Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A

Proteins need to interconvert between many conformations in order to function, many of which are formed transiently, and sparsely populated. Particularly when the lifetimes of these states approach the millisecond timescale, identifying the relevant structures and the mechanism by which they interconvert remains a tremendous challenge. Here we introduce a novel combination of accelerated MD (aMD) simulations and Markov state modelling (MSM) to explore these ‘excited’ conformational states. Applying this to the highly dynamic protein CypA, a protein involved in immune response and associated with HIV infection, we identify five principally populated conformational states and the atomistic mechanism by which they interconvert. A rational design strategy predicted that the mutant D66A should stabilise the minor conformations and substantially alter the dynamics, whereas the similar mutant H70A should leave the landscape broadly unchanged. These predictions are confirmed using CPMG and R1ρ solution state NMR measurements. By efficiently exploring functionally relevant, but sparsely populated conformations with millisecond lifetimes in silico, our aMD/MSM method has tremendous promise for the design of dynamic protein free energy landscapes for both protein engineering and drug discovery

Microscopic Particle Image Velocimetry Analysis of Multiphase Flow in a Porous Media Micromodel

Pore-scale oil displacement behavior was investigated in a porous media micromodel using microscopic particle image velocimetry (μPIV). Porous media micromodels consisting of an ordered square array of cylindrical pillars with 50 and 70% porosities were fabricated with photolithography. The oil displacement was performed with the injection of water at flow rates of 37.5, 75, and 150 μL/h. These flow rates correspond to Reynolds number of 1.1 × 10–2, 2.2 × 10–2, and 4.4 × 10–2, respectively in the 50% porous channel, and 1.84 × 10–3, 3.69 × 10–3, and 7.38 × 10–3, respectively in the 70% porous channel. The capillary numbers for these flow rates are 2.18 × 10–5, 4.36 × 10–5, and 8.72 × 10–5, respectively in the 50% porous channel, and 1.56 × 10–5, 3.12 × 10–5, and 6.23 × 10–5, respectively in the 70% porous channel. The micromodel is initially saturated with oil, with the invading water phase following the path of least resistance as it displaces the oil. The μPIV data were used to construct probability density functions (PDFs) which show an initial, nonzero, peak in transverse velocity as the water enters the micromodel. The PDFs broaden with time, indicating that the water is spreading, before retracting to a peak velocity of 0 mm/s, indicating that the water displacement has achieved equilibrium. We developed a model based on conservation of mass to describe the efficiency of the displacement process. All flow conditions demonstrate peak displacement efficiency when the amount of oil phase displacement is ∼9 pore volumes in 50% porous channel and ∼4 pore volumes in 70% porous channel.This article is published as Miah, Md Abdul Karim, Kawkab Ahasan, Todd A. Kingston, Michael G. Olsen, and Jaime J. Juárez. "Microscopic Particle Image Velocimetry Analysis of Multiphase Flow in a Porous Media Micromodel." ACS Omega (2024). doi: https://doi.org/10.1021/acsomega.4c04680. Copyright © 2024 The Authors. This publication is licensed under CC-BY-NC-ND 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Economic analysis of alternative nutritional management of dual-purpose cow herds in central coastal Veracruz, Mexico

Market information was combined with predicted input–output relationships in an economic analysis of alternative nutritional management for dual-purpose member herds of the Genesis farmer organization of central coastal Veracruz, Mexico. Cow productivity outcomes for typical management and alternative feeding scenarios were obtained from structured sets of simulations in a companion study of productivity limitations and potentials using the Cornell Net Carbohydrate and Protein System model (Version 6.0). Partial budgeting methods and sensitivity analysis were used to identify economically viable alternatives based on expected change in milk income over feed cost (change in revenues from milk sales less change in feed costs). Herd owners in coastal Veracruz have large economic incentives, from $584 to$1,131 in predicted net margin, to increase milk sales by up to 74% across a three-lactation cow lifetime by improving diets based on good quality grass and legume forages. This increment is equal to, or exceeds, in value the total yield from at least one additional lactation per cow lifetime. Furthermore, marginal rates of return (change in milk income over feed costs divided by change in variable costs when alternative practices are used) of 3.3 ± 0.8 indicate clear economic incentives to remove fundamental productivity vulnerabilities due to chronic energy deficits and impeded growth of immature cows under typical management. Sensitivity analyses indicate that the economic outcomes are robust for a variety of market conditions

Study of the properties of thermoset materials derived from epoxidized soybean oil and protein fillers

