Primase-polymerases are a functionally diverse superfamily of replication and repair enzymes

Until relatively recently, DNA primases were viewed simply as a class of proteins that synthesize short RNA primers requisite for the initiation of DNA replication. However, recent studies have shown that this perception of the limited activities associated with these diverse enzymes can no longer be justified. Numerous examples can now be cited demonstrating how the term 'DNA primase' only describes a very narrow subset of these nucleotidyltransferases, with the vast majority fulfilling multifunctional roles from DNA replication to damage tolerance and repair. This article focuses on the archaeo-eukaryotic primase (AEP) superfamily, drawing on recently characterized examples from all domains of life to highlight the functionally diverse pathways in which these enzymes are employed. The broad origins, functionalities and enzymatic capabilities of AEPs emphasizes their previous functional misannotation and supports the necessity for a reclassification of these enzymes under a category called primase-polymerases within the wider functional grouping of polymerases. Importantly, the repositioning of AEPs in this way better recognizes their broader roles in DNA metabolism and encourages the discovery of additional functions for these enzymes, aside from those highlighted here

The future of the global food system

Although food prices in major world markets are at or near a historical low, there is increasing concern about food security—the ability of the world to provide healthy and environmentally sustainable diets for all its peoples. This article is an introduction to a collection of reviews whose authors were asked to explore the major drivers affecting the food system between now and 2050. A first set of papers explores the main factors affecting the demand for food (population growth, changes in consumption patterns, the effects on the food system of urbanization and the importance of understanding income distributions) with a second examining trends in future food supply (crops, livestock, fisheries and aquaculture, and ‘wild food’). A third set explores exogenous factors affecting the food system (climate change, competition for water, energy and land, and how agriculture depends on and provides ecosystem services), while the final set explores cross-cutting themes (food system economics, food wastage and links with health). Two of the clearest conclusions that emerge from the collected papers are that major advances in sustainable food production and availability can be achieved with the concerted application of current technologies (given sufficient political will), and the importance of investing in research sooner rather than later to enable the food system to cope with both known and unknown challenges in the coming decades

Prevalence of chronic respiratory diseases in Aboriginal children: A whole population study

Background The burden of bronchiectasis is disproportionately high in Aboriginal adults, with early mortality. Bronchiectasis precursors, that is, protracted bacterial bronchitis (PBB) and chronic suppurative lung disease (CSLD), often commence in early childhood. We previously reported a 10% prevalence of PBB in Aboriginal children aged 0 to 7 years, however there are no data on prevalence of chronic lung diseases in older children. Our study aimed to determine the prevalence of PBB, CSLD, bronchiectasis, and asthma in Aboriginal children living in four communities. Methods A whole-population cross-sectional community co-designed study of Aboriginal children aged <18-years in four remote communities in Western Australia across two-time points, a month apart. Children were assessed by pediatric respiratory clinicians with spirometry undertaken (when possible) between March–September 2021. Children with respiratory symptoms were followed up via medical record audit from either the local medical clinic or via a respiratory specialist clinic through to March 2022 to establish a final diagnosis. Findings We recruited 392 (91.6%) of those in the selected communities; median age = 8.4 years (interquartile range [IQR] 5.1–11.5). Seventy children (17.9%) had a chronic respiratory pathology or abnormal spirometry results. PBB was confirmed in 30 (7.7%), CSLD = 13 (3.3%), bronchiectasis = 5 (1.3%) and asthma = 17 (4.3%). The prevalence of chronic wet cough significantly increased with increasing age. Interpretation The prevalence of PBB, CSLD and bronchiectasis is high in Aboriginal children and chronic wet cough increases with age. This study highlights the high disease burden in Aboriginal children and the urgent need for strategies to address these conditions

miR451 and AMPK Mutual Antagonism in Glioma Cell Migration and Proliferation: A Mathematical Model

Glioblastoma multiforme (GBM) is the most common and the most aggressive type of brain cancer; the median survival time from the time of diagnosis is approximately one year. GBM is characterized by the hallmarks of rapid proliferation and aggressive invasion. miR-451 is known to play a key role in glioblastoma by modulating the balance of active proliferation and invasion in response to metabolic stress in the microenvironment. The present paper develops a mathematical model of GBM evolution which focuses on the relative balance of growth and invasion. In the present work we represent the miR-451/AMPK pathway by a simple model and show how the effects of glucose on cells need to be “refined” by taking into account the recent history of glucose variations. The simulations show how variations in glucose significantly affect the level of miR-451 and, in turn, cell migration. The model predicts that oscillations in the levels of glucose increase the growth of the primary tumor. The model also suggests that drugs which upregulate miR-451, or block other components of the CAB39/AMPK pathway, will slow down glioma cell migration. The model provides an explanation for the growth-invasion cycling patterns of glioma cells in response to high/low glucose uptake in microenvironment in vitro, and suggests new targets for drugs, associated with miR-451 upregulation

