Insights into Transcriptional Regulation by Individual H3K4 Methylation Marks in S. Cerevisiae

Set1 is a lysine methyltransferase in S. cerevisiae that catalyzes the mono, di and tri methylation of the fourth lysine on the amino terminal tail of histone H3 (H3K4). Set1-like methyltransferases are evolutionarily conserved, and research has linked their function to developmental gene regulation and several cancers in higher eukaryotes. Set1 is a member of the multiprotein COMPASS complex in S. cerevisiae. The H3K4 methylation activity of COMPASS regulates gene expression and chromosome segregation in vivo. The three distinct methyl marks on histone H3K4 act in discrete ways to regulate transcription. Trimethylation of H3K4 is usually associated with active transcription whereas dimethylation of H3K4 is associated with gene repression. In this study, amino acid substitution mutants of SET1 that encode partial function Set1 proteins capable of H3K4me1, H3K4me1 and H3K4me2, or H3K4me1and H3K4me3 were analyzed to learn more about the roles of individual H3K4 methyl marks in transcription. The findings reveal a previously unappreciated role for H3K4me1 in activation of transcription of the HIS3 gene in S. cerevisiae cultures grown under histidine-starvation conditions. Surprisingly, induction of the HIS3 gene in cultures grown under histidine starvation is not accompanied by significant changes in the profiles of H3K4-methylated nucleosomes at the HIS3 gene in SET1 wild-type strains and set1 partial-function mutants. The data show that H3K4me1 supports induction of HIS3 mRNA to wild-type levels under histidine-starvation conditions and that higher-order H3K4 methylation (H3K4me2 and H3K4me3) is not required.

All Classical Adversary Methods Are Equivalent for Total Functions

We show that all known classical adversary lower bounds on randomized query complexity are equivalent for total functions and are equal to the fractional block sensitivity fbs( f ). That includes the Kolmogorov complexity bound of Laplante and Magniez and the earlier relational adversary bound of Aaronson. This equivalence also implies that for total functions, the relational adversary is equivalent to a simpler lower bound, which we call rank-1 relational adversary. For partial functions, we show unbounded separations between fbs( f ) and other adversary bounds, as well as between the adversary bounds themselves. We also show that, for partial functions, fractional block sensitivity cannot give lower bounds larger than √ n ⋅ bs( f ), where n is the number of variables and bs( f ) is the block sensitivity. Then, we exhibit a partial function f that matches this upper bound, fbs( f ) = Ω (√ n ⋅ bs( f )).

Using desirability functions when making managerial decisions in the mineral resource complex

Relevance. The ever-growing flows of information, tight deadlines for decision-making, the need to maintain competitive positions require ranking calculations to identify leaders and promote leadership factors, ranking units of business entities according to selected criteria, etc. Reliability, visualization, and often acceleration of obtaining results predetermine the appeal to mathematical techniques. Purpose of the study: substantiation of choice of the most acceptable option of the desirability function for use in the process of making managerial decisions related to the development of subsoil resources. Research method: comparative analysis of options for calculating the desirability function, comparison method, methods of mathematical statistics. Results. Two options for calculating the desirability function are considered. The first one developed by E. Harrington, who proposed a special verbal-numerical scale, which made it possible to formalize the system of preferences of different experts. The partial function of desirability, in this case, is constructed so that it is close to "satisfactory" linear one. According to recommendations, the lower and upper boundaries of “satisfactorily” correspond to the minimum and maximum values of indicators for the available data array. There is a slightly different approach to the determination of the partial function of desirability described in a number of works. The generalized desirability function is a convolution of particular functions and is defined as the geometric mean or logarithmic mean. It is possible to use weighting factors with different significance of particular desirability functions. Comparison of various approaches is made for the conditions of management of logistics and equipment of OOO Gazpromtransgaz-Yekaterinburg. An analysis of the results shows that despite discreteness of the particular desirability functions, which in the first case lie in the range from 0.37 to 0.69, and give the entire range of values from 0 to 1 in the second one, the ratings for the generalized desirability function completely coincide with regard to determining a rating of quarterly values of industrial and economic activity. It follows that both methods of calculating partial functions are legitimate, however, the first option seems more convenient technically due to the absence of values of partial desirability functions close to zero, which complicate calculations using computer technology. A third version of the rating was also tested using calculated percentage estimates of the indicators under consideration with respect to the maximum desired value (taking into account their conversion into the relative indices). As in previous cases, the rating of countries according to the generalized function of desirability turned out to be comparable with previously calculated. Conclusions. Comparative calculations confirmed the validity of both options for finding particular desirability functions, since the ratings for the generalized desirability function coincide. The first version of the calculation is more convenient due to the lack of values of particular desirability functions close to zero, which simplifies the use of computer technology

