Role of Extracellular Vesicles in the Propagation of Lung Fibrosis in Systemic Sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) has the highest mortality rate among the rheumatic diseases, with lung fibrosis leading as the cause of death. A characteristic of severe SSc-related lung fibrosis is its progressive nature. Although most research has focused on the pathology of the fibrosis, the mechanism mediating the fibrotic spread remains unclear. We hypothesized that extracellular vesicle (EV) communication drives the propagation of SSc lung fibrosis. METHODS: EVs were isolated from normal (NL) or SSc-derived human lungs and primary lung fibroblasts (pLFs). EVs were also isolated from human fibrotic lungs and pLFs induced experimentally with transforming growth factor-ß (TGFß). Fibrotic potency of EVs was assessed using functional assays in vitro and in vivo. Transmission electron microscopy, nanoparticle tracking analysis, real-time quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and immunofluorescence were used to analyze EVs, their cargo, extracellular matrix (ECM) fractions, and conditioned media. RESULTS: SSc lungs and pLFs released significantly more EVs than NL lungs, and their EVs showed increased fibrotic content and activity. TGFß-stimulated NL lung cores and pLFs increased packaging of fibrotic proteins, including fibronectin, collagens, and TGFß, into released EVs. The EVs induced a fibrotic phenotype in recipient pLFs and in vivo in mouse lungs. Furthermore, EVs interacted with and contributed to the ECM. Finally, suppressing EV release in vivo reduced severity of murine lung fibrosis. CONCLUSIONS: Our findings highlight EV communication as a novel mechanism for propagation of SSc lung fibrosis. Identifying therapies that reduce EV release, activity, and/or fibrotic cargo in SSc patient lungs may be a viable therapeutic strategy to improve fibrosis.

Ameliorating Fibrosis in Murine and Human Tissues with END55, an Endostatin-Derived Fusion Protein Made in Plants.

Organ fibrosis, particularly of the lungs, causes significant morbidity and mortality. Effective treatments are needed to reduce the health burden. A fragment of the carboxyl-terminal end of collagen XVIII/endostatin reduces skin and lung fibrosis. This fragment was modified to facilitate its production in plants, which resulted in the recombinant fusion protein, END55. We found that expression of END55 had significant anti-fibrotic effects on the treatment and prevention of skin and lung fibrosis in a bleomycin mouse model. We validated these effects in a second mouse model of pulmonary fibrosis involving inducible, lung-targeted expression of transforming growth factor ß1. END55 also exerted anti-fibrotic effects in human lung and skin tissues maintained in organ culture in which fibrosis was experimentally induced. The anti-fibrotic effect of END55 was mediated by a decrease in the expression of extracellular matrix genes and an increase in the levels of matrix-degrading enzymes. Finally, END55 reduced fibrosis in the lungs of patients with systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) who underwent lung transplantation due to the severity of their lung disease, displaying efficacy in human tissues directly relevant to human disease. These findings demonstrate that END55 is an effective anti-fibrotic therapy in different organs.

The gap between experts, farmers and non-farmers on perceived environmental vulnerability and the influence of values and beliefs.

Science has played a mixed role in guiding conservation and sustainability-oriented decision-making by individuals, policymakers, institutions, and governments. Not all science-based conservation and sustainability initiatives that address issues facing humanity and ecosystems and global problems have gained public support. Conservation decisions and policy prescriptions are and may be based on perceptions about and experiences with the environment, local land use, and ecosystems that may not align with or be grounded in science or evidence from experts in the field. Values, beliefs, and perceptions associated with nature play a critical role in how individuals view biodiversity conservation, sustainability, and natural resource management. This study first examines the gap between experts (scientists and other field experts) and the public (farmers and non-farmers) about the state of water and land resources, wildlife and associated habitats, and aquatic biodiversity in the Smoky Hill River Watershed in western Kansas. Second, the study examines the role that values and beliefs play in shaping environmental perceptions for farmers and non-farmers. Analysis confirms that a gap between experts and farmers/non-farmers does exist, especially with respect to the state of the Ogallala Aquifer, playas, rivers and streams, lakes and reservoirs, native grasslands, wildlife habitats, farmland, native fish populations, and wildlife species. Ordered-logistic regression analyses, meanwhile, indicate that farmer and non-farmer perceptions about the state of the local environment are influenced by traditional and self-interested values, as well as environmental values and beliefs, but less so by religiosity and political ideology. Despite broad takeaways, results exhibited heterogeneity across the farmer and non-farmer subpopulations. If environmental professionals cannot align ecological data, stakeholders' values/perceptions, and policies, then the existing body of technical research and management on sustainability in natural and social sciences may be of little value.

