Weaving a pattern from disparate threads: lamin function in nuclear assembly and DNA replication

The major residual structure that remains associated with the nuclear envelope following extraction of isolated nuclei or oocyte germinal vesicles with non-ionic detergents, nucleases and high salt is the lamina (Fawcett, 1966; Aaronson and Blobel, 1975; Dwyer and Blobel, 1976). The nuclear lamina is composed of intermediate filament proteins, termed lamins (Gerace and Blobel, 1980; Shelton et al., 1980), which polymerise to form a basket-weave lattice of fibrils, which covers the entire inner surface of the nuclear envelope and interlinks nuclear pores (Aebi et al., 1986; Stewart and Whytock, 1988; Goldberg and Allen, 1992). At mitosis, the nuclear envelope and the lamina both break down to allow chromosome segregation. As a consequence, each structure has to be rebuilt during anaphase and telophase, allowing cells an opportunity to reposition chromosomes (Heslop-Harrison and Bennett, 1990) and to reorganise looped chromatin domains (Franke, 1974; Franke et al., 1981; Hochstrasser et al., 1986), which may in turn control the use of subsets of genes. Because of the position that it occupies, its dynamics during mitosis and the fact that it is an essential component of proliferating cells, the lamina has been assigned a number of putative roles both in nuclear metabolism and in nuclear envelope assembly (Burke and Gerace, 1986; Nigg, 1989). However, to date there is little clear cut evidence that satisfactorily explains the function of the lamina in relation to its structure. In this Commentary we will describe some of the recent work that addresses this problem and attempt to provide a unified model for the role of lamins in nuclear envelope assembly and for the lamina in the initiation of DNA replication

Identification of an MCM4 homologue expressed specifically in the sexual stage of Plasmodium falciparum.

Mini-chromosome maintenance (MCM) proteins play an essential role in DNA replication initiation. We have isolated a novel gene encoding an MCM-like protein from the human malaria parasite Plasmodium falciparum using the vectorette technique. The gene has no introns and comprises an open reading frame encoding 1005 amino acid residues with a predicted Mr of 115 kDa. The encoded protein, termed PfMCM4, contains all conserved sequences in the MCM family and displays the highest homology to the Cdc54 (MCM4) of Saccharomyces cerevisiae. However, PfMCM4 possesses five unique amino acid inserts with sizes ranging from seven to 75 residues. Southern blotting of genomic DNA digests and chromosomal separations showed that the Pfmcm4 gene is present as a single copy per haploid genome and is located on chromosome 13. A 4000-nucleotide transcript of this gene is expressed specifically in the sexual erythrocytic stage, indicating that PfMCM4 may be involved in gametogenesis in which DNA is quickly replicated

Identification of a second proliferating cell nuclear antigen in the human malarial pathogen Plasmodium falciparum.

Proliferating cell nuclear antigen seems to exist as a single form in higher eukaryotic cells and plays multiple roles in nucleic acid metabolism. We have identified a second additional proliferating cell nuclear antigen (PfPCNA2) in Plasmodium falciparum on the basis of several lines of evidence. (1) PfPCNA2, consisting of 264 amino acid residues with a predicted molecular mass of 30.2kDa, shares only 29% identity and 53% similarity with PfPCNA1 at the amino acid level. (2) Southern blot analyses revealed that the hybridisation pattern of the Pfpcna2 gene is completely different from that of the Pfpcna1 gene. (3) Chromosomal localisation studies showed that Pfpcna2 is located on chromosome 12 while Pfpcna1 is located on chromosome 13. Northern blot analyses revealed two different transcripts of Pfpcna2, one expressed in both asexual and sexual erythrocytic stages, while the other existed only in the sexual stage, implying that PfPCNA2 may play multiple roles in DNA metabolism in different stages of the parasite. Recombinant protein of PfPCNA2, overexpressed in Escherichia coli, has been purified to near homogeneity and shown to form an oligomer, probably a trimer, as revealed by a size-exclusion chromatography and a native gel electrophoresis, suggesting that PfPCNA2, like its higher eukaryotic counterparts, may serve as a sliding platform which is capable of interaction with diverse proteins and regulation of their activities

Assessing trade-offs in large marine protected areas

This is the final version. Available on open access from Public Library of Science via the DOI in this recordData Availability: Data of coded case-studies can be viewed at: https://sesmad.dartmouth.edu/ses_casesLarge marine protected areas (LMPAs) are increasingly being established and have a high profile in marine conservation. LMPAs are expected to achieve multiple objectives, and because of their size are postulated to avoid trade-offs that are common in smaller MPAs. However, evaluations across multiple outcomes are lacking. We used a systematic approach to code several social and ecological outcomes of 12 LMPAs. We found evidence of three types of trade-offs: trade-offs between different ecological resources (supply trade-offs); trade-offs between ecological resource conditions and the well-being of resource users (supply-demand trade-offs); and trade-offs between the well-being outcomes of different resource users (demand trade-offs). We also found several divergent outcomes that were attributed to influences beyond the scope of the LMPA. We suggest that despite their size, trade-offs can develop in LMPAs and should be considered in planning and design. LMPAs may improve their performance across multiple social and ecological objectives if integrated with larger-scale conservation efforts.Social Science and Humanities Research Council of CanadaNatural Sciences and Engineering Research Council of Canad

