Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2

Saccharomyces cerevisiae target of rapamycin (TOR) complex 2 (TORC2) is an essential regulator of plasma membrane lipid and protein homeostasis. How TORC2 activity is modulated in response to changes in the status of the cell envelope is unclear. Here we document that TORC2 subunit Avo2 is a direct target of Slt2, the mitogen-activated protein kinase (MAPK) of the cell wall integrity pathway. Activation of Slt2 by overexpression of a constitutively active allele of an upstream Slt2 activator (Pkc1) or by auxin-induced degradation of a negative Slt2 regulator (Sln1) caused hyperphosphorylation of Avo2 at its MAPK phosphoacceptor sites in a Slt2-dependent manner and diminished TORC2-mediated phosphorylation of its major downstream effector, protein kinase Ypk1. Deletion of Avo2 or expression of a phosphomimetic Avo2 allele rendered cells sensitive to two stresses (myriocin treatment and elevated exogenous acetic acid) that the cell requires Ypk1 activation by TORC2 to survive. Thus, Avo2 is necessary for optimal TORC2 activity, and Slt2-mediated phosphorylation of Avo2 down-regulates TORC2 signaling. Compared with wild-type Avo2, phosphomimetic Avo2 shows significant displacement from the plasma membrane, suggesting that Slt2 inhibits TORC2 by promoting Avo2 dissociation. Our findings are the first demonstration that TORC2 function is regulated by MAPK-mediated phosphorylation.Comment: This work was supported by National Institutes of Health (NIH) Predoctoral Traineeship GM07232 and a University of California at Berkeley MacArthur and Lakhan-Pal Graduate Fellowship to K.L.L., Erwin Schroedinger Fellowship J3787-B21 from the Austrian Science Fund to AE-A, Marie Sklodowska-Curie Action H2020-MSCA-IF-2016 InsiliCardio, GA 75083 to CMA, and NIH R01 research grant GM21841 to J

Spreading of healthy mood in adolescent social networks

Depression is a major public health concern worldwide. There is evidence that social support and befriending influence mental health, and an improved understanding of the social processes that drive depression has the potential to bring significant public health benefits. We investigate transmission of mood on a social network of adolescents, allowing flexibility in our model by making no prior assumption as to whether it is low mood or healthy mood that spreads. Here, we show that while depression does not spread, healthy mood among friends is associated with significantly reduced risk of developing and increased chance of recovering from depression. We found that this spreading of healthy mood can be captured using a non-linear complex contagion model. Having sufficient friends with healthy mood can halve the probability of developing, or double the probability of recovering from, depression over a 6–12-month period on an adolescent social network. Our results suggest that promotion of friendship between adolescents can reduce both incidence and prevalence of depression

Modelling the epidemiological implications for SARS-CoV-2 of Christmas household bubbles in England

The emergence of SARS-CoV-2 saw severe detriments to public health being inflicted by COVID-19 disease throughout 2020. In the lead up to Christmas 2020, the UK Government sought an easement of social restrictions that would permit spending time with others over the Christmas period, whilst limiting the risk of spreading SARS-CoV-2. In November 2020, plans were published to allow individuals to socialise within ‘Christmas bubbles’ with friends and family. This policy involved a planned easing of restrictions in England between 23-27 December 2020, with Christmas bubbles allowing people from up to three households to meet throughout the holiday period. We estimated the epidemiological impact of both this and alternative bubble strategies that allowed extending contacts beyond the immediate household. We used a stochastic individual-based model for a synthetic population of 100,000 households, with demographic and SARS-CoV-2 epidemiological characteristics comparable to England as of November 2020. We evaluated five Christmas bubble scenarios for the period 23-27 December 2020, assuming our populations of households did not have symptomatic infection present and were not in isolation as the eased social restrictions began. Assessment comprised incidence and cumulative infection metrics. We tested the sensitivity of the results to a situation where it was possible for households to be in isolation at the beginning of the Christmas bubble period and also when there was lower adherence to testing, contact tracing and isolation interventions. We found that visiting family and friends over the holiday period for a shorter duration and in smaller groups was less risky than spending the entire five days together. The increases in infection from greater amounts of social mixing disproportionately impacted the eldest. We provide this account as an illustration of a real-time contribution of modelling insights to a scientific advisory group, the Scientific Pandemic Influenza Group on Modelling, Operational sub-group (SPI-M-O) for the Scientific Advisory Group for Emergencies (SAGE) in the UK, during the COVID-19 pandemic. This manuscript was submitted as part of a theme issue on “Modelling COVID-19 and Preparedness for Future Pandemics”

Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism

Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention

Update on Electricity Customer Choice In Ohio: Competition Continues to Outperform Traditional Monopoly Regulation (Executive Summary)

Key Findings at a Glance: Deregulated Markets Save Ohio Electricity Consumers Billions Since 2011, deregulation has saved Ohio consumers $23.9 billion. The Study Team anticipates that savings will continue for the near term to be around$3 billion per year. However, these savings may be lost, in whole or in part, if deregulated energy markets continue to be undermined by cross subsidies. Competition Outperforms Monopoly Regulation Competition has driven down average electricity prices in deregulated Midwestern states while their regulated peers have seen a steady increase in price of generated electricity

Update on Electricity Customer Choice In Ohio: Competition Continues to Outperform Traditional Monopoly Regulation (Executive Summary)

Key Findings at a Glance: Deregulated Markets Save Ohio Electricity Consumers Billions Since 2011, deregulation has saved Ohio consumers $23.9 billion. The Study Team anticipates that savings will continue for the near term to be around$3 billion per year. However, these savings may be lost, in whole or in part, if deregulated energy markets continue to be undermined by cross subsidies. Competition Outperforms Monopoly Regulation Competition has driven down average electricity prices in deregulated Midwestern states while their regulated peers have seen a steady increase in price of generated electricity

Seasonal influenza : modelling approaches to capture immunity propagation

Seasonal influenza poses serious problems for global public health, being a significant contributor to morbidity and mortality. In England, there has been a long-standing national vaccination programme, with vaccination of at-risk groups and children offering partial protection against infection. Transmission models have been a fundamental component of analysis, informing the efficient use of limited resources. However, these models generally treat each season and each strain circulating within that season in isolation. Here, we amalgamate multiple data sources to calibrate a susceptible-latent-infected-recovered type transmission model for seasonal influenza, incorporating the four main strains and mechanisms linking prior season epidemiological outcomes to immunity at the beginning of the following season. Data pertaining to nine influenza seasons, starting with the 2009/10 season, informed our estimates for epidemiological processes, virological sample positivity, vaccine uptake and efficacy attributes, and general practitioner influenza-like-illness consultations as reported by the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). We performed parameter inference via approximate Bayesian computation to assess strain transmissibility, dependence of present season influenza immunity on prior protection, and variability in the influenza case ascertainment across seasons. This produced reasonable agreement between model and data on the annual strain composition. Parameter fits indicated that the propagation of immunity from one season to the next is weaker if vaccine derived, compared to natural immunity from infection. Projecting the dynamics forward in time suggests that while historic immunity plays an important role in determining annual strain composition, the variability in vaccine efficacy hampers our ability to make long-term predictions

Assessing the potential of non-harmful, natural feeding deterrents tested on captive primates

Crop damage by non-human primates, can cause friction between local people, government wildlife agencies and conservationists. Consequently, developing effective, non-lethal methods to protect crops against primate foraging could benefit farmers, reduce conflicts between interest groups, and even promote primate conservation The purpose of this research was to (i) develop a simple, economical protocol for testing the deterrent properties of non-lethal plant substances on captive primates prior to testing in the field; (ii) examine the preliminary effectiveness of neem (Azadirachta indica) and ocimum (Ocimum kilimandscharicum) essential oils, and spent coffee grounds (SCG) as feeding deterrents in captive macaques. The test methods developed involved exposing primates to possible feeding deterrents whilst feeding and comparing to a control. This was used to identify likely repellent substances, which could then be tested in the field to determine their effectiveness against crop damage. SCG were most effective at deterring the macaques; ocimum and neem essential oils were less effective though animals appeared less willing to access food when protected by these oils than they were under control conditions