First Passage and Cooperativity of Queuing Kinetics

We model the kinetics of ligand-receptor systems, where multiple ligands may bind and unbind to the receptor, either randomly or in a specific order. Equilibrium occupation and first occurrence of complete filling of the receptor are determined and compared. At equilibrium, receptors that bind ligands sequentially are more likely to be saturated than those that bind in random order. Surprisingly however, for low cooperativity, the random process first reaches full occupancy faster than the sequential one. This is true {\it except} near a critical binding energy where a 'kinetic trap' arises and the random process dramatically slows down when the number of binding sites $N\geq 8$. These results demonstrate the subtle interplay between cooperativity and sequentiality for a wide class of kinetic phenomena, including chemical binding, nucleation, and assembly line strategies.Comment: 5pp, 5 figure

Macroporous Composite Cryogels with Embedded Polystyrene Divinylbenzene Microparticles for the Adsorption of Toxic Metabolites from Blood

Composite monolithic adsorbents were prepared by the incorporation of neutral polystyrene divinylbenzene (PS-DVB) microparticles into macroporous polymer structures produced by cryogelation of agarose or poly(vinyl alcohol). The composite materials exhibited excellent flow-through properties. Scanning electron microscopy of the composite cryogels revealed that the microparticles were covered by thin films of poly(vinyl alcohol) or agarose and thus were withheld in the monolith structure. Plain PS-DVB microparticles showed efficient adsorption of albumin-bound toxins related to liver failure (bilirubin and cholic acid) and of cytokines (tumor necrosis factor-alpha and interleukin-6). The rates of adsorption and the amount of adsorbed factors were lower for the embedded microparticles as compared to the parent PS-DVB microparticles, indicating the importance of the accessibility of the adsorbent pores. Still, the macroporous composite materials showed efficient adsorption of albuminbound toxins related to liver failure as well as efficient binding of cytokines, combined with good blood compatibility. Thus, the incorporation of microparticles into macroporous polymer structures may provide an option for the development of adsorption modules for extracorporeal blood purification

A Comparative Photophysical Study of Structural Modifications of Thioflavin T-Inspired Fluorophores.

The benzothiazolium salt, Thioflavin T (ThT), has been widely adopted as the "gold-standard" fluorescent reporter of amyloid in vitro. Its properties as a molecular rotor result in a large-scale (∼1000-fold) fluorescence turn-on upon binding to β-sheets in amyloidogenic proteins. However, the complex photophysics of ThT combined with the intricate and varied nature of the amyloid binding motif means these interactions are poorly understood. To study this important class of fluorophores, we present a detailed photophysical characterization and comparison of a novel library of 12 ThT-inspired fluorescent probes for amyloid protein (PAPs), where both the charge and donor capacity of the heterocyclic and aminobenzene components have been interrogated, respectively. This enables direct photophysical juxtaposition of two structural groups: the neutral "PAP" (class 1) and the charged "mPAP" fluorophores (class 2). We quantify binding and optical properties at both the bulk and single-aggregate levels with some derivatives showing higher aggregate affinity and brightness than ThT. Finally, we demonstrate their abilities to perform super-resolution imaging of α-synuclein fibrils with localization precisions of ∼16 nm. The properties of the derivatives provide new insights into the relationship between chemical structure and function of benzothiazole probes.EPSRC Follow on Fund, EPSRC DTC, Royal Society UR

Invasive cutaneous rhizopus infections in an immunocompromised patient population associated with hospital laundry carts

Mucormycosis is an invasive fungal infection with high morbidity and mortality that most commonly occurs in immunocompromised hosts.1–5 Cutaneous mucormycosis is rare and can be acquired through direct contact of the fungi with non-intact skin or mucous membranes.3,4,7–9 Outbreaks of mucormycosis associated with contaminated adhesive bandages, ostomy supplies, wooden tongue depressors, and linen have been published.1,6–9 This is a report of a cluster of cutaneous mucormycosis with Rhizopus that occurred in 4 immunocompromised inpatients housed primarily in the same intensive care unit (ICU) prior to infection

