Improved benchmarks for computational motif discovery

Background An important step in annotation of sequenced genomes is the identification of transcription factor binding sites. More than a hundred different computational methods have been proposed, and it is difficult to make an informed choice. Therefore, robust assessment of motif discovery methods becomes important, both for validation of existing tools and for identification of promising directions for future research. Results We use a machine learning perspective to analyze collections of transcription factors with known binding sites. Algorithms are presented for finding position weight matrices (PWMs), IUPAC-type motifs and mismatch motifs with optimal discrimination of binding sites from remaining sequence. We show that for many data sets in a recently proposed benchmark suite for motif discovery, none of the common motif models can accurately discriminate the binding sites from remaining sequence. This may obscure the distinction between the potential performance of the motif discovery tool itself versus the intrinsic complexity of the problem we are trying to solve. Synthetic data sets may avoid this problem, but we show on some previously proposed benchmarks that there may be a strong bias towards a presupposed motif model. We also propose a new approach to benchmark data set construction. This approach is based on collections of binding site fragments that are ranked according to the optimal level of discrimination achieved with our algorithms. This allows us to select subsets with specific properties. We present one benchmark suite with data sets that allow good discrimination between positive and negative instances with the common motif models. These data sets are suitable for evaluating algorithms for motif discovery that rely on these models. We present another benchmark suite where PWM, IUPAC and mismatch motif models are not able to discriminate reliably between positive and negative instances. This suite could be used for evaluating more powerful motif models. Conclusion Our improved benchmark suites have been designed to differentiate between the performance of motif discovery algorithms and the power of motif models. We provide a web server where users can download our benchmark suites, submit predictions and visualize scores on the benchmarks

Extrinsic and intrinsic controls of zooplankton diversity in lakes

Pelagic crustacean zooplankton were collected from 336 Norwegian lakes covering a wide range of latitude, altitude, lake area, mean depth, production (as chlorophyll a), and fish community structure. Mean zooplankton species richness during the ice-free season was generally low at high latitudes and altitudes. Further, lower species richness was recorded in western lakes, possibly reflecting constraints on migration and dispersal. However, despite obvious spatial limitations, geographic boundaries were only weak predictors of mean zooplankton richness. Similarly, lake surface area did not contribute positively to mean richness such as seen in other ecosystem surveys. Rather, intrinsic factors such as primary production and fish community (planktivore) structure were identified by regression analysis as the major predictors of zooplankton diversity, while a positive correlation was observed between species richness and total zooplankton biomass. However, in spite of a large number of variables included in this study, the predictive power of multiple regression models was modest (<50% variance explained), pointing to a major role for within-lake properties, as yet unidentified intrinsic forces, stochasticity, or dispersal as constraints on zooplankton diversity in these lakes

Long-term annual and spatial variation of polygyny in the white-throated dipper (Cinclus cinclus)

Mating strategies are key components in the fitness of organisms, and notably in birds the occurrence of monogamy versus polygyny has attracted wide interest. We address this by a very comprehensive dataset (2899 breeding events spanning the years 1978–2019) of the white-throated dipper Cinclus cinclus. Though the mating system of this species has been regarded as generally monogamous, we find that 7% of all breeding events were performed by polygynous males (approximately 15% of all pairs). The fraction of polygyny has been stable over the entire study period irrespective of population size. The assumption that polygyny is most common at low population density was not supported. Surprisingly, there was no difference between polygynous and monogamous males with regard to the quality of the territories they inhabited, ranked according to their overall frequency of use. The most common age group, first-year breeders, dominated among monogamous males, while among polygynous males second-year breeders were most common, followed by third and first-year breeders. The primary females were in general older than females mated to monogamous males, also when controlled for their general frequency in the population. The majority of the two females mated to a polygynous male, bred in the vicinity of each other. The probability for a male to be involved in polygyny more than once, was significantly higher than by chance, suggesting phenotypic quality differences among males. frequency of polygyny, mating strategy, monogamous, territory quality, white-throated dipper Behavioural ecology, Evolutionary ecology, Population ecologypublishedVersio

Zooplankton Diversity and Dispersal by Birds; Insights From Different Geographical Scales

Given the major ecological and evolutionary role of dispersal abilities for organisms, as well as the current interest in species' potential for further migration and colonization as a result of climatic changes or human-mediated invasions, our knowledge about dispersal abilities on spatial and temporal scales in many taxa is surprisingly limited. Zooplankton inhabit lakes and ponds that functionally are “aquatic islands” in the landscape, and both community composition and richness depend on their ability to disperse, and their post-dispersal colonization abilities. We here assess the diversity and dispersal of freshwater microcrustaceans based on three types of data; (1) &gt; 2000 lakes on mainland Norway spanning a wide range in longitude, latitude and altitude, (2) a more limited number of ponds at Svalbard that are differently affected by migrating birds, and (3) immigration and colonization of recently constructed wetlands and man-made ponds. At all scales we discuss whether observed patterns in diversity can be explicitly linked to birds as vectors, or if confounding factors such as climate, productivity, age of locality—or other means of immigration, precludes conclusive evidence. The spatial patterns of zooplankton distribution strongly suggest that local sorting is a major determinant of richness and community composition. This sorting may not necessarily lead to similar community composition (the “quorum effect”) however. Despite the fact that rapid colonization occurs at local scales, and that birds undoubtedly can transmit animals or resting stages, their role in modulating community structure and richness is still an unsettled issue due to the many confounding parameters. The fact that birds often play a dual role in shaping diversity and community composition, first by direct dispersal, and secondly via affecting post-dispersal species sorting by changing water quality and productivity, is an important aspect of zoochory. Direct experimental evidence (colonization with and without bird exclusion), or genetic analysis of zooplankton species along migration routes, would however be the only ways to establish firm evidence for this case of zoochory

