Parental environmental factors, including diet, body composition, metabolism, and stress, affect the health and chronic disease risk of people throughout their lives, as captured in the Developmental ...Origins of Health and Disease concept. Research across the epidemiological, clinical, and basic science fields has identified the period around conception as being crucial for the processes mediating parental influences on the health of the next generation. During this time, from the maturation of gametes through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring cardiovascular, metabolic, immune, and neurological morbidities, often termed developmental programming. We review periconceptional induction of disease risk from four broad exposures: maternal overnutrition and obesity; maternal undernutrition; related paternal factors; and the use of assisted reproductive treatment. Studies in both humans and animal models have demonstrated the underlying biological mechanisms, including epigenetic, cellular, physiological, and metabolic processes. We also present a meta-analysis of mouse paternal and maternal protein undernutrition that suggests distinct parental periconceptional contributions to postnatal outcomes. We propose that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.
Moving beyond MARCO Rosa, Nicholas; Watkins, Christopher J; Newman, Janet
PloS one,
03/2023, Letnik:
18, Številka:
3
Journal Article
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The use of imaging systems in protein crystallisation means that the experimental setups no longer require manual inspection to determine the outcome of the trials. However, it leads to the problem ...of how best to find images which contain useful information about the crystallisation experiments. The adoption of a deeplearning approach in 2018 enabled a four-class machine classification system of the images to exceed human accuracy for the first time. Underpinning this was the creation of a labelled training set which came from a consortium of several different laboratories. The MARCO classification model does not have the same accuracy on local data as it does on images from the original test set; this can be somewhat mitigated by retraining the ML model and including local images. We have characterized the image data used in the original MARCO model, and performed extensive experiments to identify training settings most likely to enhance the local performance of a MARCO-dataset based ML classification model.
The concept that a father’s wellbeing at the time of conception influences the development and long-term health of his offspring is now well established. However, the mechanisms underlying the ...paternal programming of offspring health are not fully defined. While sperm-mediated effects on offspring development have been investigated in detail, the significance of seminal plasma has been over-looked. Typically, the seminal plasma is viewed as a simple medium, with a main role to transport sperm into the female reproductive tract at the time of conception. However, a more sophisticated role for seminal plasma in the modulation of the maternal periconception cell-signalling, inflammatory and immunological physiology is emerging. Seminal plasma comprises a complex mix of nutrients, proteins, signalling molecules and cell-free genetic material which all interact with the endometrium to regulate gene expression, vascular remodelling, leukocyte recruitment and the priming of regulatory T cells (Tregs). These seminal plasma effects on the maternal periconception environment all act to facilitate uterine remodelling, embryo implantation and fetal development. Evidence is now emerging that poor paternal lifestyle factors such as diet, can modify these essential uterine responses, altering fetal development and ultimately long-term offspring health. The use of animal models has enhanced our understanding of the effects of seminal plasma on maternal uterine physiology, embryo development and offspring health. However, further studies are needed to define the interaction between seminal plasma components and female reproductive tissues in humans. Such studies will be central in providing better information and infertility treatments to intending parents.
Several proto-oncogenes and tumor suppressors regulate the production of ribosomes. Ribosome biogenesis is a major consumer of cellular energy, and defects result in p53 activation via repression of ...mouse double minute 2 (MDM2) homolog by the ribosomal proteins RPL5 and RPL11. Here, we report that RPL5 and RPL11 regulate p53 from the context of a ribosomal subcomplex, the 5S ribonucleoprotein particle (RNP). We provide evidence that the third component of this complex, the 5S rRNA, is critical for p53 regulation. In addition, we show that the 5S RNP is essential for the activation of p53 by p14ARF, a protein that is activated by oncogene overexpression. Our data show that the abundance of the 5S RNP, and therefore p53 levels, is determined by factors regulating 5S complex formation and ribosome integration, including the tumor suppressor PICT1. The 5S RNP therefore emerges as the critical coordinator of signaling pathways that couple cell proliferation with ribosome production.
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•The 5S RNP (5S rRNA/RPL5/RPL11) activates p53 when ribosome production is blocked•The 5S RNP is required for p53 activation by the tumor suppressor p14ARF•PICT1 controls p53 levels by regulating 5S RNP integration into the ribosome•Ribosome biogenesis is directly coupled to cellular proliferation via the 5S RNP
RPL5 and RPL11 have both been shown to inhibit the ubiquitination and therefore subsequent degradation of p53 by MDM2. Sloan, Bohnsack, and Watkins report that RPL5 and RPL11, together with the 5S rRNA, regulate p53 in the context of a ribosomal subcomplex, the 5S RNP. They show that the abundance of the 5S RNP, and therefore p53 levels, are determined by factors regulating 5S complex formation and ribosome integration, including the tumor suppressor PICT1.