Local environment and individuals' beliefs: The dynamics shaping public support for sustainability policy in an agricultural landscape.

Agricultural landscapes are the leading edge in the advancement of sustainability and climate change adaptation. The purpose of this study is to endogenize culture as shaped by natural-cultural feedback into individuals' decision-making processes on sustainability policy support. We present an agent-based model in which an adaptive cultural decision-rule quantifies the probability of an agent deciding to support a wildlife area policy for the Smoky Hill River Watershed (SHRW) in Kansas, USA. By using an ABM to examine the watershed as a coupled natural and human system, we learned that agents would adopt a new behavior, voting for the policy, if the cultural conditions were right, with high levels of beliefs and norms for freshwater and its biota. Our results indicate that individuals in the SHRW are not engaged in caring for fish, plants, and bird richness in their rivers and playas with few individuals supporting the policy in the naïve cultural setting (8.9 % of simulated population). However, enough agents would support the policy under a lower cultural threshold (40.7 % of simulated population). Our results show that sustainability policies need to account for the local culture to gain support, and if a policy is culturally meaningful, it does not need to be cheap. For an agricultural landscape, such as those commonly found in the Central Great Plains, this study presents new levers for policymakers on the conditions needed to help assemble popular support for sustainability policies.

E4 engages uPAR and enolase-1 and activates urokinase to exert antifibrotic effects.

Fibroproliferative disorders such as systemic sclerosis (SSc) have no effective therapies and result in significant morbidity and mortality. We recently demonstrated that the C-terminal domain of endostatin, known as E4, prevented and reversed both dermal and pulmonary fibrosis. Our goal was to identify the mechanism by which E4 abrogates fibrosis and its cell surface binding partner(s). Our findings show that E4 activated the urokinase pathway and increased the urokinase plasminogen activator (uPA) to type 1 plasminogen activator inhibitor (PAI-1) ratio. In addition, E4 substantially increased MMP-1 and MMP-3 expression and activity. In vivo, E4 reversed bleomycin induction of PAI-1 and increased uPA activity. In patients with SSc, the uPA/PAI-1 ratio was decreased in both lung tissues and pulmonary fibroblasts compared with normal donors. Proteins bound to biotinylated-E4 were identified as enolase-1 (ENO) and uPA receptor (uPAR). The antifibrotic effects of E4 required uPAR. Further, ENO mediated the fibrotic effects of TGF-ß1 and exerted TGF-ß1-independent fibrotic effects. Our findings suggest that the antifibrotic effect of E4 is mediated, in part, by regulation of the urokinase pathway and induction of MMP-1 and MMP-3 levels and activity in a uPAR-dependent manner, thus promoting extracellular matrix degradation. Further, our findings identify a moonlighting function for the glycolytic enzyme ENO in fibrosis.

International Migration and Development: A Dyadic Analysis of the Americas, 1970-2010.

This paper assesses the migration-development nexus from a new, relational perspective, providing a closer test of existing theories of cross-national dynamics, including migration and development. Using bilateral data, we assess the relationship between migration (im)balances and wage differentials between pairs of countries in the Americas, from 1970 to 2010. The analysis reveals a positive feedback between international migration and cross-national inequalities. Migration responds strongly to wage gaps, which motivate more uni-directional, or imbalanced migration flows in country-pairs. This relationship is particularly strong in contiguous countries. Similarly, wage gaps respond to migration imbalances, which increase per capita income differences in country-pairs, although the effect of migration on wage differentials is smaller than the effect of wage differentials on migration. Together, the results suggest that the migration-development nexus is characterized by a strong internal momentum.

