CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis

Current therapies to treat inflammatory bowel diseases have limited efficacy, significant side effects, and often wane over time. Little is known about the cellular and molecular mechanisms operative in the process of mucosal healing from colitis. To study such events, we developed a new model of reversible colitis in which adoptive transfer of CD4(+)CD45RB(hi) T cells into Helicobacter typhlonius-colonized lymphopenic mice resulted in a rapid onset of colonic inflammation that was reversible through depletion of colitogenic T cells. Remission was associated with an improved clinical and histopathological score, reduced immune cell infiltration to the intestinal mucosa, altered intestinal gene expression profiles, regeneration of the colonic mucus layer, and the restoration of epithelial barrier integrity. Notably, colitogenic T cells were not only critical for induction of colitis but also for maintenance of disease. Depletion of colitogenic T cells resulted in a rapid drop in tumor necrosis factor α (TNFα) levels associated with reduced infiltration of inflammatory immune cells to sites of inflammation. Although neutralization of TNFα prevented the onset of colitis, anti-TNFα treatment of mice with established disease failed to resolve colonic inflammation. Collectively, this new model of reversible colitis provides an important research tool to study the dynamics of mucosal healing in chronic intestinal remitting-relapsing disorders.Mucosal Immunology advance online publication 16 September 2015; doi:10.1038/mi.2015.93.

Inhibition of photosynthesis by high temperature in oak (Quercus pubescens L.) leaves grown under natural conditions closely correlates with a reversible heat-dependent reduction of the activation state of ribulose-1,5-bisphosphate carboxylase/oxygenase

Inhibition of the net photosynthetic CO2 assimilation rate (Pn) by high temperature was examined in oak (Quercus pubescens L.) leaves grown under natural conditions. Combined measurements of gas exchange and chlorophyll (Chl) a fluorescence were employed to differentiate between inhibition originating from heat effects on components of the thylakoid membranes and that resulting from effects on photosynthetic carbon metabolism. Regardless of whether temperature was increased rapidly or gradually, Pn decreased with increasing leaf temperature and was more than 90% reduced at 45 °C as compared to 25 °C. Inhibition of Pn by heat stress did not result from reduced stomatal conductance (gs), as heat-induced reduction of gs was accompanied by an increase of the intercellular CO2 concentration (Ci). Chl a fluorescence measurements revealed that between 25 and 45 °C heat-dependent alterations of thylakoid-associated processes contributed only marginally, if at all, to the inhibition of Pn by heat stress, with photosystem II being remarkably well protected against thermal inactivation. The activation state of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) decreased from about 90% at 25 °C to less than 30% at 45 °C. Heat stress did not affect Rubisco per se, since full activity could be restored by incubation with CO2 and Mg2+. Western-blot analysis of leaf extracts disclosed the presence of two Rubisco activase polypeptides, but heat stress did not alter the profile of the activase bands. Inhibition of Pn at high leaf temperature could be markedly reduced by artificially increasing Ci. A high Ci also stimulated photosynthetic electron transport and resulted in reduced non-photochemical fluorescence quenching. Recovery experiments showed that heat-dependent inhibition of Pn was largely, if not fully, reversible. The present results demonstrate that in Q. pubescens leaves the thylakoid membranes in general and photosynthetic electron transport in particular were well protected against heat-induced perturbations and that inhibition of Pn by high temperature closely correlated with a reversible heat-dependent reduction of the Rubisco activation state.

A novel approach for assessing shifting cultivation dynamics in a regional conservation hotspot - insights from nort-eastern Madagascar

The north-eastern escarpment of Madagascar has been deemed a global hotspot of biodiversity due to its high levels of endemic speciesbeing heavily threatened by accelerated deforestation rates and landscape changes. The main concern for conservation of the remaining humid primary forests is the shifting cultivation practices of local smallholder farmers for rice production. According to the mainstream narrative, human population growth leads to a shortening of crop-fallow cycles and thus to the accelerated conversion of forests to agricultural land. However, little is currently known about the dynamic changes between forest and shifting cultivation systems at the regional level. Existing land cover change analyses in this area have so far only focused on binary forest to non-forest changes and have therefore failed to account for the dynamic nature of the change processes between forest and different agriculture land use systems. This can be partly explained by the significant challenge to delineate shifting cultivation systems on land cover maps using traditional remote sensing classification approaches. To address this gap we therefore applied a novel GIS approach, that was originally developed for the assessment of shifting cultivation dynamics in Laos and has so far never been applied elsewhere, to map shifting cultivation of different crop-fallow lengths as well as permanent agriculture land use at the regional level. Change analyses of land use maps between 1995 and 2011 allowed us to comprehend the general trends of land use trajectories and their spatial variation. This more detailed understanding of land use change dynamics is key to plan for successful interventions to slow forest loss while at the same time improving local livelihoods. We further believe that this approach holds great potential for conservation monitoring in this resource-rich but povertyprone conservation hotspot.

Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

Divalent metal transporter-1 (SLC11A2/DMT1) uses the H+ electrochemical gradient as the driving force to transport divalent metal ions such as Fe2+, Mn2+ and others metals into mammalian cells. DMT1 is ubiquitously expressed, most notably in proximal duodenum, immature erythroid cells, brain and kidney. This transporter mediates H+-coupled transport of ferrous iron across the apical membrane of enterocytes. In addition, in cells such as to erythroid precursors, following transferrin receptor (TfR) mediated endocytosis; it mediates H+-coupled exit of ferrous iron from endocytic vesicles into the cytosol. Dysfunction of human DMT1 is associated with several pathologies such as iron deficiency anemia hemochromatosis, Parkinson's disease and Alzheimer's disease, as well as colorectal cancer and esophageal adenocarcinoma, making DMT1 an attractive target for drug discovery. In the present study, we performed a ligand-based virtual screening of the Princeton database (700,000 commercially available compounds) to search for pharmacophore shape analogs of recently reported DMT1 inhibitors. We discovered a new compound, named pyrimidinone 8, which mediates a reversible linear non-competitive inhibition of human DMT1 (hDMT1) transport activity with a Ki of ∼20 μM. This compound does not affect hDMT1 cell surface expression and shows no dependence on extracellular pH. To our knowledge, this is the first experimental evidence that hDMT1 can be allosterically modulated by pharmacological agents. Pyrimidinone 8 represents a novel versatile tool compound and it may serve as a lead structure for the development of therapeutic compounds for pre-clinical assessment.

Zonal playfield attributes – A stochastic approach to subjective passing affordances in football

Introduction: According to the ecological view, coordination establishes byvirtueof social context. Affordances thought of as situational opportunities to interact are assumed to represent the guiding principles underlying decisions involved in interpersonal coordination. It’s generally agreed that affordances are not an objective part of the (social) environment but that they depend on the constructive perception of involved subjects. Theory and empirical data hold that cognitive operations enabling domain-specific efficacy beliefs are involved in the perception of affordances. The aim of the present study was to test the effects of these cognitive concepts in the subjective construction of local affordances and their influence on decision making in football. Methods: 71 football players (M = 24.3 years, SD = 3.3, 21 % women) from different divisions participated in the study. Participants were presented scenarios of offensive game situations. They were asked to take the perspective of the person on the ball and to indicate where they would pass the ball from within each situation. The participants stated their decisions in two conditions with different game score (1:0 vs. 0:1). The playing fields of all scenarios were then divided into ten zones. For each zone, participants were asked to rate their confidence in being able to pass the ball there (self-efficacy), the likelihood of the group staying in ball possession if the ball were passed into the zone (group-efficacy I), the likelihood of the ball being covered safely by a team member (pass control / group-efficacy II), and whether a pass would establish a better initial position to attack the opponents’ goal (offensive convenience). Answers were reported on visual analog scales ranging from 1 to 10. Data were analyzed specifying general linear models for binomially distributed data (Mplus). Maximum likelihood with non-normality robust standard errors was chosen to estimate parameters. Results: Analyses showed that zone- and domain-specific efficacy beliefs significantly affected passing decisions. Because of collinearity with self-efficacy and group-efficacy I, group-efficacy II was excluded from the models to ease interpretation of the results. Generally, zones with high values in the subjective ratings had a higher probability to be chosen as passing destination (βself-efficacy = 0.133, p < .001, OR = 1.142; βgroup-efficacy I = 0.128, p < .001, OR = 1.137; βoffensive convenience = 0.057, p < .01, OR = 1.059). There were, however, characteristic differences in the two score conditions. While group-efficacy I was the only significant predictor in condition 1 (βgroup-efficacy I = 0.379, p < .001), only self-efficacy and offensive convenience contributed to passing decisions in condition 2 (βself-efficacy = 0.135, p < .01; βoffensive convenience = 0.120, p < .001). Discussion: The results indicate that subjectively distinct attributes projected to playfield zones affect passing decisions. The study proposes a probabilistic alternative to Lewin’s (1951) hodological and deterministic field theory and enables insight into how dimensions of the psychological landscape afford passing behavior. Being part of a team, this psychological landscape is not only constituted by probabilities that refer to the potential and consequences of individual behavior, but also to that of the group system of which individuals are part of. Hence, in regulating action decisions in group settings, informers are extended to aspects referring to the group-level. References: Lewin, K. (1951). In D. Cartwright (Ed.), Field theory in social sciences: Selected theoretical papers by Kurt Lewin. New York: Harper & Brothers.

