Growth Cone Pathfinding: a competition between deterministic and stochastic events

BACKGROUND: Growth cone migratory patterns show evidence of both deterministic and stochastic search modes. RESULTS: We quantitatively examine how these two different migration modes affect the growth cone's pathfinding response, by simulating growth cone contact with a repulsive cue and measuring the resultant turn angle. We develop a dimensionless number, we call the determinism ratio Ψ, to define the ratio of deterministic to stochastic influences driving the growth cone's migration in response to an external guidance cue. We find that the growth cone can exhibit three distinct types of turning behaviors depending on the magnitude of Ψ. CONCLUSIONS: We conclude, within the context of these in silico studies, that only when deterministic and stochastic migration factors are in balance (i.e. Ψ ~ 1) can the growth cone respond constructively to guidance cues

Truth\u27s veil: language and meaning in Merleau-Ponty and Derrida

The linguistic structuralism of Ferdinand de Saussure (1857-1913) attracted the attention of Maurice Merleau-Ponty, prompting what is thought to be Merleau-Ponty’s “linguistic turn” of 1947. Saussure’s theory of the self-referential structure of linguistic signs as constitutive of value, was tied by Merleau-Ponty to his conception of the structure of intercommunication as constitutive of human value and meaning. Jacques Derrida, in the 1960s, also appealed to Saussure’s theory in formulating his thesis of a deferring and differing relationship between linguistic signs as constitutive of meaning, but rejected what he saw as the privileging of a metaphysics of presence-to-meaning in Saussure. One set of questions raised here concerns the relationship between thought and perception and calls for a reevaluation of Merleau-Ponty’s thesis of the primacy of perception in light of his final, posthumously published work. The possibility of a full philosophical dialectic between Merleau-Ponty and Derrida was rendered impossible by Merleau-Ponty’s sudden death. In the interest of such a dialogue, this study addresses the similarities and dissimilarities in their positions regarding language and meaning within a central theme of: truth. An area of concern is how their views come to bear upon the ongoing debate between subjectivist and objectivist theories of meaning. Can we arrive at an authentic understanding and expression of truth and meaning? Getting there entails an iv understanding of the formal structure of language and its role in the genesis of linguistic meaning. This study treats the subject of the origins of language and meaning in terms of a phenomenological approach which places all origin squarely in the lived-world of experience. If we agree that our very being is constituted by and in an immersion and interaction in the world, this will suggest that meaning is posited by consciousness in a process of repetition in which thought serves to confirm an initial pre-reflective perception. Merleau-Ponty’s interwoven flesh of the world and Derrida’s interwoven textuality are proposed as alternatives to tradition\u27s reliance upon external referents in intellectualism and internal intuitions of empiricism for validation of what we name “truth”

Serial pathways from primate prefrontal cortex to autonomic areas may influence emotional expression

BACKGROUND: Experiencing emotions engages high-order orbitofrontal and medial prefrontal areas, and expressing emotions involves low-level autonomic structures and peripheral organs. How is information from the cortex transmitted to the periphery? We used two parallel approaches to map simultaneously multiple pathways to determine if hypothalamic autonomic centres are a key link for orbitofrontal areas and medial prefrontal areas, which have been associated with emotional processes, as well as low-level spinal and brainstem autonomic structures. The latter innervate peripheral autonomic organs, whose activity is markedly increased during emotional arousal. RESULTS: We first determined if pathways linking the orbitofrontal cortex with the hypothalamus overlapped with projection neurons directed to the intermediolateral column of the spinal cord, with the aid of neural tracers injected in these disparate structures. We found that axons from orbitofrontal and medial prefrontal cortices converged in the hypothalamus with neurons projecting to brainstem and spinal autonomic centers, linking the highest with the lowest levels of the neuraxis. Using a parallel approach, we injected bidirectional tracers in the lateral hypothalamic area, an autonomic center, to label simultaneously cortical pathways leading to the hypothalamus, as well as hypothalamic axons projecting to low-level brainstem and spinal autonomic centers. We found densely distributed projection neurons in medial prefrontal and orbitofrontal cortices leading to the hypothalamus, as well as hypothalamic axonal terminations in several brainstem structures and the intermediolateral column of the spinal cord, which innervate peripheral autonomic organs. We then provided direct evidence that axons from medial prefrontal cortex synapse with hypothalamic neurons, terminating as large boutons, comparable in size to the highly efficient thalamocortical system. The interlinked orbitofrontal, medial prefrontal areas and hypothalamic autonomic centers were also connected with the amygdala. CONCLUSIONS: Descending pathways from orbitofrontal and medial prefrontal cortices, which are also linked with the amygdala, provide the means for speedy influence of the prefrontal cortex on the autonomic system, in processes underlying appreciation and expression of emotions

Many-electron expansion: A density functional hierarchy for strongly correlated systems

