Modelling the contribution of hormonal and inflammatory pathways to term and preterm labour in the mouse

Labour onset results from a complex interplay between hormonal and inflammatory signals. Untimely activation of these pathways can cause preterm labour (PTL) and premature birth (<37 weeks of gestation), the primary cause of infant mortality. Throughout gestation, uterine quiescence is maintained by progesterone and its withdrawal at term induces pro-labour genes and activation of uterine contractions. Infection and inflammation are frequently associated with PTL. Recognition of bacteria by the maternal innate immune system involves activation of nuclear factor kappa-B (NFκB) and activator protein-1 (AP-1), which regulate inflammatory and pro-labour genes. The aim of this thesis was to determine the contribution of inflammatory and hormonal pathways to parturition in murine models by comparing molecular changes in myometrium throughout term gestation, PTL induced by lipopolysaccharide (LPS; inflammation-induced PTL), and RU486-induced PTL by progesterone withdrawal (non-inflammatory PTL). Term gestation was shown to involve sequential activation of NFκB and AP-1. Different LPS serotypes induced heterogeneous maternal and fetal responses in the LPS-induced PTL model. LPS O111:B4 caused the most severe phenotype of PTL within 7h and total fetal demise. This involved JNK/AP-1-mediated activation of uterine inflammation, without NFκB activation. TLR-4 ablation rescued this phenotype and JNK inhibition delayed PTL. RU486 caused PTL without modulation of inflammatory pathways. RNA-Seq was used to characterize dynamic uterine transcriptome changes antecedent to term labour or PTL (RU486 or LPS-induced). Strong similarity was observed within term gestation and RU486-induced PTL transcriptomes, while the LPS model involved distinctive inflammatory gene changes. Positive correlation was found between human and murine transcriptomes. This thesis shows that LPS-induced inflammation can override repressive effects of progesterone on pro-labour genes while abrogation of progesterone signalling prompts PTL without inflammatory gene activation. These data support the paradigm of a common terminal pathway of labour yet provides new evidence that inflammatory gene activation is not necessary for labour.Open Acces

A systemic approach to the prevention and management of the causes of Hotel Environmental Sustainability Strategy Execution Failure (HESSEF)