Development of a Novel Rabies Simulation Model for Application in a Non-endemic Environment.

Domestic dog rabies is an endemic disease in large parts of the developing world and also epidemic in previously free regions. For example, it continues to spread in eastern Indonesia and currently threatens adjacent rabies-free regions with high densities of free-roaming dogs, including remote northern Australia. Mathematical and simulation disease models are useful tools to provide insights on the most effective control strategies and to inform policy decisions. Existing rabies models typically focus on long-term control programs in endemic countries. However, simulation models describing the dog rabies incursion scenario in regions where rabies is still exotic are lacking. We here describe such a stochastic, spatially explicit rabies simulation model that is based on individual dog information collected in two remote regions in northern Australia. Illustrative simulations produced plausible results with epidemic characteristics expected for rabies outbreaks in disease free regions (mean R0 1.7, epidemic peak 97 days post-incursion, vaccination as the most effective response strategy). Systematic sensitivity analysis identified that model outcomes were most sensitive to seven of the 30 model parameters tested. This model is suitable for exploring rabies spread and control before an incursion in populations of largely free-roaming dogs that live close together with their owners. It can be used for ad-hoc contingency or response planning prior to and shortly after incursion of dog rabies in previously free regions. One challenge that remains is model parameterisation, particularly how dogs' roaming and contacts and biting behaviours change following a rabies incursion in a previously rabies free population.

Drought stress and carbon assimilation in a warming climate: Reversible and irreversible impacts

Abstract Global change is characterized by increased {CO2} concentration in the atmosphere, increasing average temperature and more frequent extreme events including drought periods, heat waves and flooding. Especially the impacts of drought and of elevated temperature on carbon assimilation are considered in this review. Effects of extreme events on the subcellular level as well as on the whole plant level may be reversible, partially reversible or irreversible. The photosynthetically active biomass depends on the number and the size of mature leaves and the photosynthetic activity in this biomass during stress and subsequent recovery phases. The total area of active leaves is determined by leaf expansion and senescence, while net photosynthesis per leaf area is primarily influenced by stomatal opening (stomatal conductance), mesophyll conductance, activity of the photosynthetic apparatus (light absorption and electron transport, activity of the Calvin cycle) and {CO2} release by decarboxylation reactions (photorespiration, dark respiration). Water status, stomatal opening and leaf temperature represent a "magic triangle" of three strongly interacting parameters. The response of stomata to altered environmental conditions is important for stomatal limitations. Rubisco protein is quite thermotolerant, but the enzyme becomes at elevated temperature more rapidly inactivated (decarbamylation, reversible effect) and must be reactivated by Rubisco activase (carbamylation of a lysine residue). Rubisco activase is present under two forms (encoded by separate genes or products of alternative splicing of the pre-mRNA from one gene) and is very thermosensitive. Rubisco activase was identified as a key protein for photosynthesis at elevated temperature (non-stomatal limitation). During a moderate heat stress Rubisco activase is reversibly inactivated, but during a more severe stress (higher temperature and/or longer exposure) the protein is irreversibly inactivated, insolubilized and finally degraded. On the level of the leaf, this loss of photosynthetic activity may still be reversible when new Rubisco activase is produced by protein synthesis. Rubisco activase as well as enzymes involved in the detoxification of reactive oxygen species or in osmoregulation are considered as important targets for breeding crop plants which are still productive under drought and/or at elevated leaf temperature in a changing climate.

