A Persistence Detector for Metabolic Network Rewiring in an Animal

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a persistence detector in a type 1, coherent feed-forward loop with an AND-logic gate to delay shunt activation upon propionate accumulation and to avoid spurious shunt activation in response to a non-sustained pulse of propionate. Together, our findings identify a persistence detector in an animal, which transcriptionally rewires propionate metabolism to maintain homeostasis

Keynote Lecture – The Interplay of Multiple Hazards and Urban Development: The context of Istanbul

Tomorrow’s Cities is the UK Research and Innovation (UKRI) Global Challenges Research Fund (GCRF) Urban Disaster Risk Hub – an interdisciplinary research hub with the aim to catalyse a transition from crisis management to multi-hazard risk-informed and inclusive planning in four cities in low-and-middle income countries. Istanbul in Turkey is one of the four cities investigated. It is one of the largest urban agglomerations in Europe where more than 15 million people reside in more than 1 million buildings. Considering that the population was 4.75 million in 1980, Istanbul’s urban sprawl was inevitable. Due to an imbalance between the population growth and housing supply, Istanbul’s urbanization was shaped by illegal construction processes producing the gecekondus in almost every part of the city (Gencer and Mentese, 2016). Unplanned urban expansion was so rapid that the urban master plan of 1980, which set the limits and strategies for urban development, became completely invalid by 1989 (Tapan, 1998). This situation led to the development of a new urban master plan in 1994 that included geoscientific analysis, and which highlighted the possibility of losses due to an earthquake on the segments of the North Anatolian Fault in the Marmara Sea. Uncontrolled and unplanned development continued in Istanbul until 1999 when two major earthquakes hit the region causing at least 18.000 deaths and $16 billion economic loss. These events changed the authorities’ perspective to earthquake risk and its mitigation. As a result, the 1998 earthquake resistant design code (published one year before the 1999 earthquakes) was widely embraced and implemented. Furthermore, several urban transformation projects have taken place in the last 20 years for reducing disaster risk. These have had varied success, with research to date showing that areas selected for urban transformation were often chosen on the basis of land value rather than hazard risk, and that a pro-poor approach is missing. Despite these efforts, Istanbul’s earthquake risk remains high. Furthermore, recent urban development plans are seeing the city expand into undeveloped lands to the west, increasing exposure to new hazards, namely flash flooding and landslides. The combined impact of these hazards is not evenly distributed, and the associated risks are heightened by poor infrastructural resilience and social vulnerabilities. Therefore, it is crucial to integrate different types of hazards and risks into the urban development context for future scenarios, so that a physically and socio-economically safer development that prioritizes the wellbeing of local communities can be facilitated. This presentation summarises the research conducted in Istanbul over the first 18 months of the Tomorrow’s Cities Project by a consortium of Turkish and UK researchers. This research spans the better characterisation of earthquake and landslide hazards, development of analysis methods for predicting the response of case study buildings to multiple hazards and a Bayesian network based approach for assessing road infrastructure resilience under multiple hazard scenarios. Furthermore, plans for building a Resilient Urban Development Decision Support Environment (RUD-DSE) for communicating the relevance of this research on future urban planning is described

WormPaths: Caenorhabditis elegans metabolic pathway annotation and visualization [preprint]

In our group, we aim to understand metabolism in the nematode Caenorhabditis elegans and its relationships with gene expression, physiology and the response to therapeutic drugs. On March 15, 2020, a stay-at-home order was put into effect in the state of Massachusetts, USA, to flatten the curve of the spread of the novel SARS-CoV2 virus that causes COVID-19. For biomedical researchers in our state, this meant putting a hold on experiments for nine weeks until May 18, 2020. To keep the lab engaged and productive, and to enhance communication and collaboration, we embarked on an in-lab project that we all found important but that we never had the time for: the detailed annotation and drawing of C. elegans metabolic pathways. As a result, we present WormPaths, which is composed of two parts: 1) the careful manual annotation of metabolic genes into pathways, categories and levels, and 2) 66 pathway maps that include metabolites, metabolite structures, genes, reactions, and pathway connections between maps. These maps are available on our WormFlux website. We show that WormPaths provides easy-to-navigate maps and that the different levels in WormPaths can be used for metabolic pathway enrichment analysis of transcriptomic data. In the unfortunate event of additional lockdowns, we envision further developing these maps to be more interactive, with an analogy of road maps that are available on mobile devices

