Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma

Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gαq/11 signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract or central nervous system. It is rare in melanomas arising in the epidermis. The mechanism for this specificity is unknown. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQQ209L oncogene. We found that GNAQQ209L, in combination with signaling from the interfollicular epidermis (IFE), stimulates dendrite extension, leads to actin cytoskeleton disorganization, inhibits proliferation and promotes apoptosis in melanocytes. The effect was reversible and paracrine. In contrast, the epidermal environment increased the survival of wildtype and BrafV600E expressing melanocytes. Hence, our studies reveal the flip side of Gaq/11 signaling, which was hitherto unsuspected. In the future, the identification of the epidermal signals that restrain the GNAQQ209L oncogene could suggest novel therapies for GNAQ and GNA11 mutant melanomas.

Redundant functions of the SLC5A transporters Rumpel, Bumpel, and Kumpel in ensheathing glial cells

Neuronal processing is energy demanding, and relies on sugar metabolism. To nurture the Drosophila nervous system, the blood-brain barrier forming glial cells take up trehalose from the hemolymph and then distribute the metabolic products further to all neurons. This function is provided by glucose and lactate transporters of the solute carrier (SLC) 5A family. Here we identified three SLC5A genes that are specifically expressed in overlapping sets of CNS glial cells, rumpel, bumpel and kumpel. We generated mutants in all genes and all mutants are viable and fertile, lacking discernible phenotypes. Loss of rumpel causes subtle locomotor phenotypes and flies display increased daytime sleep. In addition, in bumpel kumpel double mutants, and to an even greater extent in rumpel bumpel kumpel triple mutants, oogenesis is disrupted at the onset of the vitollegenic phase. This indicates a partially redundant functions between these genes. Rescue experiments exploring this effect indicate that oogenesis can be affected by CNS glial cells. Moreover, expression of heterologous mammalian SLC5A transporters, with known transport properties, suggest that Bumpel and/or Kumpel transport glucose or lactate. Overall, our results imply a redundancy in SLC5A nutrient sensing functions in Drosophila glial cells, affecting ovarian development and behavior.

Testing the agreement of trees with internal labels

Background A semi-labeled tree is a tree where all leaves as well as, possibly, some internal nodes are labeled with taxa. Semi-labeled trees encompass ordinary phylogenetic trees and taxonomies. Suppose we are given a collection $${\mathcal {P}}= \{{\mathcal {T}}_1, {\mathcal {T}}_2, \ldots , {\mathcal {T}}_k\}$$ P = { T 1 , T 2 , … , T k } of semi-labeled trees, called input trees, over partially overlapping sets of taxa. The agreement problem asks whether there exists a tree $${\mathcal {T}}$$ T , called an agreement tree, whose taxon set is the union of the taxon sets of the input trees such that the restriction of $${\mathcal {T}}$$ T to the taxon set of $${\mathcal {T}}_i$$ T i is isomorphic to $${\mathcal {T}}_i$$ T i , for each $$i \in \{1, 2, \ldots , k\}$$ i ∈ { 1 , 2 , … , k } . The agreement problems is a special case of the supertree problem, the problem of synthesizing a collection of phylogenetic trees with partially overlapping taxon sets into a single supertree that represents the information in the input trees. An obstacle to building large phylogenetic supertrees is the limited amount of taxonomic overlap among the phylogenetic studies from which the input trees are obtained. Incorporating taxonomies into supertree analyses can alleviate this issue. Results We give a $${\mathcal {O}}(n k (\sum _{i \in [k]} d_i + \log ^2(nk)))$$ O ( n k ( ∑ i ∈ [ k ] d i + log 2 ( n k ) ) ) algorithm for the agreement problem, where n is the total number of distinct taxa in $${\mathcal {P}}$$ P , k is the number of trees in $${\mathcal {P}}$$ P , and $$d_i$$ d i is the maximum number of children of a node in $${\mathcal {T}}_i$$ T i . Conclusion Our algorithm can aid in integrating taxonomies into supertree analyses. Our computational experience with the algorithm suggests that its performance in practice is much better than its worst-case bound indicates.