TRANSMISSION DYNAMICS OF ENTERIC BACTERIA IN DAY-CARE CENTERS, HOUSTON, TEXAS

An investigation was undertaken to evaluate the role of fomites in the transmission of diarrhea in day-care centers (DCC) and to elucidate the paths by which enteric organisms spread within this setting.^ During a nine-month period (December 1980-August 1981) extensive culturing of inanimate objects, as well as children and staff was done routinely each month and again repeated during diarrhea outbreaks. Air was sampled from the classrooms and toilets using a Single-Stage Sieve Sampler (Ross Industries, Midland, VA.). Stool samples were collected from both ill and well children and staff in the affected rooms only during outbreaks. Environmental samples were processed for Shigella, salmonella and fecal coliforms while stools were screened for miscellaneous enteropathogens.^ A total of 11 outbreaks occurred in the 5 DCC during the study period. Enteric pathogens were recovered in 7 (64%) of the outbreaks. Multiple pathogens were identified in 3 outbreaks. The most frequently identified pathogen in stools was Giardia lamblia which was recovered in 5 (45%) of the outbreaks. Ten of the 11 (91%) outbreaks occurred in children less than 12 months of age.^ Environmental microbiology studies together with epidemiologic information revealed that enteric organisms were transmitted from person-to-person. On routine sampling, fecal coliforms were most frequently isolated from tap handles and diaper change areas. Contamination with fetal coliforms was wide-spread during diarrhea outbreaks. Fecal coliforms were recovered with significantly greater frequency from hands, toys and other classroom objects during outbreaks than during non-outbreak period. Salmonella typhimurium was recovered from a table top during an outbreak of Salmonellosis. There was no association between the level of enteric microbial contamination in the toilet areas and the occurrence of outbreaks. No evidence was found to indicate that enteric organisms were spread by the airborne route via aerosols.^ Toys, other classroom objects and contaminated hands probably play a major role in the transmission of enteropathogens during day-care center outbreaks. The presence of many enteric agents in the environment undoubtedly explains the polymicrobial etiology of the day-care center associated diarrhea outbreaks. ^

IDENTIFICATION AND ANALYSIS OF A NOVEL ROLE FOR THE TOUSLED-LIKE KINASE IN REGULATING MITOTIC SPINDLE DYNAMICS

Deregulation of kinase activity is one example of how cells become cancerous by evading evolutionary constraints. The Tousled kinase (Tsl) was initially identified in Arabidopsis thaliana as a developmentally important kinase. There are two mammalian orthologues of Tsl and one orthologue in C. elegans, TLK-1, which is essential for embryonic viability and germ cell development. Depletion of TLK-1 leads to embryonic arrest large, distended nuclei, and ultimately embryonic lethality. Prior to terminal arrest, TLK-1-depleted embryos undergo aberrant mitoses characterized by poor metaphase chromosome alignment, delayed mitotic progression, lagging chromosomes, and supernumerary centrosomes. I discovered an unanticipated requirement for TLK-1 in mitotic spindle assembly and positioning. Normally, in the newly-fertilized zygote (P0) the maternal pronucleus migrates toward the paternal pronucleus at the posterior end of the embryo. After pronuclear meeting, the pronuclear-centrosome complex rotates 90° during centration to align on the anteroposterior axis followed by nuclear envelope breakdown (NEBD). However, in TLK-1-depleted P0 embryos, the centrosome-pronuclear complex rotation is significantly delayed with respect to NEBD and chromosome congression, Additionally, centrosome positions over time in tlk-1(RNAi) early embryos revealed a defect in posterior centrosome positioning during spindle-pronuclear centration, and 4D analysis of centrosome positions and movement in newly fertilized embryos showed aberrant centrosome dynamics in TLK-1-depleted embryos. Several mechanisms contribute to spindle rotation, one of which is the anchoring of astral microtubules to the cell cortex. Attachment of these microtubules to the cortices is thought to confer the necessary stability and forces in order to rotate the centrosome-pronuclear complex in a timely fashion. Analysis of a microtubule end-binding protein revealed that TLK-1-depleted embryos exhibit a more stochastic distribution of microtubule growth toward the cell cortices, and the types of microtubule attachments appear to differ from wild-type embryos. Additionally, fewer astral microtubules are in the vicinity of the cell cortex, thus suggesting that the delayed spindle rotation could be in part due to a lack of appropriate microtubule attachments to the cell cortex. Together with recently published biochemical data revealing the Tousled-like kinases associate with components of the dynein microtubule motor complex in humans, these data suggest that Tousled-like kinases play an important role in mitotic spindle assembly and positioning.