MARCH1 protects the lipid raft and tetraspanin web from MHCII proteotoxicity in dendritic cells

Dendritic cells (DCs) produce major histocompatibility complex II (MHCII) in large amounts to function as professional antigen presenting cells. Paradoxically, DCs also ubiquitinate and degrade MHCII in a constitutive manner. Mice deficient in the MHCII-ubiquitinating enzyme membrane-anchored RING-CH1, or the ubiquitin-acceptor lysine of MHCII, exhibit a substantial reduction in the number of regulatory T (Treg) cells, but the underlying mechanism was unclear. Here we report that ubiquitin-dependent MHCII turnover is critical to maintain homeostasis of lipid rafts and the tetraspanin web in DCs. Lack of MHCII ubiquitination results in the accumulation of excessive quantities of MHCII in the plasma membrane, and the resulting disruption to lipid rafts and the tetraspanin web leads to significant impairment in the ability of DCs to engage and activate thymocytes for Treg cell differentiation. Thus, ubiquitin-dependent MHCII turnover represents a novel quality-control mechanism by which DCs maintain homeostasis of membrane domains that support DC's Treg cell-selecting function

Molands- og Langangsvassdraget i Aust-Agder - næringsstofftilførsler, vannkvalitet, plankton og fiskebestander

Molands- og Langangsvassdraget er undersøkt i 1994-1996 mht. vannkvalitet, plankton, fiskebestander og næringssalttilførsler. I følge SFTs klassifiseringssystem må vannkvaliteten på de ulike stasjonene i vassdragene karakteriseres som "mindre god " til "dårlig" mht virkninger av næringssalter, "mindre god " til "nokså dårlig "mht. tarmbakterier, og "god " til "nokså dårlig" mht surhet. Sedimentene i Molandsvatn så ut til å ha meget høye konsentrasjoner av disykliske aromatiske hydrokarboner som er indikator på oljeforurensning. Det er beregnet en fosfortilførsel til Molandsvatn og Langangsvatn på hhv 730 og 1040 kg P/år. Av dette er bidraget fra landbruk og bebyggelse anslått til omkring 65%. De totale nitrogentilførslene er beregnet til 23,1 tonn for Molandsvatn og 32,7 tonn for Langangsvatn. Nitrogenbidraget fra lokale kilder er anslått til 40 %. Under elektrofiske i tilløpsbekker til Molandsvatn under tørrværsperioden i august 1995 ble det registrert fisk i Tveitebekken, Skjulestadbekken, Brekkeelva, Moenbekken og Våjebekken. Ved prøvefiske av Molandsvatn i september 1995 ble det fanget 6 aure, 821 tryte(abbor) og 49 suter. Det ble dermed fanget færre aure, men flere tryter (abbor) og suter enn ved prøvefisket i 1985/86.Arendal kommun

Conformation-selective rather than avidity-based binding to tumor associated antigen derived peptide-MHC enables targeting of WT1-pMHC low expressing cancer cells by anti-WT1-pMHC/CD3 T cell engagers

T cell engagers, a category of T cell-retargeting immunotherapy, are rapidly transforming clinical cancer care. However, the lack of tumor-specific targets poses a significant roadblock for broad adaptation of this therapeutic modality in many indications, often resulting in systemic on-target off-tumor toxicity. Though various tumor-derived intracellular mutations provide a massive pool of potential tumor-specific antigens, targeting them is extremely challenging, partly due to the low copy number of tumor associated antigen (TAA)-derived pMHC on tumor cell surface. Further, the interplay of binding geometry and format valency in relation to the capacity of a T cell engager to efficiently target low density cell-surface pMHC is not well understood. Using the Wilms’ tumor 1 (WT1) oncoprotein as a proof-of-principle TAA, combined with an array of IgG-like T cell engager modalities that differ in their anti-TAA valency and binding geometry, we show that the ability to induce an immunological synapse formation, resulting in potent killing of WT1 positive cancer cell lines is primarily dependent on the distinct geometrical conformations between the Fab arms of anti-WT1-HLA-A*02:01 and anti-CD3. The augmented avidity conferred by the binding of two anti-WT1-HLA-A*02:01 Fab arms has only minimal influence on cell killing potency. These findings demonstrate the need for careful examination of key design parameters for the development of next-generation T cell engagers targeting low density TAA-pMHCs on tumor cells