Environmental risk factors associated with biliary atresia in Rio Grande do sul, Brazil

Biliary atresia (BA) seems to be a multifactorial disorder in which environmental factors interact with the patient’s genetic constitution. This study aimed to analyze information concerning environmental risk factors associated with BA in southern Brazil. A case-control study with mothers of patients with BA and mothers of patients with cystic fibrosis (CF) was conducted. Inquiry included questions related to exposition to environmental risk factors during the periconceptional and gestational (second and third trimesters) periods. Mothers of BA patients had smoked during pregnancy more frequently in comparison with the mothers of CF patients, but no significant difference was found in a multivariate analysis. There was no between group difference in terms of seasonality, but the multivariate analysis showed a significant difference within the BA group between date of conception in winter compared to other seasons. In conclusion, smoking during pregnancy seemed to increase the risk of BA while date of conception in winter decreased it.info:eu-repo/semantics/publishedVersio

Environmental risk factors associated with biliary atresia in Rio Grande do Sul, Brazil

Biliary atresia (BA) seems to be a multifactorial disorder in which environmental factors interact with the patient’s genetic constitution. This study aimed to analyze information concerning environmental risk factors associated with BA in southern Brazil. A case-control study with mothers of patients with BA and mothers of patients with cystic fibrosis (CF) was conducted. Inquiry included questions related to exposition to environmental risk factors during the periconceptional and gestational (second and third trimesters) periods. Mothers of BA patients had smoked during pregnancy more frequently in comparison with the mothers of CF patients, but no significant difference was found in a multivariate analysis. There was no between group difference in terms of seasonality, but the multivariate analysis showed a significant difference within the BA group between date of conception in winter compared to other seasons. In conclusion, smoking during pregnancy seemed to increase the risk of BA while date of conception in winter decreased it.Keywords: Biliary atresia; environmental risk factor; etiology; seasonality; smokin

In vitro validation and characterization of pulsed inhaled nitric oxide administration during early inspiration

Purpose: Admixture of nitric oxide (NO) to the gas inspired with mechanical ventilation can be achieved through continuous, timed, or pulsed injection of NO into the inspiratory limb. The dose and timing of NO injection govern the inspired and intrapulmonary effect site concentrations achieved with different administration modes. Here we test the effectiveness and target reliability of a new mode injecting pulsed NO boluses exclusively during early inspiration. Methods: An in vitro lung model was operated under various ventilator settings. Admixture of NO through injection into the inspiratory limb was timed either (i) selectively during early inspiration ("pulsed delivery"), or as customary, (ii) during inspiratory time or (iii) the entire respiratory cycle. Set NO target concentrations of 5-40 parts per million (ppm) were tested for agreement with the yield NO concentrations measured at various sites in the inspiratory limb, to assess the effectiveness of these NO administration modes. Results: Pulsed delivery produced inspiratory NO concentrations comparable with those of customary modes of NO administration. At low (450 ml) and ultra-low (230 ml) tidal volumes, pulsed delivery yielded better agreement of the set target (up to 40 ppm) and inspiratory NO concentrations as compared to customary modes. Pulsed delivery with NO injection close to the artificial lung yielded higher intrapulmonary NO concentrations than with NO injection close to the ventilator. The maximum inspiratory NO concentration observed in the trachea (68 +/- 30 ppm) occurred with pulsed delivery at a set target of 40 ppm. Conclusion: Pulsed early inspiratory phase NO injection is as effective as continuous or non-selective admixture of NO to inspired gas and may confer improved target reliability, especially at low, lung protective tidal volumes

Protein crystals in adenovirus type 5-infected cells: requirements for intranuclear crystallogenesis, structural and functional analysis

