In the second result, a heuristic algorithm, called GKONP, is designed to approximate the optimal solution, involving an approach to prune insignificant terms in the objective function, and the parallel differential evolution algorithm. In the third result, the effectiveness of the GKONP algorithm is demonstrated by applying it to a discrete dynamical system model of the yeast pheromone pathways. The empirical accuracy and time efficiency are assessed in comparison to an optimal, but exhaustive search strategy.Although the in silico target gene deletion problem has enormous potential applications in genetic engineering, one must overcome the computational challenge due to its NP-hardness. The presented solution, which has been demonstrated to approximate the optimal solution in a practical amount of time, is among the few that address the computational challenge. In the experiment on the yeast pheromone pathways, the identified best subset of genes for deletion showed advantage over genes that were selected empirically. Once validated in vivo, the optimal target genes are expected to achieve higher genetic engineering effectiveness than a trial-and-error procedure

Accuracy of dual-source CT coronary angiography: first experience in a high pre-test probability population without heart rate control

The aim of this study was to assess the diagnostic accuracy of dual-source computed tomography (DSCT) for evaluation of coronary artery disease (CAD) in a population with extensive coronary calcifications without heart rate control. Thirty patients (24 male, 6 female, mean age 63.1±11.3 years) with a high pre-test probability of CAD underwent DSCT coronary angiography and invasive coronary angiography (ICA) within 14±9 days. No beta-blockers were administered prior to the scan. Two readers independently assessed image quality of all coronary segments with a diameter ≥1.5 mm using a four-point score (1: excellent to 4: not assessable) and qualitatively assessed significant stenoses as narrowing of the luminal diameter >50%. Causes of false-positive (FP) and false-negative (FN) ratings were assigned to calcifications or motion artifacts. ICA was considered the standard of reference. Mean body mass index was 28.3±3.9 kg/m(2) (range 22.4–36.3 kg/m(2)), mean heart rate during CT was 70.3±14.2 bpm (range 47–102 bpm), and mean Agatston score was 821±904 (range 0–3,110). Image quality was diagnostic (scores 1–3) in 98.6% (414/420) of segments (mean image quality score 1.68±0.75); six segments in three patients were considered not assessable (1.4%). DSCT correctly identified 54 of 56 significant coronary stenoses. Severe calcifications accounted for false ratings in nine segments (eight FP/one FN) and motion artifacts in two segments (one FP/one FN). Overall sensitivity, specificity, positive and negative predictive value for evaluating CAD were 96.4, 97.5, 85.7, and 99.4%, respectively. First experience indicates that DSCT coronary angiography provides high diagnostic accuracy for assessment of CAD in a high pre-test probability population with extensive coronary calcifications and without heart rate control

Maternal common mental disorders and infant development in Ethiopia : the P-MaMiE Birth Cohort

Background: Chronicity and severity of early exposure to maternal common mental disorders (CMD) has been associated with poorer infant development in high-income countries. In low- and middle-income countries (LAMICs), perinatal CMD is inconsistently associated with infant development, but the impact of severity and persistence has not been examined. Methods: A nested population-based cohort of 258 pregnant women was identified from the Perinatal Maternal Mental Disorder in Ethiopia (P-MaMiE) study, and 194 (75.2%) were successfully followed up until the infants were 12 months of age. Maternal CMD was measured in pregnancy and at two and 12 months postnatal using the WHO Self-Reporting Questionnaire, validated for use in this setting. Infant outcomes were evaluated using the Bayley Scales of Infant Development. Results: Antenatal maternal CMD symptoms were associated with poorer infant motor development ( β ^ -0.20; 95% CI: -0.37 to -0.03), but this became non-significant after adjusting for confounders. Postnatal CMD symptoms were not associated with any domain of infant development. There was evidence of a dose-response relationship between the number of time-points at which the mother had high levels of CMD symptoms (SRQ ≥ 6) and impaired infant motor development ( β ^ = -0.80; 95%CI -2.24, 0.65 for ante- or postnatal CMD only, β ^ = -4.19; 95%CI -8.60, 0.21 for ante- and postnatal CMD, compared to no CMD; test-for-trend χ213.08(1), p < 0.001). Although this association became non-significant in the fully adjusted model, the β ^ coefficients were unchanged indicating that the relationship was not confounded. In multivariable analyses, lower socio-economic status and lower infant weight-for-age were associated with significantly lower scores on both motor and cognitive developmental scales. Maternal experience of physical violence was significantly associated with impaired cognitive development. Conclusions: The study supports the hypothesis that it is the accumulation of risk exposures across time rather than early exposure to maternal CMD per se that is more likely to affect child development. Further investigation of the impact of chronicity of maternal CMD upon child development in LAMICs is indicated. In the Ethiopian setting, poverty, interpersonal violence and infant undernutrition should be targets for interventions to reduce the loss of child developmental potential.Peer Reviewe

Revisiting the Myths of Protein Interior: Studying Proteins with Mass-Fractal Hydrophobicity-Fractal and Polarizability-Fractal Dimensions