Territory location and quality, together with climate, affect the timing of breeding in the whitethroated dipper

Recent climate change has led to advanced spring phenology in many temperate regions. The phenological response to variation in the local environment, such as the habitat characteristics of the territories birds occupy, is less clear. The aim of this study is to understand how ecological conditions affect breeding time, and its consequences for reproduction, in a white-throated dipper Cinclus cinclus population in a river system in Norway during 34 years (1978–2011). Hatching date advanced almost nine days, indicating a response to higher temperatures and the advanced phenology in the area. Earlier breeding was found in warm springs and at lower altitudes. High population density facilitated earlier breeding close to the coast. Furthermore, when population density was low, breeding was early at territories that were rarely occupied, while in years with high density, breeding was early at territories that were frequently occupied. Also, when population density was low, earlier breeding occurred at territories that on average produced more offspring than other territories, while there was no difference in breeding time in high population years. Selection for early breeding was dependent on spring temperatures and high spring temperatures contributed to higher breeding success during the study period. We found that breeding phenology may have strong effects on fitness in the white-throated dipper, and thus that breeding time is an important ecological factor in a species that feeds mainly on aquatic rather than terrestrial prey.publishedVersio

Francisella tularensis Elicits IL-10 via a PGE2-Inducible Factor, to Drive Macrophage MARCH1 Expression and Class II Down-Regulation

Francisella tularensis is a bacterial pathogen that uses host-derived PGE2 to subvert the host's adaptive immune responses in multiple ways. Francisella-induced PGE2 acts directly on CD4 T cells to blunt production of IFN-γ. Francisella-induced PGE2 can also elicit production of a >10 kDa soluble host factor termed FTMØSN (F. tularensis macrophage supernatant), which acts on IFN-γ pre-activated MØ to down-regulate MHC class II expression via a ubiquitin-dependent mechanism, blocking antigen presentation to CD4 T cells. Here, we report that FTMØSN-induced down-regulation of MØ class II is the result of the induction of MARCH1, and that MØ expressing MARCH1 “resistant” class II molecules are resistant to FTMØSN-induced class II down-regulation. Since PGE2 can induce IL-10 production and IL-10 is the only reported cytokine able to induce MARCH1 expression in monocytes and dendritic cells, these findings suggested that IL-10 is the active factor in FTMØSN. However, use of IL-10 knockout MØ established that IL-10 is not the active factor in FTMØSN, but rather that Francisella-elicited PGE2 drives production of a >10 kDa host factor distinct from IL-10. This factor then drives MØ IL-10 production to induce MARCH1 expression and the resultant class II down-regulation. Since many human pathogens such as Salmonella typhi, Mycobacterium tuberculosis and Legionella pneumophila also induce production of host PGE2, these results suggest that a yet-to-be-identified PGE2-inducible host factor capable of inducing IL-10 is central to the immune evasion mechanisms of multiple important human pathogens

Climate change and Saharan dust drive recent cladoceran and primary production changes in remote alpine lakes of Sierra Nevada, Spain

Recent anthropogenic climate change and the exponential increase over the past few decades of Saharan dust deposition, containing ecologically important inputs of phosphorus (P) and calcium (Ca), are potentially affecting remote aquatic ecosystems. In this study, we examine changes in cladoceran assemblage composition and chlorophyll-a concentrations over the past ~150 years from high-resolution, welldated sediment cores retrieved from six remote high mountain lakes in the Sierra Nevada Mountains of Southern Spain, a region affected by Saharan dust deposition. In each lake, marked shifts in cladoceran assemblages and chlorophyll-a concentrations in recent decades indicate a regional-scale response to climate and Saharan dust deposition. Chlorophyll-a concentrations have increased since the 1970s, consistent with a response to rising air temperatures and the intensification of atmospheric deposition of Saharan P. Similar shifts in cladoceran taxa across lakes began over a century ago, but have intensified over the past ~50 years, concurrent with trends in regional air temperature, precipitation, and increased Saharan dust deposition. An abrupt increase in the relative abundance of the benthic cladoceran Alona quadrangularis at the expense of Chydorus sphaericus, and a significant increase in Daphnia pulex gr. was a common trend in these softwater lakes. Differences in the magnitude and timing of these changes are likely due to catchment and lake-specific differences. In contrast with other alpine lakes that are often affected by acid deposition, atmospheric Ca deposition appears to be a significant explanatory factor, among others, for the changes in the lake biota of Sierra Nevada that has not been previously considered. The effects observed in Sierra Nevada are likely occurring in other Mediterranean lake districts, especially in softwater, oligotrophic lakes. The predicted increases in global temperature and Saharan dust deposition in the future will further impact the ecological condition of these ecosystemsMinisterio de Educación y Ciencia (MEC), Grant/Award Number: AP2007-00352; Programa Nacional de Movilidad de Recursos Humanos de Investigaci on (MICINN); Ministerio de Medio Ambiente (MMA), Grant/Award Number: 87/2007; Ministerio de Econom ıa, Industria y Competitividad (MINECO), Grant/Award Number: CGL2011-23483; Natural Sciences and Engineering Research Council of Canad