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The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component. SD-282 represents a valuable tool to elucidate the role of p38 MAP kinase in multiple models of inflammation.

This exploratory study investigated the differences in the attitudes and perceptions about academic dishonesty between international and domestic students. Further, it examined the similarities and differences in how The Neutralization Theory (Sykes & Matza, 1957) was used by domestic and international students to explain participation in academic dishonesty. Responses to open-ended questions presented to 2,906 undergraduate students as part of a larger, web-based survey about academic integrity were utilized as data in this study. Qualitative interviews were conducted with five domestic undergraduate students and eight international undergraduate students. Data gathered from these sources indicated that there were both similarities and differences among domestic and international students in their perception of cheating behaviors. Specifically, the actions of many international students may be influenced by the high school experience in his/her home country. Additionally, while both domestic and international students experience external pressures, those that are experienced by some international students are higher stakes pressures. It was found that both domestic and international students participating in this study utilize denial of responsibility and condemnation of the condemners as neutralizing attitudes, but international student participants indicated using condemnation of the condemners more frequently than the domestic student participants. Appeal to higher loyalties was cited with great frequency among international student participants, but not among domestic student participants. This was due to international students feeling a strong obligation to assist peers from their own country. Finally, this study examines how the findings may be used in practical application by a variety of higher education professionals. The limitations of the study are examined, and several suggestions for future research are presented.

The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component. SD-282 represents a valuable tool to elucidate the role of p38 MAP kinase in multiple models of inflammation. Copyright © 2008 S. Karger AG, Basel [PUBLICATION ABSTRACT]

Climate change is intensifying the fire regime across Siberia, with the potential to alter carbon combustion and post‐fire carbon re‐accumulation trajectories. Few field‐based estimates of fire severity (e.g., carbon combustion and tree mortality) exist in Siberian larch forests (Larix spp.), which limits our ability to project how an intensified fire regime will affect regional and global climate feedbacks. Here, we present field‐based estimates of fire‐induced tree mortality and carbon loss in eastern Siberian larch forests. Our results suggest that fires in this region result in high tree mortality (means of 83% and 76% at Arctic and subarctic sites, respectively). In both absolute and relative terms, aboveground carbon loss following fire is higher in Siberian larch forests than in North America, but belowground carbon loss is considerably lower. This suggests fundamental differences in wildfire behavior and carbon dynamics between dominant vegetation types across the boreal biome. Plain Language Summary With climate change, forest fires in Siberia are expected to become more severe and more frequent, which could amplify climate change by transferring carbon from the ecosystem to the atmosphere. Although Siberian larch forests make up 20% of the boreal forest biome by area, scientific understanding of the Siberian larch fire regime is limited because the region is remote and mostly roadless. We collected data from burned and nearby unburned Siberian larch forests to understand the effects of fire on the ecosystem. We found that fires in Siberian larch forests kill, on average, about 75% of trees and result in large carbon losses to the atmosphere. These observations of tree mortality and carbon loss are higher than reported in most satellite‐based studies and demonstrate that fires in Siberian larch forests could contribute to ongoing climate change. Key Points Siberian larch forest fires cause high tree mortality despite species traits and stand structure hypothesized to promote low severity fires Compared with boreal North America, fires in Siberian larch forests result in greater aboveground C loss but lower belowground C loss