[EN] Novel bio-based thermoset formulations were prepared by using epoxidized soybean oil (ESBO), nadic methyl anhydride as a hardener and with different types of proteins as fillers. In the first part of the study, the effect of the protein-type (wheat gluten, soy protein, casein and ovalbumin) on cured ESBO materials was investigated. Thermal and mechanical properties were characterized by flexural tests, Shore D hardness, Charpy impact tests, Vicat softening temperature and heat deflection temperature. In addition, a study of the morphology of fractured surfaces by scanning electron microscopy was carried out. In general, the addition of protein-based fillers improved the mechanical and thermal properties. It was found that the highest increase of thermal and mechanical properties was achieved by ovalbumin. In the second part of the work, the effect of the total amount of ovalbumin filler was studied. Bio-based thermoset materials from ESBO and 15 wt % ovalbumin improved flexural modulus more than 150 % when compared to the unfilled material. Similar evolution was observed for other mechanical properties. Moreover, the brittleness of this composition was the minimum from the studied systems. A direct relationship between energy absorption capacity and morphologies of the failure surface was evidenced by SEM.This work is a part of the project IPT-310000-2010-037,"ECOTEXCOMP: Research and development of textile structures useful as reinforcement of composite materials with marked ecological character" funded by the "Ministerio de Ciencia e Innovacion", with an aid of 189540.20 euros, within the "Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica 2008-2011" and funded by the European Union through FEDER funds, Technology Fund 2007-2013, "Operational Programme on R+D+I for and on behalf of the companies". Also, Generalitat Valenciana ACOMP/2012/087 is acknowledged for financial support.Fombuena Borrás, V.; Sánchez Nacher, L.; Samper Madrigal, MD.; Juárez Varón, D.; Balart Gimeno, RA. (2013). Study of the properties of thermoset materials derived from epoxidized soybean oil and protein fillers. Journal of the American Oil Chemists' Society. 90(3):449-457. https://doi.org/10.1007/s11746-012-2171-2S449457903Alonso MV, Oliet M, Garcia J, Rodriguez F, Echeverria J (2006) Gelation and isoconversional kinetic analysis of lignin-phenol-formaldehyde resol resins cure. Chem Eng J 122:159–166Altuna FI, Esposito LH, Ruseckaite RA, Stefani PM (2011) Thermal and mechanical properties of anhydride-cured epoxy resins with different contents of bio-based epoxidized soybean oil. J Appl Polym Sci 120:789–798Boquillon N, Fringant C (2000) Polymer networks derived from curing of epoxidised linseed oil: influence of different catalysts and anhydride hardeners. 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Administration of Thimerosal to Infant Rats Increases Overflow of Glutamate and Aspartate in the Prefrontal Cortex: Protective Role of Dehydroepiandrosterone Sulfate

Thimerosal, a mercury-containing vaccine preservative, is a suspected factor in the etiology of neurodevelopmental disorders. We previously showed that its administration to infant rats causes behavioral, neurochemical and neuropathological abnormalities similar to those present in autism. Here we examined, using microdialysis, the effect of thimerosal on extracellular levels of neuroactive amino acids in the rat prefrontal cortex (PFC). Thimerosal administration (4 injections, i.m., 240 μg Hg/kg on postnatal days 7, 9, 11, 15) induced lasting changes in amino acid overflow: an increase of glutamate and aspartate accompanied by a decrease of glycine and alanine; measured 10–14 weeks after the injections. Four injections of thimerosal at a dose of 12.5 μg Hg/kg did not alter glutamate and aspartate concentrations at microdialysis time (but based on thimerosal pharmacokinetics, could have been effective soon after its injection). Application of thimerosal to the PFC in perfusion fluid evoked a rapid increase of glutamate overflow. Coadministration of the neurosteroid, dehydroepiandrosterone sulfate (DHEAS; 80 mg/kg; i.p.) prevented the thimerosal effect on glutamate and aspartate; the steroid alone had no influence on these amino acids. Coapplication of DHEAS with thimerosal in perfusion fluid also blocked the acute action of thimerosal on glutamate. In contrast, DHEAS alone reduced overflow of glycine and alanine, somewhat potentiating the thimerosal effect on these amino acids. Since excessive accumulation of extracellular glutamate is linked with excitotoxicity, our data imply that neonatal exposure to thimerosal-containing vaccines might induce excitotoxic brain injuries, leading to neurodevelopmental disorders. DHEAS may partially protect against mercurials-induced neurotoxicity

A History of Chagas Disease Transmission, Control, and Re-Emergence in Peri-Rural La Joya, Peru

The historically rural problem of Chagas disease is increasing in urban areas in Latin America. Peri-rural development may play a critical role in the urbanization of Chagas disease and other parasitic infections. We conducted a cross-sectional study in an urbanizing rural area in southern Peru, and we encountered a complex history of Chagas disease in this peri-rural environment. Specifically, we discovered: (1) long-standing parasite transmission leading to substantial burden of infection; (2) interruption in parasite transmission resulting from an undocumented insecticide application campaign; (3) relatively rapid re-emergence of parasite-infected vector insects resulting from an unsustained control campaign; (4) extensive migration among peri-rural inhabitants. Long-standing parasite infection in peri-rural areas with highly mobile populations provides a plausible mechanism for the expansion of parasite transmission to nearby urban centers. Lack of commitment to control campaigns in peri-rural areas may have unforeseen and undesired consequences for nearby urban centers. Novel methods and perspectives are needed to address the complexities of human migration and erratic interventions

Apolipoprotein D synthesis progressively increases in frontal cortex during human lifespan

