Hierarchical ordering of reticular networks

The structure of hierarchical networks in biological and physical systems has long been characterized using the Horton-Strahler ordering scheme. The scheme assigns an integer order to each edge in the network based on the topology of branching such that the order increases from distal parts of the network (e.g., mountain streams or capillaries) to the "root" of the network (e.g., the river outlet or the aorta). However, Horton-Strahler ordering cannot be applied to networks with loops because they they create a contradiction in the edge ordering in terms of which edge precedes another in the hierarchy. Here, we present a generalization of the Horton-Strahler order to weighted planar reticular networks, where weights are assumed to correlate with the importance of network edges, e.g., weights estimated from edge widths may correlate to flow capacity. Our method assigns hierarchical levels not only to edges of the network, but also to its loops, and classifies the edges into reticular edges, which are responsible for loop formation, and tree edges. In addition, we perform a detailed and rigorous theoretical analysis of the sensitivity of the hierarchical levels to weight perturbations. We discuss applications of this generalized Horton-Strahler ordering to the study of leaf venation and other biological networks.Comment: 9 pages, 5 figures, During preparation of this manuscript the authors became aware of a related work by Katifori and Magnasco, concurrently submitted for publicatio

Environmental Stress and Adaptational Responses: Consequences for Human Health Outcomes

With the dramatic pace of modernization of the world’s population, human adaptation as a theoretical construct and paradigm will likely become a focal scientific issue involving scientists from many disciplinary areas during the 21st Century. Macro and micro environments are in rapid flux and human populations are exposed to rapid change. The concept of adaptation, at least in the field of biological anthropology and human biology, will likely remain tied to evolutionary processes and concepts of selection and fitness. In this paper, we discuss the theoretical constructs of adaptation and adaptability and select three current examples from our ongoing research that involve studies of adaptation and evolutionary processes in modernizing populations in different locations worldwide

Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers.

BACKGROUND: Ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction. Spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with ticagrelor, as with other antiplatelet drugs. The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. A rapid-acting reversal agent would be useful. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay. RESULTS: Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P\u3c0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site. CONCLUSIONS: In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.)

Intrinsic Circadian Clock of the Mammalian Retina: Importance for Retinal Processing of Visual Information

SummaryCircadian clocks are widely distributed in mammalian tissues, but little is known about the physiological functions of clocks outside the suprachiasmatic nucleus of the brain. The retina has an intrinsic circadian clock, but its importance for vision is unknown. Here we show that mice lacking Bmal1, a gene required for clock function, had abnormal retinal transcriptional responses to light and defective inner retinal electrical responses to light, but normal photoreceptor responses to light and retinas that appeared structurally normal by light and electron microscopy. We generated mice with a retina-specific genetic deletion of Bmal1, and they had defects of retinal visual physiology essentially identical to those of mice lacking Bmal1 in all tissues and lacked a circadian rhythm of inner retinal electrical responses to light. Our findings indicate that the intrinsic circadian clock of the retina regulates retinal visual processing in vivo

Valley Splitting Theory of SiGe/Si/SiGe Quantum Wells

We present an effective mass theory for SiGe/Si/SiGe quantum wells, with an emphasis on calculating the valley splitting. The theory introduces a valley coupling parameter, $v_v$, which encapsulates the physics of the quantum well interface. The new effective mass parameter is computed by means of a tight binding theory. The resulting formalism provides rather simple analytical results for several geometries of interest, including a finite square well, a quantum well in an electric field, and a modulation doped two-dimensional electron gas. Of particular importance is the problem of a quantum well in a magnetic field, grown on a miscut substrate. The latter may pose a numerical challenge for atomistic techniques like tight-binding, because of its two-dimensional nature. In the effective mass theory, however, the results are straightforward and analytical. We compare our effective mass results with those of the tight binding theory, obtaining excellent agreement.Comment: 13 pages, 7 figures. Version submitted to PR

Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.

BACKGROUND: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. METHODS: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. RESULTS: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. CONCLUSIONS: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .)

GiA Roots: Software for the high throughput analysis of plant root system architecture

Background: Characterizing root system architecture (RSA) is essential to understanding the development and function of vascular plants. Identifying RSA-associated genes also represents an underexplored opportunity for crop improvement. Software tools are needed to accelerate the pace at which quantitative traits of RSA are estimated from images of root networks.Results: We have developed GiA Roots (General Image Analysis of Roots), a semi-automated software tool designed specifically for the high-throughput analysis of root system images. GiA Roots includes user-assisted algorithms to distinguish root from background and a fully automated pipeline that extracts dozens of root system phenotypes. Quantitative information on each phenotype, along with intermediate steps for full reproducibility, is returned to the end-user for downstream analysis. GiA Roots has a GUI front end and a command-line interface for interweaving the software into large-scale workflows. GiA Roots can also be extended to estimate novel phenotypes specified by the end-user.Conclusions: We demonstrate the use of GiA Roots on a set of 2393 images of rice roots representing 12 genotypes from the species Oryza sativa. We validate trait measurements against prior analyses of this image set that demonstrated that RSA traits are likely heritable and associated with genotypic differences. Moreover, we demonstrate that GiA Roots is extensible and an end-user can add functionality so that GiA Roots can estimate novel RSA traits. In summary, we show that the software can function as an efficient tool as part of a workflow to move from large numbers of root images to downstream analysis

