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Identification of regulatory elements is essential for understanding the mechanism behind regulating gene expression. These regulatory elements—located in or near gene—bind to proteins called transcription factors to initiate the transcription process. Their occurrences are influenced by the GC-content or nucleotide composition. For generating synthetic coding sequences with pre-specified amino acid sequence and desired GC-content, there exist two stochastic methods, multinomial and maximum entropy. Both methods rely on the probability of choosing the codon synonymous for usage in regard to a specific amino acid. In spite the latter exhibited unbiased manner, the produced sequences are not exactly obeying the GC-content constraint. In this paper, we present an algorithmic solution to produce coding sequences that follow exactly a primary amino acid sequence and a desired GC-content. The proposed tool, namely CodSeqGen, depends on random selection for smaller subsets to be traversed using the backtracking approach. • Generating random coding sequence is computationally expensive. • For proteins of length n , we need to test 6 n coding sequences to find those satisfying GC-content constraints. • CodSeqGen uses smart backtracking, and produces synonymous coding sequences with the exact desired GC-contents. • Experiments show CodSeqGen produces sequences with GC-contents that satisfy the constraints while NullSeq does not. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A 3D-QSAR model was produced for the FABP4 inhibitors. • A scaffold hopping suggested 3000 potentially active FABP4 inhibitors. • Three synthesized molecules have shown an IC 50 between 3.70 and 5.59 μM. Abstract Following on the recent publication of pharmacologically relevant effects, small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have attracted high interest. FABP4 is mainly expressed in macrophages and adipose tissue, where it regulates fatty acid storage and lipolysis, being also an important mediator of inflammation. In this regard, FABP4 recently demonstrated an interesting molecular target for the treatment of type 2 diabetes, other metabolic diseases and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized. In this paper, a quantitative structure-activity relationship (QSAR) model has been produced, in order to predict the bioactivity of FABP4 inhibitors. The methodology has been combined with a scaffold-hopping approach, allowing to identify three new molecules that act as effective inhibitors of this protein. These molecules, synthesized and tested for their FABP4 inhibitor activity, showed IC 50 values between 3.70 and 5.59 μM, with a high level of agreement with the predicted values. [ABSTRACT FROM AUTHOR]

Graphical abstract A series of oxadiazole-based S1P 1 direct-acting agonists, with high affinity for S1P 1 receptor and favorable selectivity against S1P 3 receptor was designed, synthesized and evaluated in vitro and vivo. Highlights • Oxadiazole-based derivatives were designed and progressively modified as S1P 1 agonists. • The agonism activities of compounds for S1P 1 and S1P 3 receptor were evaluated. • Most compounds show excellent activity and selectivity, particularly for 16-3b and 16 - 3g. • In vivo pharmacological, pharmacokinetics and druggability profiles were studied. • The binding mode between 16-3b and the activated S1P 1 model was also reviewed. Abstract Agonism of S1P 1 receptor has been proven to be responsible for peripheral blood lymphopenia and elicts the identification of various S1P 1 modulators. In this paper we described a series of oxadiazole-based S1P 1 direct-acting agonists disubstituted on terminal benzene ring, with high potency for S1P 1 receptor and favorable selectivity against S1P 3 receptor. In addition, two representative agents named 16-3b and 16 - 3g demonstrated impressive efficacy in lymphocyte reduction along with reduced effect on heart rate when orally administered. Furthermore, these compounds have been shown to possess desired pharmacokinetic (PK) and physicochemical profiles. The binding mode between 16 - 3b and the activated S1P 1 model was also studied. [ABSTRACT FROM AUTHOR]

