Bcl-xL gain of function and p19ARF loss of function cooperate oncogenically with Myc in vivo by distinct mechanisms

SummaryOverexpression of Bcl-xL, loss of p19ARF, and loss of p53 all accelerate Myc oncogenesis. All three lesions are implicated in suppressing Myc-induced apoptosis, suggesting that this is a common mechanism by which they synergize with Myc. However, using an acutely switchable model of Myc-induced tumorigenesis, we demonstrate that each lesion cooperates with Myc in vivo by a distinct mechanism. While Bcl-xL blocks Myc-induced apoptosis, inactivation of p19ARF enhances it. However, this increase in apoptosis is matched by increased Myc-induced proliferation. p53 inactivation shares features of both lesions, partially suppressing apoptosis while augmenting proliferation. Bcl-xL and p19ARF loss together synergize to further accelerate Myc oncogenesis. Thus, differing lesions cooperate oncogenically with Myc by discrete mechanisms that can themselves synergize with each other

mtDNA depletion confers specific gene expression profiles in human cells grown in culture and in xenograft

<p>Abstract</p> <p>Background</p> <p>Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function. However, the effects mitochondrial DNA (mtDNA) levels have on the nuclear transcriptome have not been defined under physiological conditions. In order to address this issue, we characterized the gene expression profiles of A549 lung cancer cells and their mtDNA-depleted ρ⁰counterparts grown in culture and as tumor xenografts in immune-deficient mice.</p> <p>Results</p> <p>Cultured A549 ρ⁰cells were respiration-deficient and showed enhanced levels of transcripts relevant to metal homeostasis, initiation of the epithelial-mesenchymal transition, and glucuronidation pathways. Several well-established HIF-regulated transcripts showed increased or decreased abundance relative to the parental cell line. Furthermore, growth in culture versus xenograft has a significantly greater influence on expression profiles, including transcripts involved in mitochondrial structure and both aerobic and anaerobic energy metabolism. However, both <it>in vitro </it>and <it>in vivo</it>, mtDNA levels explained the majority of the variance observed in the expression of transcripts in glucuronidation, tRNA synthetase, and immune surveillance related pathways. mtDNA levels in A549 xenografts also affected the expression of genes, such as <it>AMACR </it>and <it>PHYH</it>, involved in peroxisomal lipid metabolic pathways.</p> <p>Conclusion</p> <p>We have identified mtDNA-dependent gene expression profiles that are shared in cultured cells and in xenografts. These profiles indicate that mtDNA-depleted cells could provide informative model systems for the testing the efficacy of select classes of therapeutics, such as anti-angiogenesis agents. Furthermore, mtDNA-depleted cells grown culture and in xenografts provide a powerful means to investigate possible relationships between mitochondrial activity and gene expression profiles in normal and pathological cells.</p

The case for a West Saxon minuscule

Copyright © Cambridge University Press 1997Julian Brown's famous analysis of what he termed the Insular system of scripts marked out a number of routes, now well trodden, through the debris of undated and unlocalized manuscript material from the pre-Viking-Age British Isles. Ever since, the best hope for students of palaeography seeking to date and localize examples of early Insular minuscule has been to follow Brown's classification and identify them as Type A or B, Northumbrian or Southumbrian, and Phase I or II. Brown's schema, however, offered orientation rather than a map. As with any typology, it depends on a very few fixed points, themselves unusual because of their lack of anonymity: gospelbooks from Ireland and Northumbria dated by the survival of rare colophons, manuscripts connected with St Boniface which show the operation of a unique editorial mind. Although Brown's system has been successfully applied to the output of scriptoria whose influences, practices, connections, even locations remain mostly unknown, complications inevitably arise. This article concerns one of them, the recycling in Phase II of a type of minuscule displaying the cursiveness and capriciousness characteristic of Phase I: Type B minuscule as illustrated by the script of St Boniface

The Impact of Membrane Lipid Composition on Macrophage Activation in the Immune Defense against Rhodococcus equi and Pseudomonas aeruginosa