Aeolian features on Venus: Preliminary Magellan results

Magellan synthetic aperture radar data reveal numerous surface features that are attributed to aeolian, or wind processes. Wind streaks are the most common aeolian feature. They consist of radar backscatter patterns that are high, low, or mixed in relation to the surface on which they occur. A data base of more than 3400 wind streaks shows that low backscatter linear forms (long, narrow streaks) are the most common and that most streaks occur between 17°S to 30°S and 5°N to 53°N on smooth plains. Moreover, most streaks are associated with deposits from certain impact craters and some tectonically deformed terrains. We infer that both of these geological settings provide fine particulate material that can be entrained by the low-velocity winds on Venus. Turbulence and wind patterns generated by the topographic features with which many streaks are associated can account for differences in particle distributions and in the patterns of the wind streaks. Thus, some high backscatter streaks are considered to be zones that are swept free of sedimentary particles to expose rough bedrock; other high backscatter streaks may be lag deposits of dense materials from which low-density grains have been removed (dense materials such as ilmenite or pyrite have dielectric properties that would produce high backscatter patterns). Wind streaks generally occur on slopes < 2° and tend to be oriented toward the equator, consistent with the Hadley model of atmospheric circulation. In addition to wind streaks, other aeolian features on Venus include yardangs(?) and dune fields. The Aglaonice dune field, centered at 25°S, 340°E, covers ∼1290 km^2 and is located in an ejecta flow channel from the Aglaonice impact crater. The Meshkenet dune field, located at 67°N, 90°E, covers ∼17,120 km^2 in a valley between Ishtar Terra and Meshkenet Tessera. Wind streaks associated with both dune fields suggest that the dunes are of transverse forms in which the dune crests are perpendicular to the prevailing winds. Dunes on Venus signal the presence of sand-size (∼60 to 2,000 μm) grains. The possible yardangs are found at 9°N, 60.5°E, about 300 km southeast of the crater Mead. Although most aeolian features are concentrated in smooth plains near the equator, the occurrence of wind streaks is widespread, and some have been found at all latitudes and elevations. They demonstrate that aeolian processes operate widely on Venus. The intensity of wind erosion and deposits, however, varies with locality and is dependent on the wind regime and supply of particles

Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation

Mutations or duplications in MECP2 cause Rett and Rett-like syndromes, neurodevelopmental disorders characterized by mental retardation, motor dysfunction, and autistic behaviors. MeCP2 is expressed in many mammalian tissues and functions as a global repressor of transcription; however, the molecular mechanisms by which MeCP2 dysfunction leads to the neural-specific phenotypes of RTT remain poorly understood. Here, we show that neuronal activity and subsequent calcium influx trigger the de novo phosphorylation of MeCP2 at serine 421 (S421) by a CaMKII-dependent mechanism. MeCP2 S421 phosphorylation is induced selectively in the brain in response to physiological stimuli. Significantly, we find that S421 phosphorylation controls the ability of MeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity-dependent induction of Bdnf transcription. These findings suggest that, by triggering MeCP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates nervous system maturation and that disruption of this process in individuals with mutations in MeCP2 may underlie the neural-specific pathology of RTT

Measures of Autozygosity in Decline: Globalization, Urbanization, and Its Implications for Medical Genetics

This research investigates the influence of demographic factors on human genetic sub-structure. In our discovery cohort, we show significant demographic trends for decreasing autozygosity associated with population variation in chronological age. Autozygosity, the genomic signature of consanguinity, is identifiable on a genome-wide level as extended tracts of homozygosity. We identified an average of 28.6 tracts of extended homozygosity greater than 1 Mb in length in a representative population of 809 unrelated North Americans of European descent ranging in chronological age from 19–99 years old. These homozygous tracts made up a population average of 42 Mb of the genome corresponding to 1.6% of the entire genome, with each homozygous tract an average of 1.5 Mb in length. Runs of homozygosity are steadily decreasing in size and frequency as time progresses (linear regression, p<0.05). We also calculated inbreeding coefficients and showed a significant trend for population-wide increasing heterozygosity outside of linkage disequilibrium. We successfully replicated these associations in a demographically similar cohort comprised of a subgroup of 477 Baltimore Longitudinal Study of Aging participants. We also constructed statistical models showing predicted declining rates of autozygosity spanning the 20th century. These predictive models suggest a 14.0% decrease in the frequency of these runs of homozygosity and a 24.3% decrease in the percent of the genome in runs of homozygosity, as well as a 30.5% decrease in excess homozygosity based on the linkage pruned inbreeding coefficients. The trend for decreasing autozygosity due to panmixia and larger effective population sizes will likely affect the frequency of rare recessive genetic diseases in the future. Autozygosity has declined, and it seems it will continue doing so