Anomalous relaxation kinetics of biological lattice-ligand binding models

We discuss theoretical models for the cooperative binding dynamics of ligands to substrates, such as dimeric motor proteins to microtubules or more extended macromolecules like tropomyosin to actin filaments. We study the effects of steric constraints, size of ligands, binding rates and interaction between neighboring proteins on the binding dynamics and binding stoichiometry. Starting from an empty lattice the binding dynamics goes, quite generally, through several stages. The first stage represents fast initial binding closely resembling the physics of random sequential adsorption processes. Typically this initial process leaves the system in a metastable locked state with many small gaps between blocks of bound molecules. In a second stage the gaps annihilate slowly as the ligands detach and reattach. This results in an algebraic decay of the gap concentration and interesting scaling behavior. Upon identifying the gaps with particles we show that the dynamics in this regime can be explained by mapping it onto various reaction-diffusion models. The final approach to equilibrium shows some interesting dynamic scaling properties. We also discuss the effect of cooperativity on the equilibrium stoichiometry, and their consequences for the interpretation of biochemical and image reconstruction results.Comment: REVTeX, 20 pages, 17 figures; review, to appear in Chemical Physics; v2: minor correction

Observations of Radiation Belt Losses Due to Cyclotron Wave-Particle Interactions

Electron loss to the atmosphere plays a critical role in driving dynamics of the Earths Van Allen radiation belts and slot region. This is a review of atmospheric loss of radiation belt electrons caused by plasma wave scattering via Doppler-shifted cyclotron resonance. In particular, the focus is on observational signatures of electron loss, which include direct measurements of precipitating electrons, measured properties of waves that drive precipitation, and variations in the trapped population resulting from loss. We discuss wave and precipitation measurements from recent missions, including simultaneous multi-payload observations, which have provided new insight into the dynamic nature of the radiation belts

Firms cash management, adjustment cost and its impact on firms’ speed of adjustment-A cross country analysis

We investigate the firms’ specific attributes that determine the difference in speed of adjustment (SOA) towards the cash holdings target in the Scandinavian countries: Denmark, Norway and Sweden. We examine whether Scandinavian firms maintain an optimal level of cash holdings and determine if the active cash holdings management is associated with the firms’ higher SOA and lower adjustment costs. Our findings substantiate that a higher level of off-target cost induces professional managers to rebalance their cash level towards the optimal balance of cash holdings. Our results reveal that Scandinavian firms accelerate SOA towards cash targets primarily for the precautionary motive. Moreover, our results show that SOA is heterogeneous across Scandinavian firms based on adjustment cost and deviate cash holdings towards the target mainly with the support of internal financing. Furthermore, our empirical findings show that the SOA of Norwegian firms is significantly higher than the Danish and Swedish firms

Strain-Specific Differences in the Genetic Control of Two Closely Related Mycobacteria

The host response to mycobacterial infection depends on host and pathogen genetic factors. Recent studies in human populations suggest a strain specific genetic control of tuberculosis. To test for mycobacterial-strain specific genetic control of susceptibility to infection under highly controlled experimental conditions, we performed a comparative genetic analysis using the A/J- and C57BL/6J-derived recombinant congenic (RC) mouse panel infected with the Russia and Pasteur strains of Mycobacterium bovis Bacille Calmette Guérin (BCG). Bacillary counts in the lung and spleen at weeks 1 and 6 post infection were used as a measure of susceptibility. By performing genome-wide linkage analyses of loci that impact on tissue-specific bacillary burden, we were able to show the importance of correcting for strain background effects in the RC panel. When linkage analysis was adjusted on strain background, we detected a single locus on chromosome 11 that impacted on pulmonary counts of BCG Russia but not Pasteur. The same locus also controlled the splenic counts of BCG Russia but not Pasteur. By contrast, a locus on chromosome 1 which was indistinguishable from Nramp1 impacted on splenic bacillary counts of both BCG Russia and Pasteur. Additionally, dependent upon BCG strain, tissue and time post infection, we detected 9 distinct loci associated with bacillary counts. Hence, the ensemble of genetic loci impacting on BCG infection revealed a highly dynamic picture of genetic control that reflected both the course of infection and the infecting strain. This high degree of adaptation of host genetics to strain-specific pathogenesis is expected to provide a suitable framework for the selection of specific host-mycobacteria combinations during co-evolution of mycobacteria with humans