Thesis (MEng)--Stellenbosch University, 2022.ENGLISH ABSTRACT: Our world is at risk due to unprecedented anthropogenic global warming leading to climate change. From pre-industrial period (1850-1900) to 2006-2015, global mean surface (land and ocean) temperature (GMST) and mean land surface air temperature (MSAT) respectively increased by 0.87°C and 1.53°C, leading to increasing occurrence of severe natural disasters. Hotels (184 thousand with 17 million hotel rooms in 2018) enable significant economic growth and social progress within international tourism, the third largest industry in the world. In 2018, this industry was worth USD 1.7 trillion, contributed 10.4 per cent to world’s Gross Domestic Product (GDP), cared for 1.4 billion tourists, and employed 319 million persons (one in ten jobs). Unfortunately, hotels also have negative environmental impacts and account for one to two per cent of the five per cent global carbon dioxide emitted by the tourism industry. Hotels hence contribute to the global warming and climate change. There is a need to curb hotels’ carbon dioxide emissions with appropriate strategies. However, properly formulated strategies do not guarantee effective execution. Strategy Execution (SE) is difficult to achieve and execution failure is possible. The execution of Hotel Environmental Sustainability Strategies (HESS) is not an exception. A Hotel Environmental Sustainability Strategy Execution (HESSE) paradigm shift and behaviour change, with subsequent habits of effectiveness are hence required. The aim of this study is to address the following research problem: “There is no model that can assist hotel practitioners (HP) and academics with a systemic approach to the prevention and management of the causes of Hotel Environmental Sustainability Strategy Execution Failure (HESSEF).” The primary objective of the study is the development of the Seven Habits of Effective HESSE (7HoE HESSE) model to address this problem. In support to the primary objective, a number of secondary objectives are pursued. First, the world sustainability challenges and initiatives are described. Second, the challenges of environmental sustainability within the context of hotel management are understood and opportunities for improvement are identified. Third, the challenges of HESSE are understood. Fourth, the escalation of HESSEF is analyzed and possible HESSE paradigm shift and behaviour change for systemic HESSE enhancement are studied. Fifth, the 7HoE HESSE model for HESSE systemic enhancement is conceptualized and operationalized. Sixth, the model is verified. Seventh, the model is validated through face to-face structured interview of HP and feedback used for the model improvement. The 7HoE HESSE model is described by HP as the way forward for sustainability as it provides a good approach towards sustainability. HP highly appreciated the model describing it as a great tool, highly suitable to the hospitality industry, interesting model, straight-forward, easy to understand and well structured with appropriate monitoring HESSE processes. HP expressed high willingness to experience the 7HoE HESSE model which properly summarizes and contextualizes their reality. They are willing to experience the model as they believe it will be very useful for favouring collaboration and commitment of all hotel stakeholders. They expressed the views that the model could ensure successful execution of sustainability projects in the hotel industry.AFRIKAANSE OPSOMMING: Die planeet word bedreig deur ongekende vlakke van aardverwarming wat lei tot klimaatsverandering. Die gemiddelde Land en Oseaan temperature of the wel (GMST), sowel as gemiddelde Land en Atmosfeer temperatuur of te wel (MSAT) het onderskeidlik met 0.87 grade celcuis en 1.53 grade celcuis toegeneem sedert die pre-industrieële periode (1850- 1900). Klimaatsverandering gee aanleiding tot natuur rampe. Die hotel industrie het ‘n positiewe impak op ekonomies groei en sosiale ontwikkeling. Daar is tans nie minder as 184 duisend hotelle and 17 miljoen hotel kamers. Toerisme was pre-Covid die derde grootste industrie ter wêreld en was in 2018 USD 1.7 triljoen werd. Die industrie was verantwoordelik vir 10.4 persent van die wêreld se Bruto Nasionale Produk, en het werk verskaf aan 319 miljoen mense (een uit elke 10 werk geleenthede op aarde). Hotelle het ongelukkig ook ‘n baie negatiewe impak op die omgewing en is verantwoordelik vir tot 40 present van alle CO2 wat deur die toerisme bedryf geproduseer word. Dit is dus baie belangrik vir hotelle om strategieë. te onwikkel wat hierdie potensiele nagatiewe impak kan verlaag. Strategie Uitvoering (SU) in die algemeen is moeilik en mislukking is baie moontlik. Die uitvoer van ‘n Hotel Omgewings Volhoubaarheid Strategie (HOVS) is nie ‘n uitsondering nie. ‘n Paradigma skuif en gedragsverandering is dus noodsaaklik om effeftiewe HOVS Uitvoering (HOVSU) te verseker. Dit is dus verdermeer nodig om effektiewiteits gewoontes te kweek. Die oogmerk van hierdie studie is om die volgende navorsingsprobleem aan te spreek: “Daar bestaan tans geen model wat Hotel Operateurs (HO) en akademici kan bystaan om deur middel van ‘n systematiese benadering die oorsake van Hotel Omgewings Volhoubaarheid Strategie Uitvoerings Mislukking (HOVSUM) te verminder en te bestuur nie.” Die primêre doelwit van die studie is die ontwikkeling van ‘n gedragsveranderingsmodel wat sal aanleiding gee tot die kweek van Sewe HOVSU gewoontes (7HoE HESSE). In ondersteuning tot die primêre doelwit is ‘n aantal sekondêre doelwitte geformuleer. Eerstens is die aard en omvang van die planeet se volhoubaarheidsuitdagins en inisiatiewe beskyf. Tweendens is die omgewingsvolhoubaarheiduitdagings wat hotelle in die gesig staar beskryf. Derderds is die problematiek aangaande HOVSU ondersoek en beskryf. Vierdens is die verloop van HOVSUM en moontlikhede aangaande gedragsverandering en gewoonte vorming beskryf. Die vyde sekondêre doelwit was die formulering en operasionalisering van die 7HoE HESSE model. In die sesde plek is die model geverifieer en in die sewende plek is die model gevalideer tydens indiepte onderhoude met Hotel Operateurs en bestuurders sowel as industrie kundiges. Die terugvoer van beide operateurs en kundiges is besonder positief en die model word beskryf as ‘n eenvoudige en prakties implementeerbare instrument om die problematiek wat verband hou met die uitvoer van omgewingsvolhoubaarheid strategieë binne hotelle die hoof te bied.Master