Nutritional fatty acids are known to have an impact on membrane lipid composition of body cells, including cells of the immune system, thus providing a link between dietary fatty acid uptake, inflammation and immunity. In this study we reveal the significance of macrophage membrane lipid composition on gene expression and cytokine synthesis thereby highlighting signal transduction processes, macrophage activation as well as macrophage defense mechanisms. Using RAW264.7 macrophages as a model system, we identified polyunsaturated fatty acids (PUFA) of both the n-3 and the n-6 family to down-regulate the synthesis of: (i) the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α; (ii) the co-stimulatory molecule CD86; as well as (iii) the antimicrobial polypeptide lysozyme. The action of the fatty acids partially depended on the activation status of the macrophages. It is particularly important to note that the anti-inflammatory action of the PUFA could also be seen in case of infection of RAW264.7 with viable microorganisms of the genera R. equi and P. aeruginosa. In summary, our data provide strong evidence that PUFA from both the n-3 and the n-6 family down-regulate inflammation processes in context of chronic infections caused by persistent pathogens

Genetic Variations in IL28B and Allergic Disease in Children

Environmental changes affecting the relationship between the developing immune system and microbial exposure have been implicated in the epidemic rise of allergic disease in developed countries. While early developmental differences in T cell function are well-recognised, there is now emerging evidence that this is related to developmental differences in innate immune function. In this study we sought to examine if differences associated with innate immunity contribute to the altered immune programming recognised in allergic children. Here, we describe for the first time, the association of carriage of the T allele of the tagging single nucleotide polymorphism rs12979860 3 kb upstream of IL28B, encoding the potent innate immune modulator type III interferon lambda (IFN-λ3), and allergy in children (p = 0.004; OR 4.56). Strikingly, the association between rs12979860 genotype and allergic disease is enhanced in girls. Furthermore, carriage of the T allele at rs12979860 correlates with differences in the pro-inflammatory profile during the first five years of life suggesting this contributes to the key differences in subsequent innate immune development in children who develop allergic disease. In the context of rising rates of disease, these immunologic differences already present at birth imply very early interaction between genetic predisposition and prenatal environmental influences

Accounting for Centennial Scale Variability when Detecting Changes in ENSO: a study of the Pliocene

The El Niño Southern Oscillation (ENSO) is the dominant mode of interannual climate variability. However, climate models are inconsistent in future predictions of ENSO, and long term variations in ENSO cannot be quantified from the short instrumental records available. Here we analyse ENSO behaviour in millennial-scale climate simulations of a warm climate of the past, the mid-Pliocene Warm Period (mPWP; ∼3.3 − 3.0Ma). We consider centennial-scale variability in ENSO for both the mPWP and the preindustrial, and consider which changes between the two climates are detectable above this variability. We find that El Niño typically occurred 12% less frequently in the mPWP but with a 20% longer duration, and with stronger amplitude in precipitation and temperature. However low frequency variability in ENSO meant that Pliocene-preindustrial changes in El Niño temperature amplitude in the NINO3.4 region (5° N-5° S, 170° W-120° W) were not always detectable. The Pliocene-preindustrial El Niño temperature signal in the NINO4 region (5° N-5° S, 160° E-150° W) and the El Niño precipitation signal are usually larger than centennial scale variations of El Niño amplitude, and provide consistent indications of ENSO amplitude change. The enhanced mPWP temperature signal in the NINO4 region is associated with an increase in Central Pacific El Niño events similar to those observed in recent decades and predicted for the future. This study highlights the importance of considering centennial scale variability when comparing ENSO changes between two climate states. If centennial scale variability in ENSO has not first been established, results suggesting changes in ENSO behaviour may not be robust

Tissue-specific alternative polyadenylation at the imprinted gene Mest regulates allelic usage at Copg2

The gene Mest (also known as Peg1) is regulated by genomic imprinting in the mouse and only the paternal allele is active for transcription. MEST is similarly imprinted in humans, where it is a candidate for the growth retardation Silver-Russell syndrome. The MEST protein belongs to an ancient family of hydrolases but its function is still unknown. It is highly conserved in vertebrates although imprinted expression is only observed in marsupials and eutherians, thus a recent evolutionary event. Here we describe the identification of new imprinted RNA products at the Mest locus, longer variants of the RNA, called MestXL, transcribed >10 kb into the downstream antisense gene Copg2. During development MestXL is produced exclusively in the developing central nervous system (CNS) by alternative polyadenylation. Copg2 is biallelically expressed in the embryo except in MestXL-expressing tissues, where we observed preferential expression from the maternal allele. To analyze the function of the MestXL transcripts in Copg2 regulation, we studied the effects of a targeted allele at Mest introducing a truncation in the mRNA. We show that both the formation of the MestXL isoforms and the allelic bias at Copg2 are lost in the CNS of mutants embryos. Our results propose a new mechanism to regulate allelic usage in the mammalian genome, via tissue-specific alternative polyadenylation and transcriptional interference in sense–antisense pairs at imprinted loci