Xenopus Mcm10 is a CDK-substrate required for replication fork stability

<p>During S phase, following activation of the S phase CDKs and the DBF4-dependent kinases (DDK), double hexamers of Mcm2-7 at licensed replication origins are activated to form the core replicative helicase. Mcm10 is one of several proteins that have been implicated from work in yeasts to play a role in forming a mature replisome during the initiation process. Mcm10 has also been proposed to play a role in promoting replisome stability after initiation has taken place. The role of Mcm10 is particularly unclear in metazoans, where conflicting data has been presented. Here, we investigate the role and regulation of Mcm10 in <i>Xenopus</i> egg extracts. We show that <i>Xenopus</i> Mcm10 is recruited to chromatin late in the process of replication initiation and this requires prior action of DDKs and CDKs. We also provide evidence that Mcm10 is a CDK substrate but does not need to be phosphorylated in order to associate with chromatin. We show that in extracts depleted of more than 99% of Mcm10, the bulk of DNA replication still occurs, suggesting that Mcm10 is not required for the process of replication initiation. However, in extracts depleted of Mcm10, the replication fork elongation rate is reduced. Furthermore, the absence of Mcm10 or its phosphorylation by CDK results in instability of replisome proteins on DNA, which is particularly important under conditions of replication stress.</p

A structural heart-brain axis mediates the association between cardiovascular risk and cognitive function

Elevated vascular disease risk associates with poorer cognitive function, but the mechanism for this link is poorly understood. A leading theory, the structural-functional model argues that vascular risk may drive adverse cardiac remodelling, which, in turn, leads to chronic cerebral hypoperfusion and subsequent brain structural damage. This model predicts that variation in heart and brain structure should associate with both greater vascular risk and lower cognitive function. This study tests that prediction in a large sample of the UK Biobank (N = 11,962). We assemble and summarise vascular risk factors, cardiac magnetic resonance radiomics, brain structural and diffusion MRI indices, and cognitive assessment. We also extract “heart-brain axes” capturing the covariation in heart and brain structure. Many heart and brain measures partially explain the vascular risk—cognitive function association, like left ventricular end-diastolic volume and grey matter volume. Notably, a heart-brain axis, capturing correlation between lower myocardial intensity, lower grey matter volume, and poorer thalamic white matter integrity, completely mediates the association, supporting the structural-functional model. Our findings also complicate this theory by finding that brain structural variation cannot completely explain the heart structure—cognitive function association. Our results broadly offer evidence for the structural functional hypothesis, identify imaging biomarkers for this association by considering covariation in heart and brain structure, and generate novel hypotheses about how cardiovascular risk may link to cognitive function

Khat Use Is Associated with Impaired Working Memory and Cognitive Flexibility

Rationale Khat consumption has increased during the last decades in Eastern Africa and has become a global phenomenon spreading to ethnic communities in the rest of the world, such as The Netherlands, United Kingdom, Canada, and the United States. Very little is known, however, about the relation between khat use and cognitive control functions in khat users. Objective We studied whether khat use is associated with changes in working memory (WM) and cognitive flexibility, two central cognitive control functions. Methods Khat users and khat-free controls were matched in terms of sex, ethnicity, age, alcohol and cannabis consumption, and IQ (Raven's progressive matrices). Groups were tested on cognitive flexibility, as measured by a Global-Local task, and on WM using an N-back task. Result Khat users performed significantly worse than controls on tasks tapping into cognitive flexibility as well as monitoring of information in WM. Conclusions The present findings suggest that khat use impairs both cognitive flexibility and the updating of information in WM. The inability to monitor information in WM and to adjust behavior rapidly and flexibly may have repercussions for daily life activities

Life-course neighbourhood deprivation and brain structure in older adults: the Lothian Birth Cohort 1936

Neighbourhood disadvantage may be associated with brain health but the importance of exposure at different stages of the life course is poorly understood. Utilising the Lothian Birth Cohort 1936, we explored the relationship between residential neighbourhood deprivation from birth to late adulthood, and global and local neuroimaging measures at age 73. A total of 689 participants had at least one valid brain measures (53% male); to maximise the sample size structural equation models with full information maximum likelihood were conducted. Residing in disadvantaged neighbourhoods in mid- to late adulthood was associated with smaller total brain (β = −0.06; SE = 0.02; sample size[N] = 658; number of pairwise complete observations[n]=390), grey matter (β = −0.11; SE = 0.03; N = 658; n = 390), and normal-appearing white matter volumes (β = −0.07; SE = 0.03; N = 658; n = 390), thinner cortex (β = −0.14; SE = 0.06; N = 636; n = 379), and lower general white matter fractional anisotropy (β = −0.19; SE = 0.06; N = 665; n = 388). We also found some evidence on the accumulating impact of neighbourhood deprivation from birth to late adulthood on age 73 total brain (β = −0.06; SE = 0.02; N = 658; n = 276) and grey matter volumes (β = −0.10; SE = 0.04; N = 658; n = 276). Local analysis identified affected focal cortical areas and specific white matter tracts. Among individuals belonging to lower social classes, the brain-neighbourhood associations were particularly strong, with the impact of neighbourhood deprivation on total brain and grey matter volumes, and general white matter fractional anisotropy accumulating across the life course. Our findings suggest that living in deprived neighbourhoods across the life course, but especially in mid- to late adulthood, is associated with adverse brain morphologies, with lower social class amplifying the vulnerability