Hacia la definición de una base regional de recursos líticos en el área del Curacó : Una cantera taller: Puesto Córdoba (La Pampa, Argentina)

Como una etapa de estudio de los subsistemas tecnológicos de los cazadores-recolectores pampeanos este trabajo intenta abordar el análisis del sistema de producción lítica, a partir de una serie de variables. Uno de los objetivos fundamentales es definir la Base Regional de Recursos Líticos como una vía para la comprensión de la etapa de aprovisionamiento local y una búsqueda de factores explicativos de la presencia de materiales extra-regionales. El análisis de la procedencia de las materias primas utilizadas permite conocer la oferta local de los recursos así como las estrategias implementadas por los grupos humanos del Área para la obtención de rocas aptas para la talla. A partir del registro arqueológico estratigráfico del Sitio 1 de la localidad Tapera Moreira se evaluó cuali-cuantitativamente la variabilidad de rocas presentes, algunas de las cuales sugieren el aprovisionamiento lítico a una escala que trasciende el ámbito local. Esto se relacionarla con pautas de movilidad y captación de recursos definidas para el espacio de asentamiento del Curacó.As a stage in the study of the technological subsysrems of Pampean hunter-gatherers, this contribution approaches the analysis of the lithic production system considering a set of variables. One of the main objectives is to define a Regional Base of Uthic Resources as a means of understanding the stage of local procurement and to search for factors that would explain the presence of extra-regional materials. The analysis of the sources of the raw material utilized allows us to know the local supply of resources as well as the strategies implemented by the human groups of this area for the procurement of rocks fit for knapping. Based on the study of the stratigraphic archaeological record of Site J of the Tapera Moreira locality, the variability of the rocks present was quali-quantitatively evaluated. Some of these rocks suggest lithic procurement on a scale which transcends the local scope. This might be related to mobility and resource procurement patterns defined for the Curacó settlement space.Sociedad Argentina de Antropologí

Hacia la definición de una base regional de recursos líticos en el área del Curacó : Una cantera taller: Puesto Córdoba (La Pampa, Argentina)

Como una etapa de estudio de los subsistemas tecnológicos de los cazadores-recolectores pampeanos este trabajo intenta abordar el análisis del sistema de producción lítica, a partir de una serie de variables. Uno de los objetivos fundamentales es definir la Base Regional de Recursos Líticos como una vía para la comprensión de la etapa de aprovisionamiento local y una búsqueda de factores explicativos de la presencia de materiales extra-regionales. El análisis de la procedencia de las materias primas utilizadas permite conocer la oferta local de los recursos así como las estrategias implementadas por los grupos humanos del Área para la obtención de rocas aptas para la talla. A partir del registro arqueológico estratigráfico del Sitio 1 de la localidad Tapera Moreira se evaluó cuali-cuantitativamente la variabilidad de rocas presentes, algunas de las cuales sugieren el aprovisionamiento lítico a una escala que trasciende el ámbito local. Esto se relacionarla con pautas de movilidad y captación de recursos definidas para el espacio de asentamiento del Curacó.As a stage in the study of the technological subsysrems of Pampean hunter-gatherers, this contribution approaches the analysis of the lithic production system considering a set of variables. One of the main objectives is to define a Regional Base of Uthic Resources as a means of understanding the stage of local procurement and to search for factors that would explain the presence of extra-regional materials. The analysis of the sources of the raw material utilized allows us to know the local supply of resources as well as the strategies implemented by the human groups of this area for the procurement of rocks fit for knapping. Based on the study of the stratigraphic archaeological record of Site J of the Tapera Moreira locality, the variability of the rocks present was quali-quantitatively evaluated. Some of these rocks suggest lithic procurement on a scale which transcends the local scope. This might be related to mobility and resource procurement patterns defined for the Curacó settlement space.Sociedad Argentina de Antropologí

Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics

BACKGROUND: Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. METHODS: Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. RESULTS: We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. CONCLUSIONS: Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human "functional progesterone withdrawal." This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies

Specific Lipopolysaccharide Serotypes Induce Differential Maternal and Neonatal Inflammatory Responses in a Murine Model of Preterm Labor.

Intrauterine inflammation is recognized as a key mediator of both normal and preterm birth but is also associated with neonatal neurological injury. Lipopolysaccharide (LPS) is often used to stimulate inflammatory pathways in animal models of infection/inflammation-induced preterm labor; however, inconsistencies in maternal and neonatal responses to LPS are frequently reported. We hypothesized that LPS serotype-specific responses may account for a portion of these inconsistencies. Four different Escherichia coli LPS serotypes (O111:B4, O55:B5, O127:B8, and O128:B12) were administered to CD1 mice via intrauterine injection at gestational day 16. Although control animals delivered at term 60 ± 15 hours postinjection (p.i.), those administered with O111:B4 delivered 7 ± 2 hours p.i., O55:B5 delivered 10 ± 3 hours p.i., O127:B8 delivered 16 ± 10 hours p.i., and O128:B12 delivered 17 ± 2 hours p.i. (means ± SD). A correlation between the onset of preterm labor and myometrial activation of the inflammatory transcription factor, activator protein 1, but not NF-κB was observed. Specific LPS serotypes induced differential activation of downstream contractile and inflammatory pathways in myometrium and neonatal pup brain. Our findings demonstrate functional disparity in inflammatory pathway activation in response to differing LPS serotypes. Selective use of LPS serotypes may represent a useful tool for targeting specific inflammatory response mechanisms in these models

Functional rewiring of G protein-coupled receptor signaling in human labo

Current strategies to manage preterm labor center around inhibition of uterine myometrial contractions, yet do not improve neonatal outcomes as they do not address activation of inflammation. Here, we identify that during human labor, activated oxytocin receptor (OTR) reprograms the prostaglandin E2 receptor, EP2, in the pregnant myometrium to suppress relaxatory/Gαs-cAMP signaling and promote pro-labor/inflammatory responses via altered coupling of EP2 from Gαq/11 to Gαi/o. The ability of EP2 to signal via Gαi/o is recapitulated with in vitro OT and only following OTR activation, suggesting direct EP2-OTR crosstalk. Super-resolution imaging with computational modeling reveals OT-dependent reorganization of EP2-OTR complexes to favor conformations for Gαi over Gαs activation. A selective EP2 ligand, PGN9856i, activates the relaxatory/Gαs-cAMP pathway but not the pro-labor/inflammatory responses in term-pregnant myometrium, even following OT. Our study reveals a mechanism, and provides a potential therapeutic solution, whereby EP2-OTR functional associations could be exploited to delay preterm labor

学会抄録

Canonical pathways enrichment calculated by Ingenuity Pathway Analysis. A total of 46 pathways were detected as significantly enriched with genes differentially expressed in the pairwise comparisons indicated in the first row of the table (P < 0.05). First column on the left indicates Gene Ontology name associated with the canonical pathway. Log10P values are reported for each pathway. (XLS 38 kb