The association between poor paternal diet, perturbed embryonic development, and adult offspring ill health represents a new focus for the Developmental Origins of Health and Disease hypothesis. ...However, our understanding of the underlying mechanisms remains ill-defined. We have developed a mouse paternal low-protein diet (LPD) model to determine its impact on semen quality, maternal uterine physiology, and adult offspring health. We observed that sperm from LPD-fed male mice displayed global hypomethylation associated with reduced testicular expression of DNA methylation and folate-cycle regulators compared with normal protein diet (NPD) fed males. Furthermore, females mated with LPD males display blunted preimplantation uterine immunological, cell signaling, and vascular remodeling responses compared to controls. These data indicate paternal diet impacts on offspring health through both sperm genomic (epigenetic) and seminal plasma (maternal uterine environment) mechanisms. Extending our model, we defined sperm- and seminal plasma-specific effects on offspring health by combining artificial insemination with vasectomized male mating of dietary-manipulated males. All offspring derived from LPD sperm and/or seminal plasma became heavier with increased adiposity, glucose intolerance, perturbed hepatic gene expression symptomatic of nonalcoholic fatty liver disease, and altered gut bacterial profiles. These data provide insight into programming mechanisms linking poor paternal diet with semen quality and offspring health.
Although the association between maternal periconceptional diet and adult offspring health is well characterised, our understanding of the impact of paternal nutrition at the time of conception on ...offspring phenotype remains poorly defined. Therefore, we determined the effect of a paternal preconception low protein diet (LPD) on adult offspring cardiovascular and metabolic health in mice. Male C57BL/6 mice were fed either normal protein diet (NPD; 18% casein) or LPD (9% casein) for 7 wk before mating. At birth, a reduced male-to-female ratio (P = 0.03) and increased male offspring weight (P = 0.009) were observed in litters from LPD compared with NPD stud males with no differences in mean litter size. LPD offspring were heavier than NPD offspring at 2 and 3 wk of age (P < 0.02). However, no subsequent differences in body weight were observed. Adult male offspring derived from LPD studs developed relative hypotension (decreased by 9.2 mmHg) and elevated heart rate (P < 0.05), whereas both male and female offspring displayed vascular dysfunction and impaired glucose tolerance relative to NPD offspring. At cull (24 wk), LPD males had elevated adiposity (P = 0.04), reduced heart-to-body weight ratio (P = 0.04), and elevated circulating TNF-α levels (P = 0.015) compared with NPD males. Transcript expression in offspring heart and liver tissue was reduced for genes involved in calcium signaling (Adcy, Plcb, Prkcb) and metabolism (Fto) in LPD offspring (P < 0.03). These novel data reveal the impact of suboptimal paternal nutrition on adult offspring cardiovascular and metabolic homeostasis, and provide some insight into the underlying regulatory mechanisms.
Box C/D and H/ACA RNPs are essential ribonucleoprotein particles that are found throughout both eukaryotes small nucleolar RNPs (snoRNPs) and archaea snoRNP-like complexes (sRNPs). These complexes ...catalyze the site-specific pseudouridylation and most of the methylation of ribosomal RNA (rRNA). The numerous modifications, which are clustered in functionally important regions of the rRNA, are important for rRNA folding and ribosome function. The RNA component of the complexes small nucleolar RNA (snoRNA) or small RNA (sRNA) functions in substrate binding by base pairing with the target site and as a scaffold coordinating the organization of the complex. In eukaryotes, a subset of snoRNPs do not catalyze modification but, through base pairing to the rRNA or flanking precursor sequences, direct pre-rRNA folding and are essential for rRNA processing. In the last few years there have been significant advances in our understanding of the structure of archaeal sRNPs. High resolution structures of the archaeal C/D and H/ACA sRNPs have not only provided a detailed understanding of the molecular architecture of these complexes but also produced key insights into substrate binding and product release. In both cases, this is mediated by significant movement in the complexes. Advances have also been made in our knowledge of snoRNP recruitment and release from pre-ribosome complexes in eukaryotes. New snoRNA-rRNA interactions have been documented, and the roles of RNA helicases in releasing snoRNP complexes from the rRNA have been described.
Ribosomes are abundant, large RNA-protein complexes that are the source of all protein synthesis in the cell. The production of ribosomes is an extremely energetically expensive cellular process that ...has long been linked to human health and disease. More recently, it has been shown that ribosome biogenesis is intimately linked to multiple cellular signalling pathways and that defects in ribosome production can lead to a wide variety of human diseases. Furthermore, changes in ribosome production in response to nutrient levels in the diet lead to metabolic re-programming of the liver. Reduced or abnormal ribosome production in response to cellular stress or mutations in genes encoding factors critical for ribosome biogenesis causes the activation of the tumour suppressor p53, which leads to re-programming of cellular transcription. The ribosomal assembly intermediate 5S RNP (ribonucleoprotein particle), containing RPL5, RPL11 and the 5S rRNA, accumulates when ribosome biogenesis is blocked. The excess 5S RNP binds to murine double minute 2 (MDM2), the main p53-suppressor in the cell, inhibiting its function and leading to p53 activation. Here, we discuss the involvement of ribosome biogenesis in the homoeostasis of p53 in the cell and in human health and disease.
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