The effect of N 2 H 4 (hydrazine) on AnAOB (anaerobic ammonia oxidizing bacteria) metabolic pattern is unknown. Therefore, the main purpose of this paper was to explore the effects of exogenous N 2 H 4 on the SAA (specific anammox activity), characteristics and metabolic pathway of AnAOB. The results showed that low N 2 H 4 concentration (1–5 mg/L) continuous dosing can promote SAA. The promoting effect was found to be more obvious within the dosage of 3–5 mg/L N 2 H 4. It was also indicated that high N 2 H 4 concentration dosing (5–10 mg/L) can trigger the self-protection mechanism of AnAOB granular sludge by secreting a large amount of B-PN (binding polymeric protein). Intermittent addition of N 2 H 4 at low concentration is conducive to the long-term stable operation of anammox process. Exogenous N 2 H 4 can be directly oxidized by AnAOB to promote the consumption of NO 2 −-N and NH 4 +-N. In addition, excess electrons can also drive the process of NO 3 −-N reduction and NO 2 −-N disproportionation. Theoretically, these reaction processes need two and ten extra electrons respectively, which is not easy to occur compared with the anammox process. [Display omitted] • High N 2 H 4 concentration triggered excessive secretion of binding polymeric protein. • The oxidation of N 2 H 4 enhanced the nitrite reduction and anammox process. • N 2 H 4 drive the nitrate reduction and nitrite disproportionation process. • Low-frequency supplement of N 2 H 4 was beneficial for anammox stable operation. [ABSTRACT FROM AUTHOR]

Each phage infects its specific bacterial host strain through highly specific interactions between the baseplate-associated receptor binding protein (RBP) at the tip of the phage tail and the receptor at the host surface. Baseplates incorporate structural core modules, Dit and Tal, largely conserved among phages, and peripheral modules anchoring the RBPs. Exploiting structural information from the HHpred program and EM data from the Bielmann et al. (2015) paper, a molecular model of the A118 phage baseplate was generated from different building blocks. This model implies the occurrence of baseplate module reshuffling and suggests that listerial phage A118 may have been derived from lactococcal phage TP901-1 through host species exchange. With the increase of available viral module structures, modelling phage baseplates will become easier and more reliant, and will provide insightful information on the nature of the phage host receptor and its mode of recognition. [ABSTRACT FROM AUTHOR]

Abstract: Positive-stranded RNA viruses subvert subcellular membranes to built viral replicases complexes (VRCs) in infected cells. Tombusviruses use peroxisomal membranes for the assembly of their VRCs and they can efficiently switch to the endoplasmic reticulum membrane in the absence of peroxisomes. In this paper, we show that the ER-resident Sec39p vesicular transport protein is critical for the formation of active VRCs in yeast model host. Repression of Sec39p expression in yeast or in plants resulted in greatly reduced tombusvirus accumulation. Moreover, the purified tombusvirus replicase from Sec39p-depleted yeast cells showed low in vitro activity. Also, tombusvirus RNA replication was poor in cell-free extracts or in isolated ER membranes from yeast with repressed Sec39p expression. The tombusvirus p33 replication protein was mislocalized to the ER when Sec39p was depleted in yeast. Overall, Sec39p is the first peroxisomal biogenesis protein characterized that is critical for tombusvirus replication in yeast and plants. [Copyright &y& Elsevier]

Abstract: The ARID is an ancient DNA-binding domain that is conserved throughout the evolution of higher eukaryotes. The ARID consensus sequence spans about 100 amino acid residues, and structural studies identify the major groove contact site as a modified helix-turn-helix motif. ARID-containing proteins exhibit a range of cellular functions, including participation in chromatin remodeling, and regulation of gene expression during cell growth, differentiation, and development. A subset of ARID family proteins binds DNA specifically at AT-rich sites; the remainder bind DNA nonspecifically. Orthologs to each of the seven distinct subfamilies of mammalian ARID-containing proteins are found in insect genomes, indicating the minimum age for the organization of these higher metazoan subfamilies. Many of these ancestral genes were duplicated and fixed over time to yield the 15 ARID-containing genes that are found in the human, mouse, and dog genomes. This paper describes a nomenclature, recommended by the Mouse Genomic Nomenclature Committee (MGNC) and accepted by the Human Genome Organization (HUGO) Gene Nomenclature Committee, for these mammalian ARID-containing genes that reflects this evolutionary history. [Copyright &y& Elsevier]