Apolipoprotein D (apo D) is a lipocalin present in the nervous system that may be related to processes of reinnervation, regeneration and neuronal cell protection. In the other way, apo D expression has been correlated, in some brain regions, with normal aging and neurodegenerative diseases. To elucidate the regional and cellular expression of apo D in normal human brain during aging, we performed a detailed and extensive study in samples of post-mortem human cerebral cortices. To achieve this study, slot blot techniques, for protein and mRNA, as well as immunohistochemistry and hybridohistochemistry methods were used. A positive correlation for apo D expression with aging was found; furthermore, mRNA levels, as well as the protein ones, were higher in the white than in the grey matter. Immunohistochemistry and non-isotopic HIS showed that apo D is synthesized in both neurons and glial cells. Apo D expression is notorious in oligodendrocytes but with aging the number of neurons that synthesize apo D is increased. Our results indicate that apo D could play a fundamental role in central nervous system aging and in the reduction of products derivated from lipid peroxidation. The increment in the expression of apo D with aging can be included in a global mechanism of cellular protection to prevent the deleterious effects caused by aging

A reporting format for leaf-level gas exchange data and metadata

Leaf-level gas exchange data support the mechanistic understanding of plant fluxes of carbon and water. These fluxes inform our understanding of ecosystem function, are an important constraint on parameterization of terrestrial biosphere models, are necessary to understand the response of plants to global environmental change, and are integral to efforts to improve crop production. Collection of these data using gas analyzers can be both technically challenging and time consuming, and individual studies generally focus on a small range of species, restricted time periods, or limited geographic regions. The high value of these data is exemplified by the many publications that reuse and synthesize gas exchange data, however the lack of metadata and data reporting conventions make full and efficient use of these data difficult. Here we propose a reporting format for leaf-level gas exchange data and metadata to provide guidance to data contributors on how to store data in repositories to maximize their discoverability, facilitate their efficient reuse, and add value to individual datasets. For data users, the reporting format will better allow data repositories to optimize data search and extraction, and more readily integrate similar data into harmonized synthesis products. The reporting format specifies data table variable naming and unit conventions, as well as metadata characterizing experimental conditions and protocols. For common data types that were the focus of this initial version of the reporting format, i.e., survey measurements, dark respiration, carbon dioxide and light response curves, and parameters derived from those measurements, we took a further step of defining required additional data and metadata that would maximize the potential reuse of those data types. To aid data contributors and the development of data ingest tools by data repositories we provided a translation table comparing the outputs of common gas exchange instruments. Extensive consultation with data collectors, data users, instrument manufacturers, and data scientists was undertaken in order to ensure that the reporting format met community needs. The reporting format presented here is intended to form a foundation for future development that will incorporate additional data types and variables as gas exchange systems and measurement approaches advance in the future. The reporting format is published in the U.S. Department of Energy's ESS-DIVE data repository, with documentation and future development efforts being maintained in a version control system

COVIDiSTRESS Global Survey dataset on psychological and behavioural consequences of the COVID-19 outbreak

This N = 173,426 social science dataset was collected through the collaborative COVIDiSTRESS Global Survey - an open science effort to improve understanding of the human experiences of the 2020 COVID-19 pandemic between 30th March and 30th May, 2020. The dataset allows a cross-cultural study of psychological and behavioural responses to the Coronavirus pandemic and associated government measures like cancellation of public functions and stay at home orders implemented in many countries. The dataset contains demographic background variables as well as measures of Asian Disease Problem, perceived stress (PSS-10), availability of social provisions (SPS-10), trust in various authorities, trust in governmental measures to contain the virus (OECD trust), personality traits (BFF-15), information behaviours, agreement with the level of government intervention, and compliance with preventive measures, along with a rich pool of exploratory variables and written experiences. A global consortium from 39 countries and regions worked together to build and translate a survey with variables of shared interests, and recruited participants in 47 languages and dialects. Raw plus cleaned data and dynamic visualizations are available.Measurement(s) psychological measurement center dot anxiety-related behavior trait center dot Stress center dot response to center dot Isolation center dot loneliness measurement center dot Emotional Distress Technology Type(s) Survey Factor Type(s) geographic location center dot language center dot age of participant center dot responses to the Coronavirus pandemic Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location global Machine-accessible metadata file describing the reported data:Peer reviewe

Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages

Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.We thank S. Lecher, S. Li and J. Zallet for technical support. Calculations were performed at the sciCORE scientific computing core facility at the University of Basel. This work was supported by the Swiss National Science Foundation (grants 310030_166687 (S.G.) and 320030_153442 (M.E.) and Swiss HIV Cohort Study grant 740 to L.F.), the European Research Council (309540-EVODRTB to S.G.), TB-PAN-NET (FP7-223681 to S.N.), PathoNgenTrace projects (FP7-278864-2 to S.N.), SystemsX.ch (S.G.), the German Center for Infection Research (DZIF; S.N.), the Novartis Foundation (S.G.), the Natural Science Foundation of China (91631301 to Q.G.), and the National Institute of Allergy and Infectious Diseases (5U01-AI069924-05) of the US National Institutes of Health (M.E.)