In the era of precision medicine, digital technologies and artificial intelligence, drug discovery and development face unprecedented opportunities for product and business model innovation, ...fundamentally changing the traditional approach of how drugs are discovered, developed and marketed. Critical to this transformation is the adoption of new technologies in the drug development process, catalyzing the transition from serendipity-driven to data-driven medicine. This paradigm shift comes with a need for both translation and precision, leading to a modern Translational Precision Medicine approach to drug discovery and development. Key components of Translational Precision Medicine are multi-omics profiling, digital biomarkers, model-based data integration, artificial intelligence, biomarker-guided trial designs and patient-centric companion diagnostics. In this review, we summarize and critically discuss the potential and challenges of Translational Precision Medicine from a cross-industry perspective.
In the recent years, many protocols aimed at reproducibly sequencing reduced-genome subsets in non-model organisms have been published. Among them, RAD-sequencing is one of the most widely used. It ...relies on digesting DNA with specific restriction enzymes and performing size selection on the resulting fragments. Despite its acknowledged utility, this method is of limited use with degraded DNA samples, such as those isolated from museum specimens, as these samples are less likely to harbor fragments long enough to comprise two restriction sites making possible ligation of the adapter sequences (in the case of double-digest RAD) or performing size selection of the resulting fragments (in the case of single-digest RAD). Here, we address these limitations by presenting a novel method called hybridization RAD (hyRAD). In this approach, biotinylated RAD fragments, covering a random fraction of the genome, are used as baits for capturing homologous fragments from genomic shotgun sequencing libraries. This simple and cost-effective approach allows sequencing of orthologous loci even from highly degraded DNA samples, opening new avenues of research in the field of museum genomics. Not relying on the restriction site presence, it improves among-sample loci coverage. In a trial study, hyRAD allowed us to obtain a large set of orthologous loci from fresh and museum samples from a non-model butterfly species, with a high proportion of single nucleotide polymorphisms present in all eight analyzed specimens, including 58-year-old museum samples. The utility of the method was further validated using 49 museum and fresh samples of a Palearctic grasshopper species for which the spatial genetic structure was previously assessed using mtDNA amplicons. The application of the method is eventually discussed in a wider context. As it does not rely on the restriction site presence, it is therefore not sensitive to among-sample loci polymorphisms in the restriction sites that usually causes loci dropout. This should enable the application of hyRAD to analyses at broader evolutionary scales.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Why generalist and specialist species coexist in nature is a question that has interested evolutionary biologists for a long time. While the coexistence of specialists and generalists exploiting ...resources on a single ecological dimension has been theoretically and empirically explored, biological systems with multiple resource dimensions (e.g. trophic, ecological) are less well understood. Yet, such systems may provide an alternative to the classical theory of stable evolutionary coexistence of generalist and specialist species on a single resource dimension. We explore such systems and the potential trade-offs between different resource dimensions in clownfishes. All species of this iconic clade are obligate mutualists with sea anemones yet show interspecific variation in anemone host specificity. Moreover, clownfishes developed variable environmental specialization across their distribution. In this study, we test for the existence of a relationship between host-specificity (number of anemones associated with a clownfish species) and environmental-specificity (expressed as the size of the ecological niche breadth across climatic gradients). We find a negative correlation between host range and environmental specificities in temperature, salinity and pH, probably indicating a trade-off between both types of specialization forcing species to specialize only in a single direction. Trade-offs in a multi-dimensional resource space could be a novel way of explaining the coexistence of generalist and specialists.
Protection of large natural forest landscapes is a highly important task to help fulfill different international strategic initiatives to protect forest biodiversity, to reduce carbon emissions from ...deforestation and forest degradation, and to stimulate sustainable forest management practices. This paper introduces a new approach for mapping large intact forest landscapes (IFL), defined as an unbroken expanse of natural ecosystems within areas of current forest extent, without signs of significant human activity, and having an area of at least 500 km2. We have created a global IFL map using existing fine-scale maps and a global coverage of high spatial resolution satellite imagery. We estimate the global area of IFL within the current extent of forest ecosystems (forest zone) to be 13.1 million km² or 23.5% of the forest zone. The vast majority of IFL are found in two biomes: Dense Tropical and Subtropical Forests (45.3%) and Boreal Forests (43.8%). The lowest proportion of IFL is found in Temperate Broadleaf and Mixed Forests. The IFL exist in 66 of the 149 countries that together make up the forest zone. Three of them—Canada, Russia, and Brazil—contain 63.8% of the total IFL area. Of the world’s IFL area, 18.9% has some form of protection, but only 9.7% is strictly protected, i.e., belongs to IUCN protected areas categories I–III. The world IFL map presented here is intended to underpin the development of a general strategy for nature conservation at the global and regional scales. It also defines a baseline for monitoring deforestation and forest degradation that is well suited for use with operational and cost-effective satellite data. All project results and IFL maps are available on a dedicated web site (http://www.intactforests.org).
The pathogenesis and clinical heterogeneity of Parkinson's disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of ...cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into "endotypes". The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.
Transdiscourse as a Concept of Digital Worlds Kostikova, Anna A.; Spartak, Sergey A.