Recruitment Variability in North Atlantic Cod and Match-Mismatch Dynamics

Background Fisheries exploitation, habitat destruction, and climate are important drivers of variability in recruitment success. Understanding variability in recruitment can reveal mechanisms behind widespread decline in the abundance of key species in marine and terrestrial ecosystems. For fish populations, the match-mismatch theory hypothesizes that successful recruitment is a function of the timing and duration of larval fish abundance and prey availability. However, the underlying mechanisms of match-mismatch dynamics and the factors driving spatial differences between high and low recruitment remain poorly understood. Methodology/Principal Findings We used empirical observations of larval fish abundance, a mechanistic individual-based model, and a reanalysis of ocean temperature data from 1960 to 2002 to estimate the survival of larval cod (Gadus morhua). From the model, we quantified how survival rates changed during the warmest and coldest years at four important cod spawning sites in the North Atlantic. The modeled difference in survival probability was not large for any given month between cold or warm years. However, the cumulative effect of higher growth rates and survival through the entire spawning season in warm years was substantial with 308%, 385%, 154%, and 175% increases in survival for Georges Bank, Iceland, North Sea, and Lofoten cod stocks, respectively. We also found that the importance of match-mismatch dynamics generally increased with latitude. Conclusions/Significance Our analyses indicate that a key factor for enhancing survival is the duration of the overlap between larval and prey abundance and not the actual timing of the peak abundance. During warm years, the duration of the overlap between larval fish and their prey is prolonged due to an early onset of the spring bloom. This prolonged season enhances cumulative growth and survival, leading to a greater number of large individuals with enhanced potential for survival to recruitment

The Interaction between Early Life Epilepsy and Autistic-Like Behavioral Consequences: A Role for the Mammalian Target of Rapamycin (mTOR) Pathway

Early life seizures can result in chronic epilepsy, cognitive deficits and behavioral changes such as autism, and conversely epilepsy is common in autistic children. We hypothesized that during early brain development, seizures could alter regulators of synaptic development and underlie the interaction between epilepsy and autism. The mammalian Target of Rapamycin (mTOR) modulates protein translation and is dysregulated in Tuberous Sclerosis Complex, a disorder characterized by epilepsy and autism. We used a rodent model of acute hypoxia-induced neonatal seizures that results in long term increases in neuronal excitability, seizure susceptibility, and spontaneous seizures, to determine how seizures alter mTOR Complex 1 (mTORC1) signaling. We hypothesized that seizures occurring at a developmental stage coinciding with a critical period of synaptogenesis will activate mTORC1, contributing to epileptic networks and autistic-like behavior in later life. Here we show that in the rat, baseline mTORC1 activation peaks during the first three postnatal weeks, and induction of seizures at postnatal day 10 results in further transient activation of its downstream targets phospho-4E-BP1 (Thr37/46), phospho-p70S6K (Thr389) and phospho-S6 (Ser235/236), as well as rapid induction of activity-dependent upstream signaling molecules, including BDNF, phospho-Akt (Thr308) and phospho-ERK (Thr202/Tyr204). Furthermore, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed early increases in glutamatergic neurotransmission and seizure susceptibility and attenuated later life epilepsy and autistic-like behavior. Together, these findings suggest that in the developing brain the mTORC1 signaling pathway is involved in epileptogenesis and altered social behavior, and that it may be a target for development of novel therapies that eliminate the progressive effects of neonatal seizures

Phagocytosis is the main CR3-mediated function affected by the lupus-associated variant of CD11b in human myeloid cells.

The CD11b/CD18 integrin (complement receptor 3, CR3) is a surface receptor on monocytes, neutrophils, macrophages and dendritic cells that plays a crucial role in several immunological processes including leukocyte extravasation and phagocytosis. The minor allele of a non-synonymous CR3 polymorphism (rs1143679, conversation of arginine to histidine at position 77: R77H) represents one of the strongest genetic risk factor in human systemic lupus erythematosus, with heterozygosity (77R/H) being the most common disease associated genotype. Homozygosity for the 77H allele has been reported to reduce adhesion and phagocytosis in human monocytes and monocyte-derived macrophages, respectively, without affecting surface expression of CD11b. Herein we comprehensively assessed the influence of R77H on different CR3-mediated activities in monocytes, neutrophils, macrophages and dendritic cells. R77H did not alter surface expression of CD11b including its active form in any of these cell types. Using two different iC3b-coated targets we found that the uptake by heterozygous 77R/H macrophages, monocytes and neutrophils was significantly reduced compared to 77R/R cells. Allele-specific transduced immortalized macrophage cell lines demonstrated that the minor allele, 77H, was responsible for the impaired phagocytosis. R77H did not affect neutrophil adhesion, neutrophil transmigration in vivo or Toll-like receptor 7/8-mediated cytokine release by monocytes or dendritic cells with or without CR3 pre-engagement by iC3b-coated targets. Our findings demonstrate that the reduction in CR3-mediated phagocytosis associated with the 77H CD11b variant is not macrophage-restricted but demonstrable in other CR3-expressing professional phagocytic cells. The association between 77H and susceptibility to systemic lupus erythematosus most likely relates to impaired waste disposal, a key component of lupus pathogenesis