Phenotypic Characterization of Transgenic Mice Expressing Human IGFBP-5.

Pulmonary fibrosis is one of the important causes of morbidity and mortality in fibroproliferative disorders such as systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding protein-5 (IGFBP-5) is a conserved member of the IGFBP family of proteins that is overexpressed in SSc and IPF lung tissues. In this study, we investigated the functional role of IGFBP-5 in the development of fibrosis in vivo using a transgenic model. We generated transgenic mice ubiquitously expressing human IGFBP-5 using CRISPR/Cas9 knock-in. Our data show that the heterozygous and homozygous mice are viable and express human IGFBP-5 (hIGFBP-5). Transgenic mice had increased expression of extracellular matrix (ECM) genes, especially Col3a1, Fn, and Lox in lung and skin tissues of mice expressing higher transgene levels. Histologic analysis of the skin tissues showed increased dermal thickness, and the lung histology showed subtle changes in the heterozygous and homozygous mice as compared with the wild-type mice. These changes were more pronounced in animals expressing higher levels of hIGFBP-5. Bleomycin increased ECM gene expression in wild-type mice and accentuated an increase in ECM gene expression in transgenic mice, suggesting that transgene expression exacerbated bleomycin-induced pulmonary fibrosis. Primary lung fibroblasts cultured from lung tissues of homozygous transgenic mice showed significant increases in ECM gene expression and protein levels, further supporting the observation that IGFBP-5 resulted in a fibrotic phenotype in fibroblasts. In summary, transgenic mice expressing human IGFBP-5 could serve as a useful animal model for examining the function of IGFBP-5 in vivo.

Producer Attitudes Toward Groundwater Conservation in the U.S. Ogallala-High Plains.

We present descriptive findings on attitudes towards groundwater conservation and management from a survey of 1,226 producers farming in the High Plains/Ogallala aquifer region of the United States. We find that a super-majority of producers agree that groundwater should be conserved rather than entirely depleted. The majority perceives groundwater depletion to be a serious problem. Producers perceive depletion to be a greater problem for their communities than for their own farming operations. There is overwhelming agreement that groundwater should be conserved for altruistic reasons to benefit future generations in the community. Most producers believe they have limited personal capacity for additional groundwater conservation on their farms, and few are involved in voluntary group conservation initiatives. We suggest that a key element of the conservation challenge is social and that future efforts should focus on developing networks, capacities, and cultures of groundwater conservation on the High Plains.

A Population-Based Study of Coupling and Physical Activity by Sexual Orientation for Men.

Research has suggested that men in relationships are more physically active than men who are single. This study provides a weighted analysis of physical activity by coupling status for men of different sexual orientations. Aggregated data from the United States 2013-2014 National Health Interview Survey were used to conduct multivariate logistic regression analyses. Compared to straight men (n = 29,926), gay men (n = 623) were less likely to be in a relationship (AOR 0.32, CI: 0.25-0.41). Coupled gay men did more physical activity than coupled straight men and were 1.62 (CI: 1.05-2.50) times more likely to be active, 1.67 (CI: 1.10-2.51) times more likely to be high active, 1.89 (CI: 1.24-2.89) times more likely to engage in muscle-strengthening activities, and 2.00 (CI: 1.28-3.11) times more likely to meet aerobic and muscle-strengthening recommendations. Coupling facilitates physical activity for men. However, more research is needed to help explore underlying mechanisms for differences by sexuality.

Evaluating environmental change and behavioral decision-making for sustainability policy using an agent-based model: A case study for the Smoky Hill River Watershed, Kansas.