Vestnik Rossiĭskogo universiteta druzhby narodov. Serii͡a︡ Literaturovedenie, zhurnalistika,
12/2021, Letnik:
26, Številka:
4
Journal Article
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The paper presents the current transformations of media culture in the conditions of crucial digitalization of society. Everyday life is fundamentally mediatized and this process is beyond the ...control and understanding, both by an individual, and by the professional community and society as a whole. Rather, we observe a general disturbing sense of violation of the usual boundaries of definitions and norms. In response to the crisis of comprehension and understanding, philosophy of language and communication turns back to the idea of discursivity of human civilization and proposes to adapt and rethink the concept of possible worlds and its descriptions in the aim to renew social strategies and communications. The increasing demand for methodological support of communication activities indicates the growing significance of cabinet philosophy, in particular philosophy of language and communication. This strategy of the scientific approach will allow us to build a research relevant to the subject-transdisciplinary. Based on an analysis of history of ideas and modern Russian methodology of transdisciplinarity, the authors put forward a hypothesis in terms of the philosophy of language on the development of digital mediated discourse in a transdimensional unity and the generation of different discourses.
AIM: Macroevolutionary patterns and processes change substantially depending on levels of taxonomic and ecological organization, and the resolution of environmental and spatial variability. In ...comparative methods, the resolution of environmental and spatial variability often defines the number of selective regimes used to test whether phenotypic characteristics are adaptively correlated with the environment. Here, we examine how investigator choice of the number of selective regimes, determined by varying the resolution of among‐species variability in the species climatic niche (hereafter called ‘ecological scale’), influences trait morphological diversification among Eriogonoideae species. We assess whether adaptive or neutral processes drive the evolution of several morphological traits in these species. LOCATION: South‐western North America. METHODS: We applied a phylogenetic framework of three evolutionary models to four morphological traits and the climatic niches of Eriogonoideae (in the buckwheat family, Polygonaceae). We tested whether morphological traits evolve in relation to climate by adaptive or neutral process, and whether the resulting patterns of morphological variability are conserved or convergent across the clade. We inspected adaptive models of evolution under different levels of resolution of among‐species variability of the climatic niche. RESULTS: We show that morphological traits and climate niches of Eriogonoideae species are not phylogenetically conserved. Further, adaptive evolution of phenotypic traits is specific to climatic niche occupancy across this clade. Finally, the likely evolutionary process and the level of detectable niche conservatism change depending on the resolution of environmental variability of the climatic niche. MAIN CONCLUSIONS: Our study demonstrates the need to consider both the resolution of environmental variability and alternative evolutionary models to understand the morphological diversification that accompanies divergent adaptive evolution of lineages to climatic conditions.
Understanding the variations in the rate of molecular evolution among lineages may provide clues on the processes that molded extant biodiversity. Here, we report the high rate of molecular evolution ...in Lycaenidae and Riodinidae compared to other families of butterflies (Papilionoidea). We assembled a phylogeny of butterflies using eight molecular markers and comprising 4,891 species. We found that the rate of molecular evolution is higher in Lycaenidae and Riodinidae compared to the other families, but only the nuclear protein coding sequence Wingless showed a marked difference, while Elongation factor 1-alpha showed a more moderate difference. In contrast, Cytochrome Oxidase subunit 1 showed no difference between Lyacenidae and Riodinidae, and other butterflies. In parallel, we calculated the rates of diversification in all subfamilies of the Papilionoidea using the method-of-moments estimator for stem-group ages, which does not require a fully solved phylogeny for the target clades. We found that the Lycaeninae lineage, from the Lycaenidae family had the highest rate of diversification among all lineages. Among the life-history traits that could explain differences in molecular evolution and diversification rate, lycaenids display mutualistic or antagonistic interactions with ants, a higher level of host plant specialization and reduced dispersal abilities compared to other butterfly families. Since the current study is limited by a unique contrast, the relationship with traits cannot be evaluated statistically. Future studies should measure myrmecophily and dispersal abilities quantitatively across a more detailed phylogeny of lycaenids to test for an association between shifts in the strength of mutualism, rates of molecular evolution and the diversification of lineages.
The evolution of organisms is crucially dependent on the evolution of intraspecific variation. Its interactions with selective agents in the biotic and abiotic environments underlie many processes, ...such as intraspecific competition, resource partitioning and, eventually, species formation. Nevertheless, comparative models of trait evolution neither allow explicit testing of hypotheses related to the evolution of intraspecific variation nor do they simultaneously estimate rates of trait evolution by accounting for both trait mean and variance. Here, we present a model of phenotypic trait evolution using a hierarchical Bayesian approach that simultaneously incorporates interspecific and intraspecific variation. We assume that species-specific trait means evolve under a simple Brownian motion process, whereas species-specific trait variances are modeled with Brownian or Ornstein-Uhlenbeck processes. After evaluating the power of the method through simulations, we examine whether life-history traits impact evolution of intraspecific variation in the Eriogonoideae (buckwheat family, Polygonaceae). Our model is readily extendible to more complex scenarios of the evolution of inter-and intraspecific variation and presents a step toward more comprehensive comparative models for macroevolutionary studies.
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Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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