A robust marker to describe mass, hydrophobicity and polarizability distribution holds the key to deciphering structural and folding constraints within proteins. Since each of these distributions is inhomogeneous in nature, the construct should be sensitive in describing the patterns therein. We show, for the first time, that the hydrophobicity and polarizability distributions in protein interior follow fractal scaling. It is found that (barring ‘all-α’) all the major structural classes of proteins have an amount of unused hydrophobicity left in them. This amount of untapped hydrophobicity is observed to be greater in thermophilic proteins, than that in their (structurally aligned) mesophilic counterparts. ‘All-β’(thermophilic, mesophilic alike) proteins are found to have maximum amount of unused hydrophobicity, while ‘all-α’ proteins have been found to have minimum polarizability. A non-trivial dependency is observed between dielectric constant and hydrophobicity distributions within (α+β) and ‘all-α’ proteins, whereas absolutely no dependency is found between them in the ‘all-β’ class. This study proves that proteins are not as optimally packed as they are supposed to be. It is also proved that origin of α-helices are possibly not hydrophobic but electrostatic; whereas β-sheets are predominantly hydrophobic in nature. Significance of this study lies in protein engineering studies; because it quantifies the extent of packing that ensures protein functionality. It shows that myths regarding protein interior organization might obfuscate our knowledge of actual reality. However, if the later is studied with a robust marker of strong mathematical basis, unknown correlations can still be unearthed; which help us to understand the nature of hydrophobicity, causality behind protein folding, and the importance of anisotropic electrostatics in stabilizing a highly complex structure named ‘proteins’

Information storing by biomagnetites

Since the discovery of the presence of biogenic magnetites in living organisms, there have been speculations on the role that these biomagnetites play in cellular processes. It seems that the formation of biomagnetite crystals is a universal phenomenon and not an exception in living cells. Many experimental facts show that features of organic and inorganic processes could be indistinguishable at nanoscale levels. Living cells are quantum "devices" rather than simple electronic devices utilizing only the charge of conduction electrons. In our opinion, due to their unusual biophysical properties, special biomagnetites must have a biological function in living cells in general and in the brain in particular. In this paper we advance a hypothesis that while biomagnetites are developed jointly with organic molecules and cellular electromagnetic fields in cells, they can record information about the Earth's magnetic vector potential of the entire flight in migratory birds.Comment: 17 pages, 3 figure

FRET Detection of Lymphocyte Function-Associated Antigen-1 Conformational Extension

Lymphocyte function-associated antigen 1 (LFA-1, CD11a/CD18, αLβ2-integrin) and its ligands are essential for adhesion between T-cells and antigen-presenting cells, formation of the immunological synapse, and other immune cell interactions. LFA-1 function is regulated through conformational changes that include the modulation of ligand binding affinity and molecular extension. However, the relationship between molecular conformation and function is unclear. Here fluorescence resonance energy transfer (FRET) with new LFA-1-specific fluorescent probes showed that triggering of the pathway used for T-cell activation induced rapid unquenching of the FRET signal consistent with extension of the molecule. Analysis of the FRET quenching at rest revealed an unexpected result that can be interpreted as a previously unknown LFA-1 conformation

T Cells' Immunological Synapses Induce Polarization of Brain Astrocytes In Vivo and In Vitro: A Novel Astrocyte Response Mechanism to Cellular Injury

Astrocytes usually respond to trauma, stroke, or neurodegeneration by undergoing cellular hypertrophy, yet, their response to a specific immune attack by T cells is poorly understood. Effector T cells establish specific contacts with target cells, known as immunological synapses, during clearance of virally infected cells from the brain. Immunological synapses mediate intercellular communication between T cells and target cells, both in vitro and in vivo. How target virally infected astrocytes respond to the formation of immunological synapses established by effector T cells is unknown.Herein we demonstrate that, as a consequence of T cell attack, infected astrocytes undergo dramatic morphological changes. From normally multipolar cells, they become unipolar, extending a major protrusion towards the immunological synapse formed by the effector T cells, and withdrawing most of their finer processes. Thus, target astrocytes become polarized towards the contacting T cells. The MTOC, the organizer of cell polarity, is localized to the base of the protrusion, and Golgi stacks are distributed throughout the protrusion, reaching distally towards the immunological synapse. Thus, rather than causing astrocyte hypertrophy, antiviral T cells cause a major structural reorganization of target virally infected astrocytes.Astrocyte polarization, as opposed to hypertrophy, in response to T cell attack may be due to T cells providing a very focused attack, and thus, astrocytes responding in a polarized manner. A similar polarization of Golgi stacks towards contacting T cells was also detected using an in vitro allogeneic model. Thus, different T cells are able to induce polarization of target astrocytes. Polarization of target astrocytes in response to immunological synapses may play an important role in regulating the outcome of the response of astrocytes to attacking effector T cells, whether during antiviral (e.g. infected during HIV, HTLV-1, HSV-1 or LCMV infection), anti-transplant, autoimmune, or anti-tumor immune responses in vivo and in vitro