Intranuclear crystalline inclusions have been observed in the nucleus of epithelial cells infected with Adenovirus serotype 5 (Ad5) at late steps of the virus life cycle. Using immuno-electron microscopy and confocal microscopy of cells infected with various Ad5 recombinants modified in their penton base or fiber domains, we found that these inclusions represented crystals of penton capsomers, the heteromeric capsid protein formed of penton base and fiber subunits. The occurrence of protein crystals within the nucleus of infected cells required the integrity of the fiber knob and part of the shaft domain. In the knob domain, the region overlapping residues 489–492 in the FG loop was found to be essential for crystal formation. In the shaft, a large deletion of repeats 4 to 16 had no detrimental effect on crystal inclusions, whereas deletion of repeats 8 to 21 abolished crystal formation without altering the level of fiber protein expression. This suggested a crucial role of the five penultimate repeats in the crystallisation process. Chimeric pentons made of Ad5 penton base and fiber domains from different serotypes were analyzed with respect to crystal formation. No crystal was found when fiber consisted of shaft (S) from Ad5 and knob (K) from Ad3 (heterotypic S5-K3 fiber), but occurred with homotypic S3K3 fiber. However, less regular crystals were observed with homotypic S35-K35 fiber. TB5, a monoclonal antibody directed against the Ad5 fiber knob was found by immunofluorescence microscopy to react with high efficiency with the intranuclear protein crystals in situ. Data obtained with Ad fiber mutants indicated that the absence of crystalline inclusions correlated with a lower infectivity and/or lower yields of virus progeny, suggesting that the protein crystals might be involved in virion assembly. Thus, we propose that TB5 staining of Ad-infected 293 cells can be used as a prognostic assay for the viability and productivity of fiber-modified Ad5 vectors

How puzzles are shaping our understanding of biodiversity: A call for more research into biodiversity representation in educational games

Games as a didactic tool (e. g., puzzles) are gaining recognition in environmental education to promote skill development, but also to develop a specific understanding of the natural world. However, a children’s puzzle containing representations of nature may unwillingly lead to “misconceptions” of biodiversity themes and processes, and an over-simplification of the relationship between people and nature. To solve this problem, positive connotations of biodiversity may prompt a conceptual change to a more nuanced, multifaceted conception of biodiversity

Novel framework to improve water management adaptation under climate change scenarios

The impacts of projected climate change on freshwater resources are increasingly promoting the adoption of different approaches to water management, due to the likely occurrence of reduced water supplies and early-stage drought conditions in many river basins across Southern Europe. The traditional strategy to cope with water scarcity has largely relied on hard-path measures aimed at expanding the existing supply capacity by great investments in centralized, large-scale infrastructures such as dams and distribution systems. This approach is, however, becoming more and more unsustainable, giving way to effective soft-path solutions based on improved predictive capacities, optimal decision making and drought risk management. Given the need to ensure a more sustainable and efficient water management under current and projected scenarios, the study presents a novel decision-analytic framework to assist decision-makers in designing and assessing alternative soft-path measures in order to increase the adaptation of the system to a changing climate. The framework is being developed within the SO-WATCH project and it will be demonstrated on the Lake Como river basin (Italy) by implementing a four-stage procedure as follows: i) calibration and validation of a physical model comprising three sub-models simulating, respectively, the upstream catchment processes (TOPKAPI-ETH), the lake dynamics and water releases (DISTRILAKE) and the water balance in the irrigation system downstream the lake (IDRAGRA), ii) coupling of the hydrological model with a multi-agent systems model developed to reproduce human decisions and their effects on the system dynamics (e.g. dam operations and farmers practices), iii) definition and impact assessment of hydro-climatic and socio-technoeconomic scenarios supported by the calculation of drought indicators and iv) design and evaluation of soft-path measures to improve the efficiency of the water system. Preliminary results based on different climate change projections for the time period 2096-2100 (ensemble of different Global Climate Models, Regional Climate Models and Radiative Concentration Pathways as of the IPCC Fifth Assessment Report) reveal a general reduction of the lake inflows in spring and summer, with an increasing frequency of drought conditions under the business-as-usual scenario. In order to design the most effective soft-path measures, a newly developed index, the Transpiration Deficit Index (D-TDI), will be applied along with other commonly used indexes. D-TDI takes into account the transpiration deficit (i.e. difference between potential and actual transpiration) computed by the IDRAGRA model on a daily basis and cumulated over a selected time span and allows an effective identification of drought prone areas