Wellbeing indicators affecting female entrepreneurship in OECD countries

[EN] The objective of this research is to know which wellbeing indicators, such as work-life balance, educational level, income or job security, are related to the rate of female entrepreneurship in 29 OECD countries. In addition, these countries have been classified according to the motivation of the entrepreneur either by necessity or by opportunity. The empiric study is focused on 29 OECD countries covering the different geographic areas (Western Europe, Central and Eastern Europe, Middle East, etc.) Due to the fact that the sample is relatively small, it is essential to use a selective approach when selecting the causal conditions. To this end, fsQCA is the most appropriate methodology for such a small data set. A total of 5 variables have been used: an independent variable (female TEA ratio), and four dependent variables (work life balance, educational level, sustainable household income and job security). Data measuring female TEA ratio have been obtained from Global Entrepreneur Monitor (GEM in Global report, 2015) data base, while data measuring wellbeing dimensions were taken from the Better Life Index (OECD in How¿s life? Measuring wellbeing, 2015. http://www.oecdbetterlifeindex.org). The results of this piece of research show that countries with high sustainable household income together with high level of education achieves high female entrepreneurship ratio with both, a good work-life balance (despite of a high unemployment probability), or a high labour-personal imbalance (in this latter, with a low probability of unemployment).This work has been funded by the R + D project for emerging research groups with reference (GVA) GV/2016/078.Ribes-Giner, G.; Moya Clemente, I.; Cervelló Royo, RE.; Perelló Marín, MR. (2019). Wellbeing indicators affecting female entrepreneurship in OECD countries. 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Metal hydrides for concentrating solar thermal power energy storage

The development of alternative methods for thermal energy storage is important for improving the efficiency and decreasing the cost for Concentrating Solar-thermal Power (CSP). We focus on the underlying technology that allows metal hydrides to function as Thermal Energy Storage (TES) systems and highlight the current state-of-the-art materials that can operate at temperatures as low as room-temperature and as high as 1100 oC. The potential of metal hydrides for thermal storage is explored while current knowledge gaps about hydride properties, such as hydride thermodynamics, intrinsic kinetics and cyclic stability, are identified. The engineering challenges associated with utilising metal hydrides for high-temperature thermal energy storage are also addressed

Epicardial cells derived from human embryonic stem cells augment cardiomyocyte-driven heart regeneration.

The epicardium and its derivatives provide trophic and structural support for the developing and adult heart. Here we tested the ability of human embryonic stem cell (hESC)-derived epicardium to augment the structure and function of engineered heart tissue in vitro and to improve efficacy of hESC-cardiomyocyte grafts in infarcted athymic rat hearts. Epicardial cells markedly enhanced the contractility, myofibril structure and calcium handling of human engineered heart tissues, while reducing passive stiffness compared with mesenchymal stromal cells. Transplanted epicardial cells formed persistent fibroblast grafts in infarcted hearts. Cotransplantation of hESC-derived epicardial cells and cardiomyocytes doubled graft cardiomyocyte proliferation rates in vivo, resulting in 2.6-fold greater cardiac graft size and simultaneously augmenting graft and host vascularization. Notably, cotransplantation improved systolic function compared with hearts receiving either cardiomyocytes alone, epicardial cells alone or vehicle. The ability of epicardial cells to enhance cardiac graft size and function makes them a promising adjuvant therapeutic for cardiac repair.: This work was supported by the British Heart Foundation (BHF; Grants NH/11/1/28922, G1000847, FS/13/29/30024 and FS/18/46/33663), Oxford-Cambridge Centre for Regenerative Medicine (RM/13/3/30159), the UK Medical Research Council (MRC) and the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre funding (SS), as well as National Institutes of Health Grants P01HL094374, P01GM081619, R01HL12836 and a grant from the Fondation Leducq Transatlantic Network of Excellence (CEM). J.B. was supported by a Cambridge National Institute for Health Research Biomedical Research Centre Cardiovascular Clinical Research Fellowship and subsequently, by a BHF Studentship (Grant FS/13/65/30441). DI received a University of Cambridge Commonwealth Scholarship. LG is supported by BHF Award RM/l3/3/30159 and LPO is funded by a Wellcome Trust Fellowship (203568/Z/16/Z). NF was supported by BHF grants RG/13/14/30314. NL was supported by the Biotechnology and Biological Sciences Research Council (Institute Strategic Programmes BBS/E/B/000C0419 and BBS/E/B/000C0434). SS and MB were supported by the British Heart Foundation Centre for Cardiovascular Research Excellence. Core support was provided by the Wellcome-MRC Cambridge Stem Cell Institute (203151/Z/16/Z), The authors thank Osiris for provision of the primary mesenchymal stem cells (59