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for therapeutic development. The observation that the Phe508del-CFTR mutant protein is temperature sensitive provided proof of principle that mutant CFTR could escape proteosomal degradation and retain partial function. Several specific protein interactors and quality control checkpoints encountered by CFTR during its proteostasis have been investigated for therapeutic purposes, but remain incompletely understood. Furthermore, pharmacological manipulation of many CFTR interactors has not been thoroughly investigated for the rescue of Phe508del-CFTR. However, high-throughput screening technologies helped identify several small molecule modulators that rescue CFTR from proteosomal degradation and restore partial function to the protein. Here, we discuss the current state of CFTR transcriptomic and biogenesis research and small molecule therapy development. We also review recent progress in CFTR proteostasis modulators and discuss how such treatments could complement current FDA-approved small molecules.

Insufficient Effort Responding as a Partial Function of Implicit Aggression

In recent years, researchers have devoted greater attention to insufficient effort responding (IER), in which participants fail to attend to instructions, do not read item content carefully, or intentionally engage in random responding. While IER is typically considered a purely methodological concern, recent research has begun to examine whether it also has a substantive basis (e.g., personality). Here we extend the nomological network surrounding IER by examining the role of implicit aggression. In three studies, we demonstrate that higher levels of implicit aggression are indeed related to IER even after controlling for previously established correlates of IER. Furthermore, we also demonstrate that IER, as measured by the selection of illogical responses to Conditional Reasoning Tests of Aggression, can predict theoretically relevant behavioral criteria. The theoretical and practical implications of this work are discussed.

On Algebras of Algorithms and Specifications over Uninterpreted Data

Summary This paper continues formalization in Mizar [2, 1] of basic notions of the composition-nominative approach to program semantics [13] which was started in [8, 11]. The composition-nominative approach studies mathematical models of computer programs and data on various levels of abstraction and generality and provides tools for reasoning about their properties. Besides formalization of semantics of programs, certain elements of the composition-nominative approach were applied to abstract systems in a mathematical systems theory [4, 6, 7, 5, 3]. In the paper we introduce a definition of the notion of a binominative function over a set D understood as a partial function which maps elements of D to D. The sets of binominative functions and nominative predicates [11] over given sets form the carrier of the generalized Glushkov algorithmic algebra [14]. This algebra can be used to formalize algorithms which operate on various data structures (such as multidimensional arrays, lists, etc.) and reason about their properties. We formalize the operations of this algebra (also called compositions) which are valid over uninterpretated data and which include among others the sequential composition, the prediction composition, the branching composition, the monotone Floyd-Hoare composition, and the cycle composition. The details on formalization of nominative data and the operations of the algorithmic algebra over them are described in [10, 12, 9].

An Inference System of an Extension of Floyd-Hoare Logic for Partial Predicates

Summary In the paper we give a formalization in the Mizar system [2, 1] of the rules of an inference system for an extended Floyd-Hoare logic with partial pre- and post-conditions which was proposed in [7, 9]. The rules are formalized on the semantic level. The details of the approach used to implement this formalization are described in [5]. We formalize the notion of a semantic Floyd-Hoare triple (for an extended Floyd-Hoare logic with partial pre- and post-conditions) [5] which is a triple of a pre-condition represented by a partial predicate, a program, represented by a partial function which maps data to data, and a post-condition, represented by a partial predicate, which informally means that if the pre-condition on a program’s input data is defined and true, and the program’s output after a run on this data is defined (a program terminates successfully), and the post-condition is defined on the program’s output, then the post-condition is true. We formalize and prove the soundness of the rules of the inference system [9, 7] for such semantic Floyd-Hoare triples. For reasoning about sequential composition of programs and while loops we use the rules proposed in [3]. The formalized rules can be used for reasoning about sequential programs, and in particular, for sequential programs on nominative data [4]. Application of these rules often requires reasoning about partial predicates representing preand post-conditions which can be done using the formalized results on the Kleene algebra of partial predicates given in [8].