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Abstract Transient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid derivative NBA is a potent and specific TRPM4 inhibitor, but its binding site in TRPM4 has been unknown, although this information is crucial for drug development targeting TRPM4. We determine three cryo-EM structures of full-length human TRPM4 embedded in native lipid nanodiscs without inhibitor, bound to NBA, and an anthranilic acid derivative, IBA. We found that the small molecules NBA and IBA were bound in a pocket formed between the S3, S4, and TRP helices and the S4-S5 linker of TRPM4. Our structural data and results from patch clamp experiments enable validation of a binding site for small molecule inhibitors, paving the way for further drug development targeting TRPM4.

Nigeria's bean market is still characterized by inefficient and weak integration due to inadequate price information and market infrastructure. Therefore, the study investigates the price variation and transmission of beans markets in Nigeria's Southwest region. The study employed an average monthly price of white and brown beans in rural and urban markets spanning March 2014 to July 2019. Coefficient of variation (CV), Augmented Dickey-Fuller (ADF), Johansen co-integration test and Granger-Causality tests were the analytical tools used for the analysis. The results of CV indicated a spike variation of beans prices over the periods. Urban brown beans experienced the lowest variability of 1.56% in 2015, while rural brown beans experienced the highest variability of 30.03% in 2014. The co-integration test established a long-run dynamic between bean products of different varieties in the same market. However, it failed in the same products in different markets using a bivariate co-integration test. The multivariate co-integration test’s results affirmed that bean markets are strongly linked together in the long-run. The results of Granger-causality showed uni-directional and bi-directional causalities in the beans markets. Rural white beans assumed the lead position and formed the major price transmission in the beans’ markets in the area. Therefore, for more efficiency in the beans’ rural and urban markets, the government should design appropriate market strategies such as accessible market information and infrastructures.

Abstract The mechanism by which specific protein-DNA complexes induce programmed replication fork stalling in the eukaryotic genome remains poorly understood. In order to shed light on this process we carried out structural investigations on the essential fission yeast protein Sap1. Sap1 was identified as a protein involved in mating-type switching in Schizosaccharomyces pombe, and has been shown to be involved in programmed replication fork stalling. Interestingly, Sap1 assumes two different DNA binding modes. At the mating-type locus dimers of Sap1 bind the SAS1 sequence in a head-to-head arrangement, while they bind to replication fork blocking sites at rDNA and Tf2 transposons in a head-to-tail mode. In this study, we have solved the crystal structure of the Sap1 DNA binding domain and we observe that Sap1 molecules interact in the crystal using a head-to-tail arrangement that is compatible with DNA binding. We find that Sap1 mutations which alleviate replication-fork blockage at Tf2 transposons in CENP-B mutants map to the head-to-tail interface. Furthermore, several other mutations introduced in this interface are found to be lethal. Our data suggests that essential functions of Sap1 depend on its head-to-tail oligomerization.

In all kingdoms of life, DNA is used to encode hereditary information. Propagation of the genetic material between generations requires timely and accurate duplication of DNA by semiconservative replication prior to cell division to ensure each daughter cell receives the full complement of chromosomes. DNA synthesis of daughter strands starts at discrete sites, termed replication origins, and proceeds in a bidirectional manner until all genomic DNA is replicated. Despite the fundamental nature of these events, organisms have evolved surprisingly divergent strategies that control replication onset. Here, we discuss commonalities and differences in replication origin organization and recognition in the three domains of life.

This paper takes a social constructionist perspective to explain how dominant constructions of 'sex' and 'gender' have been built upon deeply embedded substructure of gender differences and the expected roles of women in the public sphere and in private domain in nearly all societies. The paper aims at exploring the argument that sex, like gender, is a socially constructed concept. It examines the construction of sex and gender from various perspectives including feminist perspectives and those opposing arguments from the biological determinist point of view. Next, the paper discusses an aspect of the normative construction of sex/gender as proposed by the post-structuralist school of thought and finally examines some cultural implications of the conventional understanding of sex. The paper concludes that sex is strongly influenced by social factors, ideas and other sociocultural contexts including the norms, values and beliefs embedded in different societies, along with some traditional practices. [ABSTRACT FROM AUTHOR]

This paper is based on research that explores young people's sexuality and sexual relationships as shaped within the socio-cultural context of Nigeria, occasioned by the absence of young people's voices from the literature examining their sexualities. By considering young people's sexuality beyond biological and rational action, this study takes a social constructionist perspective to explain how dominant social norms, cultural values, beliefs and practices influence young people's sexual practices and negotiations. Specifically, through an analysis of qualitative data from 10 focus groups and 16 in-depth interviews with young women and young men, aged 16 to 25, the study illuminates the different social contexts in which the young people were sexual and gendered actors. Analysis of their narratives reveals how they were actively involved in negotiating their sexualities and sexual practices in the form of accepting, rejecting, compromising or juggling with the various norms embedded in their local context. The study concludes that socio-cultural context played an essential role in young people's sexualities and sexual practices, while limited economic resources also had an impact. [ABSTRACT FROM AUTHOR]