How epigenetic evolution can guide genetic evolution (abstract)

The expression level of a gene in future generations can be modified both by genetic mutations and by the attachment of methyl groups to the DNA. Since the DNA methylation pattern along a genome is inherited, methylation patterns constitute a significant epigenetic inheritance mechanism that is subject to evolution by natural selection. The variation rate of methylation patterns is generally higher than that of DNA which suggests that evolution of methylation patterns might be more rapid than that of genetic evolution. But, common consequences of methylation, such as reduced expression of methylated genes, could also be produced by genetic changes and these would have higher heritability. The question we address in this work is how the evolution of epigenetic methylation-dependent phenotypes might interact with the evolution of genetic DNA-determined phenotypes. There is no biological mechanism known to directly transfer methyl groups into equivalent DNA changes. However, in principle an indirect mechanism could cause evolved methylation patterns to enable the subsequent evolution of equivalent genetic patterns in a manner analogous to the Baldwin effect (Baldwin, Am. Nat., 30:441-451, 1896; Jablonka et al, TREE, 13:206-210, 1998). The Baldwin effect describes how non-heritable acquired characteristics can influence the evolution of equivalent genetic characteristics without any direct Lamarckian inheritance of acquired characters. This occurs because the ability to acquire or learn a new behaviour changes the selective pressures acting on genetic changes. Specifically, genetic changes that support this behaviour, e.g. by reducing learning time by making a small part of the behaviour genetically innate, may be selected for when the learning mechanism is present even though these same genetic changes may not be selected for when the learning mechanism is absent. Over generations, the modified selection pressures so produced can cause genetic assimilation of a phenotype that was previously acquired, even to the extent of making the acquisition mechanism subsequently redundant. Thus a learned behaviour can guide the evolution of an equivalent innate behaviour (Hinton & Nowlan, Complex Systems, 1: 495-502, 1987). In the Baldwin effect a rapid mechanism of lifetime adaptation guides the relatively slow genetic evolution of the same behaviour. By analogy, Jablonka et al have suggested that “genetic adaptations may be guided by heritable induced or learnt phenotypic adaptations”. Here we hypothesise that “inherited epigenetic variations may be able to ‘hold’ an adapted state for long enough to allow similar genetic variations to catch up”, as they put it, even if the epigenetic variations are not induced or learnt but simply evolved by natural selection on methylation patterns. We assume that an individual may only express one phenotype in its lifetime, but that a given genome will persist relatively unchanged on a timescale that allows its methylome to adapt by natural selection. Thus, in contrast to the Baldwin effect, in this case two mechanisms of evolution by natural selection are coupled — one acting at a different variation rate from the other. We present a simple model to illustrate how a rapidly evolving methylome can guide a slowly evolving but highly-heritable genome. This is used to show that methylome evolution can enable genetic evolution to cross fitness valleys that would otherwise require multiple genetic changes that were each selected against. This finding suggests that the relatively rapid evolution of methylation patterns can produce novel phenotypes that are subsequently genetically assimilated in DNA evolution without direct transfer or appeal to induced phenotypes. This can enable the genetic evolution of new phenotypes that would not be found by genetic evolution alone, even if methylation is not significant in the ultimate phenotype

Spatiotemporal determinants of seasonal gleaning

1. Many coastal communities depend on ecosystems for goods and services that contribute to human well-being. As long-standing interactions between people and nature are modified by global environmental change, dynamic and diversified livelihood strategies that enable seasonal adaptation will be critical for vulnerable coastal communities. However, the success of such strategies depends on a range of poorly understood influences. 2. Gleaning, the hand-based collection of marine organisms from littoral habitats, provides an interesting case study of dynamic change in social-ecological interac- tions. It is an important coastal livelihood strategy, yet seasonal gleaning dynamics have not been empirically explored in contemporary communities. We examined seasonal gleaning in eight coastal communities on Atauro Island, Timor-Leste, using household surveys and satellite-derived maps of shallow-water benthic habitats. Our analysis explored the factors affecting household decisions to glean in each season, the relationship between gleaning and seafood consumption, and seasonal gleaning pressure on near-shore coastal resources. 3. Dynamic marine harvesting strategies differed among households and gleaning activity was seasonally heterogeneous. Not all gleaning households gleaned dur- ing the season characterised by rough sea conditions despite rough season glean- ing being associated with greater seafood consumption stability among seasons. Households also gleaned less regularly, and catches were smaller, in the rough season. 4. Differences in seasonal participation in gleaning were explained mostly by type and extent of shallow habitat proximate to a community. In the calm season, household gleaning was positively related to the total area of shallow habitat, and in the rough season the percentage of hard-bottom shallow habitat was also an important predictor of gleaning activity. 5.Our findings illustrate how changes in the biophysical environment mediate human–nature interactions at fine scales through time and space. Consequently, this research highlights the importance of context-specific perspectives for under- standing drivers and dynamics in fishing pressure on littoral ecosystems, access to ecosystem benefits and limits to adaptation. Factors influencing when livelihood activities are feasible and desirable are important for evaluating the social impacts of climate change, particularly in the context of rural communities in the Global South