Sustainability has been at the forefront of the environmental research agenda of the integrated anthroposphere, hydrosphere, and biosphere since the last century and will continue to be critically important for future environmental science. However, linking humans and the environment through effective policy remains a major challenge for sustainability research and practice. Here we address this gap using an agent-based model (ABM) for a coupled natural and human systems in the Smoky Hill River Watershed (SHRW), Kansas, USA. For this freshwater-dependent agricultural watershed with a highly variable flow regime influenced by human-induced land-use and climate change, we tested the support for an environmental policy designed to conserve and protect fish biodiversity in the SHRW. We develop a proof of concept interdisciplinary ABM that integrates field data on hydrology, ecology (fish richness), social-psychology (value-belief-norm) and economics, to simulate human agents' decisions to support environmental policy. The mechanism to link human behaviors to environmental changes is the social-psychological sequence identified by the value-belief-norm framework and is informed by hydrological and fish ecology models. Our results indicate that (1) cultural factors influence the decision to support the policy; (2) a mechanism modifying social-psychological factors can influence the decision-making process; (3) there is resistance to environmental policy in the SHRW, even under potentially extreme climate conditions; and (4) the best opportunities for policy acceptance were found immediately after extreme environmental events. The modeling approach presented herein explicitly links biophysical and social science has broad generality for sustainability problems.

Sociohydrology: Scientific Challenges in Addressing the Sustainable Development Goals.

The Sustainable Development Goals (SDGs) of the United Nations Agenda 2030 represent an ambitious blueprint to reduce inequalities globally and achieve a sustainable future for all mankind. Meeting the SDGs for water requires an integrated approach to managing and allocating water resources, by involving all actors and stakeholders, and considering how water resources link different sectors of society. To date, water management practice is dominated by technocratic, scenario-based approaches that may work well in the short term but can result in unintended consequences in the long term due to limited accounting of dynamic feedbacks between the natural, technical, and social dimensions of human-water systems. The discipline of sociohydrology has an important role to play in informing policy by developing a generalizable understanding of phenomena that arise from interactions between water and human systems. To explain these phenomena, sociohydrology must address several scientific challenges to strengthen the field and broaden its scope. These include engagement with social scientists to accommodate social heterogeneity, power relations, trust, cultural beliefs, and cognitive biases, which strongly influence the way in which people alter, and adapt to, changing hydrological regimes. It also requires development of new methods to formulate and test alternative hypotheses for the explanation of emergent phenomena generated by feedbacks between water and society. Advancing sociohydrology in these ways therefore represents a major contribution toward meeting the targets set by the SDGs, the societal grand challenge of our time.

MNE-BIDS: Organizing electrophysiological data into the BIDS format and facilitating their analysis.

The development of the Brain Imaging Data Structure (BIDS; Gorgolewski et al., 2016) gave the neuroscientific community a standard to organize and share data. BIDS prescribes file naming conventions and a folder structure to store data in a set of already existing file formats. Next to rules about organization of the data itself, BIDS provides standardized templates to store associated metadata in the form of Javascript Object Notation (JSON) and tab separated value (TSV) files. It thus facilitates data sharing, eases metadata querying, and enables automatic data analysis pipelines. BIDS is a rich system to curate, aggregate, and annotate neuroimaging databases.

Rhodiola rosea Exerts Antiviral Activity in Athletes Following a Competitive Marathon Race.

Rhodiola rosea, a medicinal plant with demonstrated adaptogenic properties, has recently been reported to contain active compounds with antimicrobial activity. The goal of this study was to measure the antiviral and antibacterial properties of the bioactive metabolites of Rhodiola rosea in the serum of experienced marathon runners following supplementation. Marathon runners, randomly divided into two groups, ingested 600 mg/day of Rhodiola rosea (n = 24, 6 female, 18 male) or placebo (n = 24, 7 females, 17 males) for 30 days prior to, the day of, and 7 days post-marathon. Blood serum samples were collected the day before, 15 min post-, and 1.5 h post-marathon. Serum from Rhodiola rosea-supplemented runners collected after marathon running did not attenuate the marathon-induced susceptibility of HeLa cells to killing by vesicular stomatitis virus. However, the use of Rhodiola rosea induced antiviral activity at early times post-infection by delaying an exercise-dependent increase in virus replication (P = 0.013 compared to placebo). Serum from both groups collected 15 min post-marathon significantly promoted the growth of Escherichia coli in culture as compared to serum collected the day before the marathon (P = 0.003, all subjects). Furthermore, the serum from subjects ingesting Rhodiola rosea did not display antibacterial properties at any time point as indicated by a lack of group differences immediately (P = 0.785) or 1.5 h (P = 0.633) post-marathon. These results indicate that bioactive compounds in the serum of subjects ingesting Rhodiola rosea may exert protective effects against virus replication following intense and prolonged exercise by inducing antiviral activity.