JC Virus T-Antigen Regulates Glucose Metabolic Pathways in Brain Tumor Cells

Recent studies have reported the detection of the human neurotropic virus, JCV, in a significant population of brain tumors, including medulloblastomas. Accordingly, expression of the JCV early protein, T-antigen, which has transforming activity in cell culture and in transgenic mice, results in the development of a broad range of tumors of neural crest and glial origin. Evidently, the association of T-antigen with a range of tumor-suppressor proteins, including p53 and pRb, and signaling molecules, such as β-catenin and IRS-1, plays a role in the oncogenic function of JCV T-antigen. We demonstrate that T-antigen expression is suppressed by glucose deprivation in medulloblastoma cells and in glioblastoma xenografts that both endogenously express T-antigen. Mechanistic studies indicate that glucose deprivation-mediated suppression of T-antigen is partly influenced by 5′-activated AMP kinase (AMPK), an important sensor of the AMP/ATP ratio in cells. In addition, glucose deprivation-induced cell cycle arrest in the G1 phase is blocked with AMPK inhibition, which also prevents T-antigen downregulation. Furthermore, T-antigen prevents G1 arrest and sustains cells in the G2 phase during glucose deprivation. On a functional level, T-antigen downregulation is partially dependent on reactive oxygen species (ROS) production during glucose deprivation, and T-antigen prevents ROS induction, loss of ATP production, and cytotoxicity induced by glucose deprivation. Additionally, we have found that T-antigen is downregulated by the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), and the pentose phosphate inhibitors, 6-aminonicotinamide and oxythiamine, and that T-antigen modulates expression of the glycolytic enzyme, hexokinase 2 (HK2), and the pentose phosphate enzyme, transaldolase-1 (TALDO1), indicating a potential link between T-antigen and metabolic regulation. These studies point to the possible involvement of JCV T-antigen in medulloblastoma proliferation and the metabolic phenotype and may enhance our understanding of the role of viral proteins in glycolytic tumor metabolism, thus providing useful targets for the treatment of virus-induced tumors

Narcissism and the strategic pursuit of short-term mating : universal links across 11 world regions of the International Sexuality Description Project-2.

Previous studies have documented links between sub-clinical narcissism and the active pursuit of short-term mating strategies (e.g., unrestricted sociosexuality, marital infidelity, mate poaching). Nearly all of these investigations have relied solely on samples from Western cultures. In the current study, responses from a cross-cultural survey of 30,470 people across 53 nations spanning 11 world regions (North America, Central/South America, Northern Europe, Western Europe, Eastern Europe, Southern Europe, Middle East, Africa, Oceania, Southeast Asia, and East Asia) were used to evaluate whether narcissism (as measured by the Narcissistic Personality Inventory; NPI) was universally associated with short-term mating. Results revealed narcissism scores (including two broad factors and seven traditional facets as measured by the NPI) were functionally equivalent across cultures, reliably associating with key sexual outcomes (e.g., more active pursuit of short-term mating, intimate partner violence, and sexual aggression) and sex-related personality traits (e.g., higher extraversion and openness to experience). Whereas some features of personality (e.g., subjective well-being) were universally associated with socially adaptive facets of Narcissism (e.g., self-sufficiency), most indicators of short-term mating (e.g., unrestricted sociosexuality and marital infidelity) were universally associated with the socially maladaptive facets of narcissism (e.g., exploitativeness). Discussion addresses limitations of these cross-culturally universal findings and presents suggestions for future research into revealing the precise psychological features of narcissism that facilitate the strategic pursuit of short-term mating

Narcisismo y búsqueda estratégica del emparejamiento a corto plazo a través de las culturas: Enlaces omnipresentes a través de 11 regiones mundiales del Proyecto de la descripción de la sexualidad internacional 2