Sharing success - understanding barriers and enablers to secondary prophylaxis delivery for rheumatic fever and rheumatic heart disease

Background: Rheumatic fever (RF) and rheumatic heart disease (RHD) cause considerable morbidity and mortality amongst Australian Aboriginal and Torres Strait Islander populations. Secondary antibiotic prophylaxis in the form of 4-weekly benzathine penicillin injections is the mainstay of control programs. Evidence suggests, however, that delivery rates of such prophylaxis are poor. Methods: This qualitative study used semi-structured interviews with patients, parents/care givers and health professionals, to explore the enablers of and barriers to the uptake of secondary prophylaxis. Data from participant interviews (with 11 patients/carers and 11 health practitioners) conducted in four far north Queensland sites were analyzed using the method of constant comparative analysis. Results: Deficits in registration and recall systems and pain attributed to injections were identified as barriers to secondary prophylaxis uptake. There were also varying perceptions regarding responsibility for ensuring injection delivery. Enablers of secondary prophylaxis uptake included positive patient-healthcare provider relationships, supporting patient autonomy, education of patients, care givers and healthcare providers, and community-based service delivery. Conclusion: The study findings provide insights that may facilitate enhancement of secondary prophylaxis delivery systems and thereby improve uptake of secondary prophylaxis for RF/RHD

Crystal structure and thermal behavior of Bi ₆ Te ₂ O ₁₅:Investigation of synthetic and natural pingguite

The previously unknown crystal structure of pingguite was determined and refined from laboratory X-ray powder diffraction data using a synthetic sample. Additional single crystal diffraction of natural pingguite confirms that the crystal structure of the synthetic sample is identical to the natural mineral. This new crystal structure calls for a revised chemistry of the rare mineral pingguite to Bi6Te2O15 instead of the previously reported formula Bi6Te2O13. Pingguite contains TeVI only and not TeIV as previously reported. Pingguite undergoes an irreversible phase transition around 840 ∘C which is characterized by a loss of oxygen and a reduction from TeVI to TeIV resulting in a δ-Bi2O3 like type structure. In addition, we report the Raman spectroscopic data on the natural pingguite

Precision Nutrition and the Microbiome, Part I: Current State of the Science

peer-reviewedThe gut microbiota is a highly complex community which evolves and adapts to its host over a lifetime. It has been described as a virtual organ owing to the myriad of functions it performs, including the production of bioactive metabolites, regulation of immunity, energy homeostasis and protection against pathogens. These activities are dependent on the quantity and quality of the microbiota alongside its metabolic potential, which are dictated by a number of factors, including diet and host genetics. In this regard, the gut microbiome is malleable and varies significantly from host to host. These two features render the gut microbiome a candidate ‘organ’ for the possibility of precision microbiomics—the use of the gut microbiome as a biomarker to predict responsiveness to specific dietary constituents to generate precision diets and interventions for optimal health. With this in mind, this two-part review investigates the current state of the science in terms of the influence of diet and specific dietary components on the gut microbiota and subsequent consequences for health status, along with opportunities to modulate the microbiota for improved health and the potential of the microbiome as a biomarker to predict responsiveness to dietary components. In particular, in Part I, we examine the development of the microbiota from birth and its role in health. We investigate the consequences of poor-quality diet in relation to infection and inflammation and discuss diet-derived microbial metabolites which negatively impact health. We look at the role of diet in shaping the microbiome and the influence of specific dietary components, namely protein, fat and carbohydrates, on gut microbiota composition

Precision nutrition and the microbiome part ii: Potential opportunities and pathways to commercialisation

Modulation of the human gut microbiota through probiotics, prebiotics and dietary fibre are recognised strategies to improve health and prevent disease. Yet we are only beginning to understand the impact of these interventions on the gut microbiota and the physiological consequences for the human host, thus forging the way towards evidence-based scientific validation. However, in many studies a percentage of participants can be defined as ‘non-responders’ and scientists are beginning to unravel what differentiates these from ‘responders;’ and it is now clear that an individual’s baseline microbiota can influence an individual’s response. Thus, microbiome composition can potentially serve as a biomarker to predict responsiveness to interventions, diets and dietary components enabling greater opportunities for its use towards disease prevention and health promotion. In Part I of this two-part review, we reviewed the current state of the science in terms of the gut microbiota and the role of diet and dietary components in shaping it and subsequent consequences for human health. In Part II, we examine the efficacy of gut-microbiota modulating therapies at different life stages and their potential to aid in the management of undernutrition and overnutrition. Given the significance of an individual’s gut microbiota, we investigate the feasibility of microbiome testing and we discuss guidelines for evaluating the scientific validity of evidence for providing personalised microbiome-based dietary advice. Overall, this review highlights the potential value of the microbiome to prevent disease and maintain or promote health and in doing so, paves the pathway towards commercialisation

Methylation age as a correlate for allele burden, disease status, and clinical response in myeloproliferative neoplasm patients treated with vorinostat.

The myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal neoplastic disorders. Driver mutations in JAK2, CALR, and MPL genes have been identified in the majority of cases. Alongside these, an increasing number of genes are repeatedly identified as mutated in MPN. These, including ASXL1, TET2, DMNT3A, and EZH2, have key roles in epigenetic regulation. Dysregulation of epigenetic processes is therefore a key feature of MPN. Vorinostat is a pan histone deacetylase inhibitor (HDACi) that has been investigated in MPN. DNA methylation (DNAm) is a well-defined epigenetic mechanism of transcription modification. It is known to be affected by ageing, lifestyle, and disease. Epigenetic ageing signatures have been previously described allowing calculation of a methylation age (MA). In this study we examined the effect of vorinostat on MA in MPN cell lines and in patients with polycythaemia vera (PV) and essential thrombocythaemia (ET) treated with vorinostat as part of a clinical trial. An older MA was observed in patients with a higher JAK2 V617F allele burden and those with a longer duration of disease. PV patients had a MA older than that predicted whilst MA was younger than predicted in ET. Treatment with vorinostat resulted in a younger MA in PV patients and older MA in ET patients, in both cases a trend towards the normal chronological age. When MA change was compared against response, nonresponse was associated with a younger than predicted MA in ET patients and a higher than predicted MA in PV patients. The link between MA and JAK2 mutant allele burden implies that allele burden has a role not only in clinical phenotype and disease evolution in MPN patients, but also in the overall methylation landscape of the mutated cells

Best Practices for Virtual Care: A Consensus Statement From the Canadian Rheumatology Association

Objective. To develop best practice statements for the provision of virtual care in adult and pediatric rheumatology for the Canadian Rheumatology Association\u27s (CRA) Telehealth Working Group (TWG). Methods. Four members of the TWG representing adult, pediatric, university-based, and community rheumatology practices defined the scope of the project. A rapid literature review of existing systematic reviews, policy documents, and published literature and abstracts on the topic was conducted between April and May 2021. The review informed a candidate set of 7 statements and a supporting document. The statements were submitted to a 3-round (R) modified Delphi process with 22 panelists recruited through the CRA and patient advocacy organizations. Panelists rated the importance and feasibility of the statements on a Likert scale of 1-9. Statements with final median ratings between 7-9 with no disagreement were retained in the final set. Results. Twenty-one (95%) panelists participated in R1, 15 (71%) in R2, and 18 (82%) in R3. All but 1 statement met inclusion criteria during R1. Revisions were made to 5/7 statements following R2 and an additional statement was added. All statements met inclusion criteria following R3. The statements addressed the following themes in the provision of virtual care: adherence to existing standards and regulations, appropriateness, consent, physical examination, patient-reported outcomes, use in addition to in-person visits, and complex comanagement of disease. Conclusion. The best practice statements represent a starting point for advancing virtual care in rheumatology. Future educational efforts to help implement these best practices and research to address identified knowledge gaps are planned

Use of the oral beta blocker bisoprolol to reduce the rate of exacerbation in people with chronic obstructive pulmonary disease (COPD): a randomised controlled trial (BICS)

Background: Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease. Methods: BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV1 < 80% predicted, FEV1/FVC < 0.7), a self-reported history of ≥ 2 exacerbations requiring treatment with antibiotics and/or oral corticosteroids in a 12-month period since March 2019, age ≥ 40 years and a smoking history ≥ 10 pack years. A computerised randomisation system will allocate 1574 participants with equal probability to intervention or control groups, stratified by centre and recruitment in primary/secondary care. The intervention is bisoprolol (1.25 mg tablets) or identical placebo. The dose of bisoprolol/placebo is titrated up to a maximum of 4 tablets a day (5 mg bisoprolol) over 4–7 weeks depending on tolerance to up-dosing of bisoprolol/placebo—these titration assessments are completed by telephone or video call. Participants complete the remainder of the 52-week treatment period on the final titrated dose (1, 2, 3, 4 tablets) and during that time are followed up at 26 and 52 weeks by telephone or video call. The primary outcome is the total number of participant reported COPD exacerbations requiring oral corticosteroids and/or antibiotics during the 52-week treatment period. A sub-study will risk stratify participants for heart failure by echocardiography and measurement of blood biomarkers. Discussion: The demonstration that bisoprolol reduces the incidence of exacerbations would be relevant not only to patients and clinicians but also to healthcare providers, in the UK and globally. Trial registration: Current controlled trials ISRCTN10497306. Registered on 16 August 201