Density functional theory (DFT) is the de facto method for the electronic structure of weakly correlated systems. But for strongly correlated materials, common density functional approximations break down. Here, we derive a many-electron expansion (MEE) in DFT that accounts for successive one-, two-, three-, ... particle interactions within the system. To compute the correction terms, the density is first decomposed into a sum of localized, nodeless one-electron densities (ρ_{i}). These one-electron densities are used to construct relevant two- (ρ_{i}+ρ_{j}), three- (ρ_{i}+ρ_{j}+ρ_{k}), ... electron densities. Numerically exact results for these few-particle densities can then be used to correct an approximate density functional via any of several many-body expansions. We show that the resulting hierarchy gives accurate results for several important model systems: the Hubbard and Peierls-Hubbard models in 1D and the pure Hubbard model in 2D. We further show that the method is numerically convergent for strongly correlated systems: applying successively higher order corrections leads to systematic improvement of the results. MEE thus provides a hierarchy of density functional approximations that applies to both weakly and strongly correlated systems.National Science Foundation (U.S.) (NSF (CHE-1464804))David & Lucile Packard Foundation (grant

Cross-cultural and intercultural pragmatics

Sociopragmatics is a rapidly growing field and this is the first ever handbook dedicated to this exciting area of study. Bringing together an international team of leading editors and contributors, it provides a comprehensive, cutting-edge overview of the key concepts, topics, settings and methodologies involved in sociopragmatic research. The chapters are organised in a systematic fashion, and span a wide range of theoretical research on how language communicates multiple meanings in context, how it influences our daily interactions and relationships with others, and how it helps construct our social worlds. Providing insight into a fascinating array of phenomena and novel research directions, the Handbook is not only relevant to experts of pragmatics but to any reader with an interest in language and its use in different contexts, including researchers in sociology, anthropology and communication, and students of applied linguistics and related areas, as well as professional practitioners in communication research

Effects of HIF-1α and HIF2α on Growth and Metabolism of Clear-Cell Renal Cell Carcinoma 786-0 Xenografts

In cultured clear-cell renal carcinoma (CCRCC) 786-0 cells transfected with HIF1α (HIF-1+), HIF-2α (HIF-2+), or empty vector (EV), no significant differences were observed in the growth rates in vitro, but when grown in vivo as xenografts HIF-2α significantly increased, and HIF-1α significantly decreased growth rates, compared to EV tumors. Factors associated with proliferation were increased and factors associated with cell death were decreased in HIF-2+ tumors. Metabolite profiles showed higher glucose and lower lactate and alanine levels in the HIF-2+ tumors whilst immunostaining demonstrated higher pyruvate dehydrogenase and lower pyruvate dehydrogenase kinase 1, compared to control tumors. Taken together, these results suggest that overexpression of HIF-2α in CCRCC 786-0 tumors regulated growth both by maintaining a low level of glycolysis and by allowing more mitochondrial metabolism and tolerance to ROS induced DNA damage. The growth profiles observed may be mediated by adaptive changes to a more oxidative phenotype

Effects of Allergen Sensitization on Response to Therapy in Children with Eosinophilic Esophagitis

Background: In children with eosinophilic esophagitis (EoE) foods are the most common disease triggers, but environmental allergens are also suspected culprits. Objective: To determine the effects of environmental allergen sensitization on response to treatment in children with EoE in the southeastern United States. Methods: Patients 2 to 18 years old who were referred to the Arkansas Children’s Hospital Eosinophilic Gastrointestinal Disorders Clinic from January 2012 to January 2016 were enrolled in a prospective, longitudinal cohort study with collection of demographics, clinical symptoms, medical history, allergy sensitization profiles, and response to treatment over time. Comparisons were made between complete responders (peak esophageal eosinophil count \u3c 15 per high-power field [HPF]) and nonresponders (\u3e 25 eosinophils per HPF) after treatment with diet elimination alone, swallowed corticosteroids alone, or diet elimination and swallowed corticosteroids. Sensitization patterns to environmental allergens found in the southeastern United States were analyzed for the effect on treatment response. Results: A total of 223 individuals were enrolled. Of these, 182 had environmental allergy profiling and at least one endoscopy while receiving proton pump inhibitor (PPI) therapy. Twenty-nine individuals had PPI-responsive EoE and were excluded from further analysis, leaving 123 individuals with none-PPI-responsive EoE who were further analyzed; 72 (58.5%) were complete responders and 33 (26.8%) were nonresponders. Seventeen individuals (13.8%) were partial responders (≥ 1 but ≤ 25 eosinophils per HPF) and excluded from further analysis. Nonresponders were more likely to be sensitized to perennial allergens (P = .02). There was no significant difference in response based on seasonal allergen sensitization. Individuals with mold or cockroach sensitization were more likely to fail combination diet and swallowed corticosteroid treatment (P = .02 and P = .002). Conclusion: Perennial allergen and mold sensitization may lead to nonresponse to EoE treatment in some patients. Additional studies are needed to further understand the effect of environmental allergens on EoE

Evolutionary consequences of feedbacks between within-host competition and disease control

Lay Summary: Competition often occurs among diverse parasites within a single host, but control efforts could change its strength. We examined how the interplay between competition and control could shape the evolution of parasite traits like drug resistance and disease severity

The Ever-Increasing Array of Novel Inborn Errors of Immunity : an Interim Update by the IUIS Committee

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.Peer reviewe