Robust trends of landscape dynamics in the Arctic Lena Delta with temporally dense Landsat time-series stacks, with links to GeoTIFFs

Arctic permafrost landscapes are among the most vulnerable and dynamic landscapes globally, but due to their extent and remoteness most of the landscape changes remain unnoticed. In order to detect disturbances in these areas we developed an automated processing chain for the calculation and analysis of robust trends of key land surface indicators based on the full record of available Landsat TM, ETM +, and OLI data. The methodology was applied to the ~ 29,000 km**2 Lena Delta in Northeast Siberia, where robust trend parameters (slope, confidence intervals of the slope, and intercept) were calculated for Tasseled Cap Greenness, Wetness and Brightness, NDVI, and NDWI, and NDMI based on 204 Landsat scenes for the observation period between 1999 and 2014. The resulting datasets revealed regional greening trends within the Lena Delta with several localized hot-spots of change, particularly in the vicinity of the main river channels. With a 30-m spatial resolution various permafrost-thaw related processes and disturbances, such as thermokarst lake expansion and drainage, fluvial erosion, and coastal changes were detected within the Lena Delta region, many of which have not been noticed or described before. Such hotspots of permafrost change exhibit significantly different trend parameters compared to non-disturbed areas. The processed dataset, which is made freely available through the data archive PANGAEA, will be a useful resource for further process specific analysis by researchers and land managers. With the high level of automation and the use of the freely available Landsat archive data, the workflow is scalable and transferrable to other regions, which should enable the comparison of land surface changes in different permafrost affected regions and help to understand and quantify permafrost landscape dynamics.

Modelling calving front dynamics using a level-set method: application to Jakobshavn Isbræ, West Greenland, links model results in MATLAB format

Calving is a major mechanism of ice discharge of the Antarctic and Greenland ice sheets, and a change in calving front position affects the entire stress regime of marine terminating glaciers. The representation of calving front dynamics in a 2-D or 3-D ice sheet model remains non-trivial. Here, we present the theoretical and technical framework for a level-set method, an implicit boundary tracking scheme, which we implement into the Ice Sheet System Model (ISSM). This scheme allows us to study the dynamic response of a drainage basin to user-defined calving rates. We apply the method to Jakobshavn Isbræ, a major marine terminating outlet glacier of the West Greenland Ice Sheet. The model robustly reproduces the high sensitivity of the glacier to calving, and we find that enhanced calving triggers significant acceleration of the ice stream. Upstream acceleration is sustained through a combination of mechanisms. However, both lateral stress and ice influx stabilize the ice stream. This study provides new insights into the ongoing changes occurring at Jakobshavn Isbræ and emphasizes that the incorporation of moving boundaries and dynamic lateral effects, not captured in flow-line models, is key for realistic model projections of sea level rise on centennial timescales.

Pollen and non-pollen palynomorph records of the Holocene part of the composite sediment core TMD from lake Tso Moriri (NW India) and of modern surface samples from the Tso Moriri region

The high-altitude lake Tso Moriri (32°55'46'' N, 78°19'24'' E; 4522 m a.s.l.) is situated at the margin of the ISM and westerly influences in the Trans-Himalayan region of Ladakh. Human settlements are rare and domestic and wild animals are concentrating at the alpine meadows. A set of modern surface samples and fossil pollen from deep-water TMD core was evaluated with a focus on indicator types revealing human impact, grazing activities and lake system development during the last ca. 12 cal ka BP. Furthermore, the non-pollen palynomorph (NPP) record, comprising remains of limnic algae and invertebrates as well as fungal spores and charred plant tissue fragments, were examined in order to attest palaeolimnic phases and human impact, respectively. Changes in the early and middle Holocene limnic environment are mainly influenced by regional climatic conditions and glacier-fed meltwater flow in the catchment area. The NPP record indicates low lake productivity with high influx of freshwater between ca. 11.5 and 4.5 cal ka BP which is in agreement with the regional monsoon dynamics and published climate reconstructions. Geomorphologic observations suggest that during this period of enhanced precipitation the lake had a regular outflow and contributed large amounts of water to the Sutlej River, the lower reaches of which were integral part of the Indus Civilization area. The inferred minimum fresh water input and maximum lake productivity between ca. 4.5-1.8 cal ka BP coincides with the reconstruction of greatest aridity and glaciation in the Korzong valley resulting in significantly reduced or even ceased outflow. We suggest that lowered lake levels and river discharge on a larger regional scale may have caused irrigation problems and harvest losses in the Indus valley and lowlands occupied by sedentary agricultural communities. This scenario, in turn, supports the theory that, Mature Harappan urbanism (ca. 4.5-3.9 cal ka BP) emerged in order to facilitate storage, protection, administration, and redistribution of crop yields and secondly, the eventual collapse of the Harappan Culture (ca. 3.5-3 cal ka BP) was promoted by prolonged aridity. There is no clear evidence for human impact around Tso Moriri prior to ca. 3.7 cal ka BP, with a more distinct record since ca. 2.7 cal ka BP. This suggests that the sedimentary record from Tso Moriri primarily archives the regional climate history.