Graphene based all-optical spatial terahertz modulator.

We demonstrate an all-optical terahertz modulator based on single-layer graphene on germanium (GOG), which can be driven by a 1.55 µm CW laser with a low-level photodoping power. Both the static and dynamic THz transmission modulation experiments were carried out. A spectrally wide-band modulation of the THz transmission is obtained in a frequency range from 0.25 to 1 THz, and a modulation depth of 94% can be achieved if proper pump power is applied. The modulation speed of the modulator was measured to be ~ 200 KHz using a 340 GHz carrier. A theoretical model is proposed for the modulator and the calculation results indicate that the enhanced THz modulation is mainly due to the third order nonlinear effect in the optical conductivity of the graphene monolayer.

The protective effects of a polyphenol-enriched protein powder on exercise-induced susceptibility to virus infection.

Prolonged and intensive exercise induces transient immunosuppression and is associated with an increased risk and severity of infections. The goal of this study was to characterize the antiviral and antibacterial properties of the bioactive metabolites of a blueberry-green tea-polyphenol soy protein complex (PSPC) in the serum of supplemented subjects during a 3-day intensified training period. Long-distance runners, randomly divided into two groups, ingested 40 g/day PSPC or placebo (soy protein and colorings) for 17 days, with a 3-day running period inserted at day 14. Blood serum samples were collected pre-14 days and post-14 days supplementation, and immediately and 14 h after the third day of running. The post-exercise serum from both groups significantly promoted the growth of Escherichia coli and Staphylococcus aureus in culture by 20-70%, but returned to normal levels following recovery. Furthermore, the serum from subjects ingesting PSPC did not display antibacterial properties at any time point. In contrast, there was a significant difference in the ability of serum from PSPC-supplemented versus placebo-supplemented athletes to protect cells in culture from killing by vesicular stomatitis virus following strenuous exercise. In addition, the serum of subjects who ingested PSPC significantly delayed an exercise-induced increase in virus replication. These results indicate that polyphenol complexes containing blueberry and green tea have the potential to protect athletes from virus infections following rigorous exercise.

Does immigration have a Matthew Effect? A cross-national analysis of international migration and international income inequality, 1960-2005.

This paper empirically assesses how immigration affects international inequality by testing the relationship between immigration and national economic development across countries in different world income groups. A series of cross-national, longitudinal analyses demonstrate that, on average, immigration has a rather small, but positive long-term effect on development levels. However, the findings also indicate that immigration has a Matthew Effect (Merton, 1968) in the world-economy: immigration disproportionately benefits higher-income countries. Moreover, the wealthiest countries reap the largest gains from immigration. Thus, from the perspective of destination countries, immigration does not appear to be a panacea for international inequality. Instead, the results indicate that immigration actually reproduces, and even exacerbates, international inequality.

A NOVEL ASSAY OF ACYL-COA:DIACYLGLYCEROL ACYLTRANSFERASE ACTIVITY UTILIZING FLUORESCENT SUBSTRATE(1).

Common methods for assaying acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymatic activity rely upon radiolabeled substrates or product assay. We developed a novel assay that directly quantifies endogenous DGAT activity through the use of a fluorescently labeled substrate. We performed this assay with microsomal protein, 2-(6-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoyl-1-hexadecanoyl-sn-glycero-3-diacylglycerol (NBD-DAG), and oleoyl-CoA substrates. DGAT activity was analyzed in three species of algae as well as rat liver. The protocol proved to be sensitive and reliable. This assay may be used to facilitate research in the areas of biodiesel, oilseed crops, and triacylglycerol-related human pathologies.