Oligonucleotides Featuring a Covalently Mercurated 6-Phenylcarbazole Residue as High-Affinity Hybridization Probes for Thiopyrimidine-Containing Sequences

Short oligonucleotides incorporating either 1-mercuri-6-phenylcarbazole, 8-mercuri-6-phenylcarbazole, or 1,8-dimercuri-6-phenylcarbazole C-nucleoside in the middle of the chain have been synthesized and studied for their potential as hybridization probes for sequences containing thiopyrimidine nucleobases. All of these oligonucleotides formed very stable duplexes with complementary sequences pairing the organometallic moiety with either 2- or 4-thiothymine. The isomeric monomercurated oligonucleotides were also able to discriminate between 2- and 4-thiothymine based on the different melting temperatures of the respective duplexes. DFT-optimized structures of the most stable mononuclear Hg-II-mediated base pairs featured a coordinated covalent bond between Hg-II and either S2 or S4 and a hydrogen bond between the carbazole nitrogen and N3. The dinuclear Hg-II-mediated base pairs, in turn, were geometrically very similar to the one previously reported to form between 1,8-dimercuri-6-phenylcarbazole and thymine and had one Hg-II ion coordinated to a thio and the other one to an oxo substituent

DESIGN AND PERFORMANCE ANALYSIS OF FULL ADDER USING 6-T XOR–XNOR CELL

In this paper, the design and simulation of a high-speed, low power 6-T XOR-XNOR circuit is carried out. Also, the design and simulation of 1-bit hybrid full adder (consisting of 16 transistors) using XOR-XNOR circuit, sum, and carry, is performed to improve the area and speed performance. Its performance is being compared with full adder designs with 20 and 18 transistors, respectively. The performance of the proposed circuits is measured by simulating them in Microwind tool using 180 and 90nm CMOS technology. The performance of the proposed circuit is measured in terms of power, delay, and PDP (Power Delay Product)

Nanomagnet-facilitated pharmaco-compatibility for cancer diagnostics: Underlying risks and the emergence of ultrasmall nanomagnets

Article summarizes various progressive aspects of nanomagnets pertaining to their production with an emphasis on sustainable biomimetic approaches, particularly cancer therapy

Implications of Extreme Climatic Events on Marine Fisheries Sector

Implications of Extreme Climatic Events on Marine Fisheries Secto

The Lsm1-7/Pat1 complex binds to stress-activated mRNAs and modulates the response to hyperosmotic shock

RNA-binding proteins (RBPs) establish the cellular fate of a transcript, but an understanding of these processes has been limited by a lack of identified specific interactions between RNA and protein molecules. Using MS2 RNA tagging, we have purified proteins associated with individual mRNA species induced by osmotic stress, STL1 and GPD1. We found members of the Lsm1-7/Pat1 RBP complex to preferentially bind these mRNAs, relative to the non-stress induced mRNAs, HYP2 and ASH1. To assess the functional importance, we mutated components of the Lsm1-7/Pat1 RBP complex and analyzed the impact on expression of osmostress gene products. We observed a defect in global translation inhibition under osmotic stress in pat1 and lsm1 mutants, which correlated with an abnormally high association of both non-stress and stress-induced mRNAs to translationally active polysomes. Additionally, for stress-induced proteins normally triggered only by moderate or high osmostress, in the mutants the protein levels rose high already at weak hyperosmosis. Analysis of ribosome passage on mRNAs through co-translational decay from the 5' end (5P-Seq) showed increased ribosome accumulation in lsm1 and pat1 mutants upstream of the start codon. This effect was particularly strong for mRNAs induced under osmostress. Thus, our results indicate that, in addition to its role in degradation, the Lsm1-7/Pat1 complex acts as a selective translational repressor, having stronger effect over the translation initiation of heavily expressed mRNAs. Binding of the Lsm1-7/Pat1p complex to osmostress-induced mRNAs mitigates their translation, suppressing it in conditions of weak or no stress, and avoiding a hyperresponse when triggered

Rational Extension of the Ribosome Biogenesis Pathway Using Network-Guided Genetics

Gene networks are an efficient route for associating candidate genes with biological processes. Here, networks are used to discover more than 15 new genes for ribosomal subunit maturation, rRNA processing, and ribosomal export from the nucleus

A proteomics approach to decipher the molecular nature of planarian stem cells

Background In recent years, planaria have emerged as an important model system for research into stem cells and regeneration. Attention is focused on their unique stem cells, the neoblasts, which can differentiate into any cell type present in the adult organism. Sequencing of the Schmidtea mediterranea genome and some expressed sequence tag projects have generated extensive data on the genetic profile of these cells. However, little information is available on their protein dynamics. Results We developed a proteomic strategy to identify neoblast-specific proteins. Here we describe the method and discuss the results in comparison to the genomic high-throughput analyses carried out in planaria and to proteomic studies using other stem cell systems. We also show functional data for some of the candidate genes selected in our proteomic approach. Conclusions We have developed an accurate and reliable mass-spectra-based proteomics approach to complement previous genomic studies and to further achieve a more accurate understanding and description of the molecular and cellular processes related to the neoblasts

Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer

Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations. Understanding how these mutations impact on ER function is a prerequisite for identifying methods to treat breast cancer patients featuring such mutations. Towards this end, we used CRISPR-Cas9 genome editing to make a single allele knock-in of the most commonly mutated amino acid residue, tyrosine 537, in the estrogen-responsive MCF7 breast cancer cell line. Genomic analyses using RNA-seq and ER ChIP-seq demonstrated that the Y537S mutation promotes constitutive ER activity globally, resulting in estrogen-independent growth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen and fulvestrant. Further, we show that the basal transcription factor TFIIH is constitutively recruited by ER-Y537S, resulting in ligand-independent phosphorylation of Serine 118 (Ser118) by the TFIIH kinase, cyclin-dependent kinase (CDK)7. The CDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growth of MCF7-Y537S cells. These studies confirm the functional importance of ER mutations in endocrine resistance, demonstrate the utility of knock-in mutational models for investigating alternative therapeutic approaches and highlight CDK7 inhibition as a potential therapy for endocrine-resistant breast cancer mediated by ER mutations

The role of mammalian poly(A)-binding proteins in co-ordinating mRNA turnover

The function of cytoplasmic PABPs [poly(A)-binding proteins] in promoting mRNA translation has been intensively studied. However, PABPs also have less clearly defined functions in mRNA turnover including roles in default deadenylation, a major rate-limiting step in mRNA decay, as well as roles in the regulation of mRNA turnover by cis-acting control elements and in the detection of aberrant mRNA transcripts. In the present paper, we review our current understanding of the complex roles of PABP1 in mRNA turnover, focusing on recent progress in mammals and highlighting some of the major questions that remain to be addressed