Small farm reservoirs are abundant in many agricultural regions across the globe and have the potential to be large contributing sources of carbon dioxide (CO2) and methane (CH4) to agricultural landscapes. Compared to natural ponds, these artificial waterbodies remain overlooked in both agricultural greenhouse gas (GHG) inventories and inland water global carbon (C) budgets. Improved understanding of the environmental controls of C emissions from farm reservoirs is required to address and manage their potential importance in agricultural GHG budgets. Here, we conducted a regional-scale survey (∼ 235 000 km2) to measure CO2 and CH4 surface concentrations and diffusive fluxes across 101 small farm reservoirs in Canada's largest agricultural area. A combination of abiotic, biotic, hydromorphologic, and landscape variables were modelled using generalized additive models (GAMs) to identify regulatory mechanisms. We found that CO2 concentration was estimated by a combination of internal metabolism and groundwater-derived alkalinity (66.5 % deviance explained), while multiple lines of evidence support a positive association between eutrophication and CH4 production (74.1 % deviance explained). Fluxes ranged from −21 to 466 and 0.14 to 92 mmol m−2 d−1 for CO2 and CH4, respectively, with CH4 contributing an average of 74 % of CO2-equivalent (CO2-e) emissions based on a 100-year radiative forcing. Approximately 8 % of farm reservoirs were found to be net CO2-e sinks. From our models, we show that the GHG impact of farm reservoirs can be greatly minimized with overall improvements in water quality and consideration to position and hydrology within the landscape.

The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development. This Perspective outlines the Human Developmental Cell Atlas initiative, which uses state-of-the-art technologies to map and model human development across gestation, and discusses the early milestones that have been achieved.

Permafrost soils store between 1330 and 1580 Pg carbon (C), which is 3 times the amount of C in global vegetation, almost twice the amount of C in the atmosphere, and half of the global soil organic C pool. Despite the massive amount of C in permafrost, estimates of soil C storage in the high-latitude permafrost region are highly uncertain, primarily due to undersampling at all spatial scales; circumpolar soil C estimates lack sufficient continental spatial diversity, regional intensity, and replication at the field-site level. Siberian forests are particularly undersampled, yet the larch forests that dominate this region may store more than twice as much soil C as all other boreal forest types in the continuous permafrost zone combined. Here we present above- and belowground C stocks from 20 sites representing a gradient of stand age and structure in a larch watershed of the Kolyma River, near Chersky, Sakha Republic, Russia. We found that the majority of C stored in the top 1 m of the watershed was stored belowground (92 %), with 19 % in the top 10 cm of soil and 40 % in the top 30 cm. Carbon was more variable in surface soils (10 cm; coefficient of variation (CV)  =  0.35 between stands) than in the top 30 cm (CV  =  0.14) or soil profile to 1 m (CV  =  0.20). Combined active-layer and deep frozen deposits (surface – 15 m) contained 205 kg C m−2 (yedoma, non-ice wedge) and 331 kg C m−2 (alas), which, even when accounting for landscape-level ice content, is an order of magnitude more C than that stored in the top meter of soil and 2 orders of magnitude more C than in aboveground biomass. Aboveground biomass was composed of primarily larch (53 %) but also included understory vegetation (30 %), woody debris (11 %) and snag (6 %) biomass. While aboveground biomass contained relatively little (8 %) of the C stocks in the watershed, aboveground processes were linked to thaw depth and belowground C storage. Thaw depth was negatively related to stand age, and soil C density (top 10 cm) was positively related to soil moisture and negatively related to moss and lichen cover. These results suggest that, as the climate warms, changes in stand age and structure may be as important as direct climate effects on belowground environmental conditions and permafrost C vulnerability.

Molecular recognition reagents are key tools for understanding biological processes and are used universally by scientists to study protein expression, localisation and interactions. Antibodies remain the most widely used of such reagents and many show excellent performance, although some are poorly characterised or have stability or batch variability issues, supporting the use of alternative binding proteins as complementary reagents for many applications. Here we report on the use of Affimer proteins as research reagents. We selected 12 diverse molecular targets for Affimer selection to exemplify their use in common molecular and cellular applications including the (a) selection against various target molecules; (b) modulation of protein function in vitro and in vivo; (c) labelling of tumour antigens in mouse models; and (d) use in affinity fluorescence and super-resolution microscopy. This work shows that Affimer proteins, as is the case for other alternative binding scaffolds, represent complementary affinity reagents to antibodies for various molecular and cell biology applications.

Dendritic cells (DCs) direct CD4 + T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4 + T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation. How anti-helminth and allergic immune responses are initiated is poorly understood. Here the authors show that to trigger these responses, dendritic cells specifically require methyl-CpG-binding domain-2, a protein promoting repressed chromatin state.