Telerehabilitation versus traditional centre-based pulmonary rehabilitation for people with chronic respiratory disease: protocol for a randomised controlled trial

Background: Pulmonary rehabilitation is an effective therapeutic intervention for people with chronic respiratory disease. However, fewer than 5% of eligible individuals receive pulmonary rehabilitation on an annual basis, largely due to limited availability of services and difficulties associated with travel and transport. The Rehabilitation Exercise At Home (REAcH) study is an assessor-blinded, multi-centre, randomised controlled equivalence trial designed to compare the efficacy of home-based telerehabilitation and traditional centre-based pulmonary rehabilitation in people with chronic respiratory disease. Methods: Participants will undertake an 8-week group-based pulmonary rehabilitation program of twice-weekly supervised exercise training, either in-person at a centre-based pulmonary rehabilitation program or remotely from their home via the Internet. Supervised exercise training sessions will include 30 min of aerobic exercise (cycle and/ or walking training). Individualised education and self-management training will be delivered. All participants will be prescribed a home exercise program of walking and strengthening activities. Outcomes will be assessed by a blinded assessor at baseline, after completion of the intervention, and 12-months post intervention. The primary outcome is change in dyspnea score as measured by the Chronic Respiratory Questionnaire – dyspnea domain (CRQ-D). Secondary outcomes will evaluate the efficacy of telerehabilitation on 6- min walk distance, endurance cycle time during a constant work rate test, physical activity and quality of life. Adherence to pulmonary rehabilitation between the two models will be compared. A full economic analysis from a societal perspective will be undertaken to determine the cost-effectiveness of telerehabilitation compared to centre-based pulmonary rehabilitation. Discussion: Alternative models of pulmonary rehabilitation are required to improve both equity of access and patient-related outcomes. This trial will establish whether telerehabilitation can achieve equivalent improvement in outcomes compared to traditional centre-based pulmonary rehabilitation. If efficacious and cost-effective, the proposed telerehabilitation model is designed to be rapidly deployed into clinical practice.Narelle S. Cox, Christine F. McDonald, Jennifer A. Alison, Ajay Mahal, Richard Wootton, Catherine J. Hill, Janet Bondarenko, Heather Macdonald, Paul O’Halloran, Paolo Zanaboni, Ken Clarke, Deidre Rennick, Kaye Borgelt, Angela T. Burge, Aroub Lahham, Bruna Wageck, Hayley Crute, Pawel Czupryn, Amanda Nichols and Anne E. Hollan

The Dynamical Mechanism of Auto-Inhibition of AMP-Activated Protein Kinase

We use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK). A recent X-ray and mutagenesis experiment (Chen, et al Nature 2009, 459, 1146) of the AMPK homolog S. Pombe sucrose non-fermenting 1 (SNF1) has proposed a new conformational switch model involving the movement of the kinase domain (KD) between an inactive unphosphorylated open state and an active or semi-active phosphorylated closed state, mediated by the autoinhibitory domain (AID), and a similar mutagenesis study showed that rat AMPK has the same auto-inhibition mechanism. However, there is no direct dynamical evidence to support this model and it is not clear whether other functionally important local structural components are equally inhibited. By using the same SNF1 KD-AID fragment as that used in experiment, we show that AID inhibits the catalytic function by restraining the KD into an unproductive open conformation, thereby limiting local structural rearrangements, while mutations that disrupt the interactions between the KD and AID allow for both the local structural rearrangement and global interlobe conformational transition. Our calculations further show that the AID also greatly impacts the structuring and mobility of the activation loop

Clubroot (Plasmodiophora brassicae Woronin): an agricultural and biological challenge worldwide

Clubroot disease and the causal microbe Plasmodiophora brassicae offer abundant challenges to agriculturists and biological scientists. This microbe is well fitted for the environments which it inhabits. Plasmodiophora brassicae exists in soil as microscopic well protected resting spores and then grows actively and reproduces while shielded inside the roots of host plants. The pathogen is active outside the host for only short periods. Consequently, scientific studies are made challenging by the biological context of the host and pathogen and the technology required to investigate and understand that relationship. Controlling clubroot disease is a challenge for farmers, crop consultants and plant pathology practitioners because of the limited options which are available. Full symptom expression happens solely in members of the Brassicaceae family. Currently, only a few genes expressing strong resistance to P. brassicae are known and readily available. Agrochemical control is similarly limited by difficulties in molecule formulation which combines efficacy with environmental acceptability. Manipulation of husbandry encouraging improvements in soil structure, texture, nutrient composition and moisture content can reduce populations of P. brassicae. Integrating such strategies with rotation and crop management will reduce but not eliminate this disease. There are indications that forms of biological competition may be mobilised as additions to integrated control strategies. The aim of this review is to chart key themes in the development of scientific biological understanding of this host-pathogen relationship by offering signposts to grapple with clubroot disease which devastates crops and their profitability. Particular attention is given to the link between soil and nutrient chemistry and activity of this microbe