Previous studies have documented links between sub-clinical narcissism and the active pursuit of short-term mating strategies (e.g., unrestricted sociosexuality, marital infidelity, mate poaching). Nearly all of these investigations have relied solely on samples from Western cultures. In the current study, responses from a cross-cultural survey of 30,470 people across 53 nations spanning 11 world regions (North America, Central/South America, Northern Europe, Western Europe, Eastern Europe, Southern Europe, Middle East, Africa, Oceania, Southeast Asia, and East Asia) were used to evaluate whether narcissism (as measured by the Narcissistic Personality Inventory; NPI) was universally associated with short-term mating. Results revealed narcissism scores (including two broad factors and seven traditional facets as measured by the NPI) were functionally equivalent across cultures, reliably associating with key sexual outcomes (e.g., more active pursuit of short-term mating, intimate partner violence, and sexual aggression) and sex-related personality traits (e.g., higher extraversion and openness to experience). Whereas some features of personality (e.g., subjective well-being) were universally associated with socially adaptive facets of Narcissism (e.g., self-sufficiency), most indicators of short-term mating (e.g., unrestricted sociosexuality and marital infidelity) were universally associated with the socially maladaptive facets of narcissism (e.g., exploitativeness). Discussion addresses limitations of these cross-culturally universal findings and presents suggestions for future research into revealing the precise psychological features of narcissism that facilitate the strategic pursuit of short-term mating.Estudios previos, en primer lugar a través de las muestras de culturas occidentales, han documentado asociaciones sistemáticas del narcisismo subclínico con múltiples indicadores de estrategias del emparejamiento a corto plazo (p. ej. sociosexualidad ilimitada, infidelidad, caza de pareja). En este estudio se han usado respuestas de la encuesta transcultural de 30.470 personas de 53 naciones de 11 regiones mundiales (América del Norte, América del Sur/América Central, Europa del Norte, Europa del Oeste, Europa del Este, Europa del Sur, Oriente Próximo, África, Asia del Sur/Sudoeste de Asia, Asia del Este y Oceanía) para evaluar si el narcisismo (medido por el Inventario de Personalidad Narcisista; NPI) se asocia panuniversalmente con los indicadores del emparejamiento a corto plazo, tanto en la dirección, como en la intensidad. Los resultados sugieren que el narcisismo (incluidos muchos aspectos suyos medidos por el NPI) tiene las mismas asociaciones básicas con los rasgos de personalidad relacionados con el sexo (p. ej. extraversión alta) y con los resultados sexuales claves (p. ej. búsqueda más activa de las estrategias del emparejamiento a corto plazo) a través de las 11 mayores regiones mundiales del PDSI 2. La discusión se enfoca en las implicaciones y limitaciones del estudio actual

Percutaneous left atrial appendage closure reduces cost of care independent of the institutional cumulative caseload in patients with non-valvular atrial fibrillation

Background Data on the impact of the cumulative percutaneous left atrial appendage closure (LAAC) caseload on cardiovascular outpatient and hospitalisation costs are limited. Methods The present single-institution analysis includes patients treated consecutively from the beginning of our LAAC experience in January 2012 until December 2016. Pre- and post-LAAC costs for hospitalisation and ambulatory visits were included. Results A total of 676 patients underwent percutaneous LAAC (using the Watchman device): 49 (2012), 78 (2013), 211 (2014), 210 (2015), and 129 (2016). LAAC procedural costs were stable over the years (overall median euro9639; 2012: euro9630; 2013: euro10,003; 2014: euro9841; 2015: euro9394; 2016: euro9530; p = 0.8) and there was no correlation between cumulative caseload and procedural costs (p = 0.9). Although annualised cardiovascular management costs after LAAC were lower than before LAAC (median difference between pre-LAAC and post-LAAC yearly costs: euro727; 2012: euro235; 2013: euro1187; 2014: euro716; 2015: euro527; 2016: euro1052; p = 0.5 among years analysed) from the beginning of the cumulative procedural experience, a significant reduction in costs was observed only from 2014 onwards. Institutional cumulative LAAC caseload and year of procedure were not related to the amount of reduction in the costs for cardiovascular care. Conclusion LAAC led to cost-of-care savings from the beginning of our institutional procedural experience

Percutaneous left atrial appendage closure reduces cost of care independent of the institutional cumulative caseload in patients with non-valvular atrial fibrillation

Background Data on the impact of the cumulative percutaneous left atrial appendage closure (LAAC) caseload on cardiovascular outpatient and hospitalisation costs are limited. Methods The present single-institution analysis includes patients treated consecutively from the beginning of our LAAC experience in January 2012 until December 2016. Pre- and post-LAAC costs for hospitalisation and ambulatory visits were included. Results A total of 676 patients underwent percutaneous LAAC (using the Watchman device): 49 (2012), 78 (2013), 211 (2014), 210 (2015), and 129 (2016). LAAC procedural costs were stable over the years (overall median euro9639; 2012: euro9630; 2013: euro10,003; 2014: euro9841; 2015: euro9394; 2016: euro9530; p = 0.8) and there was no correlation between cumulative caseload and procedural costs (p = 0.9). Although annualised cardiovascular management costs after LAAC were lower than before LAAC (median difference between pre-LAAC and post-LAAC yearly costs: euro727; 2012: euro235; 2013: euro1187; 2014: euro716; 2015: euro527; 2016: euro1052; p = 0.5 among years analysed) from the beginning of the cumulative procedural experience, a significant reduction in costs was observed only from 2014 onwards. Institutional cumulative LAAC caseload and year of procedure were not related to the amount of reduction in the costs for cardiovascular care. Conclusion LAAC led to cost-of-care savings from the beginning of our institutional procedural experience.Cardiolog