Equipping Health Professions Educators to Better Address Medical Misinformation

As part of a cooperative agreement with the US Centers for Disease Control and Prevention (Federal Award Identification Number [FAIN]: NU50CK000586), the Association of American Medical Colleges (AAMC) began a strategic initiative in 2022 both to increase confidence in COVID-19 vaccines and to address medical misinformation and mistrust through education in health professions contexts. Specifically, the AAMC solicited proposals for integrating competency-based, interprofessional strategies to mitigate health misinformation into new or existing curricula. Five Health Professions Education Curricular Innovations subgrantees received support from the AAMC in 2022 and reflected on the implementation of their ideas in a series of meetings over several months. Subgrantees included the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Florida International University Herbert Wertheim College of Medicine, the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, the Maine Medical Center/Tufts University School of Medicine, and the University of Chicago Pritzker School of Medicine. This paper comprises insights from each of the teams and overarching observations regarding the challenges and opportunities involved with leveraging health professions education to address medical misinformation and improve patient health

Political transition and emergent forest-conservation issues in Myanmar.

Political and economic transitions have had substantial impacts on forest conservation. Where transitions are underway or anticipated, historical precedent and methods for systematically assessing future trends should be used to anticipate likely threats to forest conservation and design appropriate and prescient policy measures to counteract them. Myanmar is transitioning from an authoritarian, centralized state with a highly regulated economy to a more decentralized and economically liberal democracy and is working to end a long-running civil war. With these transitions in mind, we used a horizon-scanning approach to assess the 40 emerging issues most affecting Myanmar's forests, including internal conflict, land-tenure insecurity, large-scale agricultural development, demise of state timber enterprises, shortfalls in government revenue and capacity, and opening of new deforestation frontiers with new roads, mines, and hydroelectric dams. Averting these threats will require, for example, overhauling governance models, building capacity, improving infrastructure- and energy-project planning, and reforming land-tenure and environmental-protection laws. Although challenges to conservation in Myanmar are daunting, the political transition offers an opportunity for conservationists and researchers to help shape a future that enhances Myanmar's social, economic, and environmental potential while learning and applying lessons from other countries. Our approach and results are relevant to other countries undergoing similar transitions

Managing Oil Palm Plantations More Sustainably: Large-Scale Experiments Within the Biodiversity and Ecosystem Function in Tropical Agriculture (BEFTA) Programme

Conversion of tropical forest to agriculture results in reduced habitat heterogeneity, and associated declines in biodiversity and ecosystem functions. Management strategies to increase biodiversity in agricultural landscapes have therefore often focused on increasing habitat complexity; however, the large-scale, long-term ecological experiments that are needed to test the effects of these strategies are rare in tropical systems. Oil palm (Elaeis guineensis Jacq.)—one of the most widespread and important tropical crops—offers substantial potential for developing wildlife-friendly management strategies because of its long rotation cycles and tree-like structure. Although there is awareness of the need to increase sustainability, practical options for how best to manage oil palm plantations, for benefits to both the environment and crop productivity, have received little research attention. In this paper we introduce the Biodiversity and Ecosystem Function in Tropical Agriculture (BEFTA) Programme: a long-term research collaboration between academia and industry in Sumatra, Indonesia. The BEFTA Programme aims to better understand the oil palm agroecosystem and test sustainability strategies. We hypothesise that adjustments to oil palm management could increase structural complexity, stabilise microclimate, and reduce reliance on chemical inputs, thereby helping to improve levels of biodiversity and ecosystem functions. The Programme has established four major components: (1) assessing variability within the plantation under business-as-usual conditions; (2) the BEFTA Understory Vegetation Project, which tests the effects of varying herbicide regimes; (3) the Riparian Ecosystem Restoration in Tropical Agriculture (RERTA) Project, which tests strategies for restoring riparian habitat; and (4) support for additional collaborative projects within the Programme landscape. Across all projects, we are measuring environmental conditions, biodiversity, and ecosystem functions. We also measure oil palm yield and production costs, in order to assess whether suggested sustainability strategies are feasible from an agronomic perspective. Early results show that oil palm plantation habitat is more variable than might be expected from a monoculture crop, and that everyday vegetation management decisions have significant impacts on habitat structure. The BEFTA Programme highlights the value of large-scale collaborative projects for understanding tropical agricultural systems, and offers a highly valuable experimental set-up for improving our understanding of practices to manage oil palm more sustainably