On the influence of template size, canonicalization and exclusivity for retrosynthesis and reaction prediction applications

Heuristic and machine learning models for rank-ordering reaction templates comprise an important basis for computer-aided organic synthesis regarding both product prediction and retrosynthetic pathway planning. Their viability relies heavily on the quality and characteristics of the underlying template database. With the advent of automated reaction and template extraction software and consequently the creation of template databases too large to be curated manually, a data-driven approach to assess and improve the quality of template sets is needed. We therefore systematically studied the influence of template generality, canonicalization and exclusivity on the performance of different template ranking models. We find that duplicate and non-exclusive templates, \textit{i.e.} templates which describe the same chemical transformation on identical or overlapping sets of molecules, decrease both the accuracy of the ranking algorithm and the applicability of the respective top-ranked templates significantly. To remedy the negative effects of non-exclusivity, we developed a general and computationally efficient framework to deduplicate and hierarchically correct templates. As a result, performance improved for both heuristic and machine learning template ranking algorithms across different template sizes. The canonicalization and correction code was made freely available.

Statistical relationships between the rule-making activity of state bodies in Russia

The article provides the analysis of the relationship between the rule-making activity of Russia’s state authorities: parliament, president, government and federal executive bodies. The analysis of Granger causality, carried out for statistical series of federal authorities rulemaking activity, indicates that the level of laws specification largely determines the level of by-laws specification (government decrees and orders of federal executive bodies), thereby exerting a significant impact on entire Russian regulatory framework volume. Econometric analysis based on a corpus of federal laws and aggregated corpus of regulations shows that the entire rule-making activity of the Russian parliament and federal authorities is explained by overlapping sets of factors. The findings indicate that to consolidate the effect of the “regulatory guillotine” it may be useful to develop mechanisms (procedural rules) that correct the balance between the pace and quality of developing legislative initiatives.

Statistical relationships between the rule-making activity of state bodies in Russia

The article provides the analysis of the relationship between the rule-making activity of Russia’s state authorities: parliament, president, government and federal executive bodies. The analysis of Granger causality, carried out for statistical series of federal authorities rulemaking activity, indicates that the level of laws specification largely determines the level of by-laws specification (government decrees and orders of federal executive bodies), thereby exerting a significant impact on entire Russian regulatory framework volume. Econometric analysis based on a corpus of federal laws and aggregated corpus of regulations shows that the entire rule-making activity of the Russian parliament and federal authorities is explained by overlapping sets of factors. The findings indicate that to consolidate the effect of the “regulatory guillotine” it may be useful to develop mechanisms (procedural rules) that correct the balance between the pace and quality of developing legislative initiatives.

Comparative evolution of vegetative branching in sorghum

Tillering and secondary branching are two plastic traits with high agronomic importance, especially in terms of the ability of plants to adapt to changing environments. We describe a quantitative trait analysis of tillering and secondary branching in two novel BC1F2 populations totaling 246 genotypes derived from backcrossing two Sorghum bicolor x S. halepense F1 plants to a tetraploidized S. bicolor. A two-year, two-environment phenotypic evaluation in Bogart, GA and Salina, KS permitted us to identify major effect and environment specific QTLs. Significant correlation between tillering and secondary branching followed by discovery of overlapping sets of QTLs continue to support the developmental relationship between these two organs and suggest the possibility of pleiotropy. Comparisons with two other populations sharing S. bicolor BTx623 as a common parent but sampling the breadth of the Sorghum genus, increase confidence in QTL detected for these two plastic traits and provide insight into the evolution of morphological diversity in the Eusorghum clade. Correspondence between flowering time and vegetative branching supports other evidence in suggesting a pleiotropic effect of flowering genes. We propose a model to predict biomass weight from plant architecture related traits, quantifying contribution of each trait to biomass and providing guidance for future breeding experiments.

Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma

Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gαq/11 signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract or central nervous system. It is rare in melanomas arising in the epidermis. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQQ209L oncogene, providing a new model for oncogene specificity in cancer. The presence of epidermal cells inhibited cell division and fragmented dendrites of melanocytes expressing GNAQQ209L in culture, while they promoted the growth of normal melanocytes. Differential gene expression analysis of FACS sorted epidermal melanocytes showed that cells expressing GNAQQ209L exhibit an oxidative stress and apoptosis signature previously linked to vitiligo. Furthermore, PLCB4, the direct downstream effector of Gαq/11 signaling, is frequently mutated in cutaneous melanoma alongside P53 and NF1. Our results suggest that a deficiency of PLCB4 promotes cutaneous melanomagenesis by reducing GNAQ driven signaling. Hence, our studies reveal the flip side of the GNAQ/PLCB4 signaling pathway, which was hitherto unsuspected. In the future, understanding how epidermal crosstalk restrains the GNAQQ209L oncogene could suggest novel melanoma therapies.

Mite communities (Acari: Mesostigmata, Oribatida) in the red belt conk, Fomitopsis pinicola (Polyporales), in Polish forests

The fruiting bodies of bracket fungi are a specific microhabitat colonized by various invertebrates of which mites (Acari) are rarely studied, and if they are, the study is usually faunistic. The aim of the research was to determine whether the diversification of mite assemblages (Mesostigmata, Oribatida) inhabiting the fruiting bodies of Fomitopsis pinicola (Sw.) P. Karst. (Polyporales) are connected with the character of the forests and/or the degree of decay (DD) of the fruiting bodies. The research was conducted at Białowieża National Park (BNP), in forests close to natural ones and in Karkonosze National Park (KNP) which was affected by a large-scale forest dieback in the 1980s. Eighty fruiting bodies (40 at each study site) of F. pinicola belonging to four DD categories were collected. In total, 4,345 individuals of 120 mite species were recorded at BNP, and 13,912 individuals of 96 species were recorded at KNP. Analyses revealed that the sample dispersion at each study site was comparable, nevertheless the samples from each study site were clearly grouped into slightly overlapping sets which allow observation of the differences between them. In the less decayed fungi (DD 1 and 2) there were fewer mite species and individual mites than in the more decayed samples (DD 3 and 4). There were also significant differences between the fauna of the fungi in each particular DD: the fauna of DD 1 differed from all others, whereas the fauna of heavily decayed fungi (DD 3 and 4) was more comparable.

Legal Aspects of Adaptation Finance under the UNFCCC Regime with Special Reference to the Adaptation Fund

This article addresses the legal aspects of the financing of adaptation to climate change, with special consideration given to one of the climate funds – the Adaptation Fund (AF). In the complex structure of climate finance, the AF attracts attention as it differs from other funds in several aspects. As an exception from other United Nations (UNs) climate funds, AF has not been recognised as an operating entity of the Financial Mechanism of the Convention. AF is also an unprecedented example under the Convention of a fund serving in parallel two decision-making bodies (CMP and CMA) under two agreements (Kyoto Protocol and Paris Agreement) ratified by non-overlapping sets of parties; with a Fund Board elected by both bodies collectively. AFs funding source is specific, it was designed to be financed from shares of the proceeds of sales of certified emission reduction units (CERs) generated by Clean Development Mechanism (CDM) projects but since 2012 there is a limited possibility of offsetting the emissions with CERs under the EU emissions trading system (ETS). For several years Parties were unable to agree the operating principles and procedures of a new mechanism established in article 6(4) of the Paris Agreement, which will resemble CDM, and would constitute a source of funding for the AF. Once this source of funding is available, the AF would cease to serve the Kyoto Protocol. Despite the above problems, AF was seen as a good example of how future climate funding can be designed. We examine the evolution of the above legal problems, including the most recent decisions and conclusions adopted during Conference of Parties (COP)25 in Madrid.