INVESTIGATING THE ROLE OF THE P63 ISOFORM ΔNP63 IN LUNG STEM CELL POPULATIONS AND LUNG CANCER

Cell of origin studies have determined separate populations of lung progenitor cells that give rise to lung adenocarcinoma and squamous cell carcinoma. ΔNp63 is known to regulate lung development but its role in lung cancer progression remains unclear. We utilized a ΔNp63-specific conditional knockout mouse model to determine ΔNp63’s role in lung progenitor cells and lung cancer. In vivo and in vitro experiments revealed a role for ΔNp63 in maintaining lung progenitor cells. ChIP-seq results indicate that deletion of ΔNp63 results in robust loss of enhancer histone marks at cell identity genes for lung progenitor populations of basal cells and AT2 cells. Analysis of ΔNp63-regulated pathways uncovered that ΔNp63 regulates cell-type-specific genes as well as common genes for basal cells and AT2 cells. Our experiments using a deactivated cas9 system showed that co-targeting of ΔNp63 and the enhancer activator p300 to p63 binding motifs significantly enhanced the transcription of ΔNp63-regulated genes, indicating that ΔNp63 directly regulates enhancer region activity. These novel findings suggest that ΔNp63 acts as a master regulator of transcriptional and epigenetic networks in lung progenitor cells whose oncogenic characteristics are essential to the initiation and progression of lung cancer

Stocktaking Global Warming:The outcomes of the 2023 Dubai Climate Summit (COP28)

This briefing reviews outcomes of the 28th United Nations Climate Change Conference of the Parties (COP28)held in Dubai, United Arab Emirates in late 2023. In particular, it considered the first Global Stocktake [GST] of actions taken by signatory nations to the 2015 Paris Agreement on Climate Change. The GST examined the potential impact of bottom-up national pledges on ‘greenhouse gas’ [GHG] mitigation required to limit global warming to 1.5°C above pre-industrial levels by the end of the 21st Century. The achievements at COP28 were mixed, and disappointed many from the climate-vulnerable states at high risk from extreme weather events and rising sea levels. There is a significant GHG emissions gap between that needed to “keep 1.5°C alive” and climate actions identified in the GST. Nonetheless, the Parties agreed to “transition away from fossil fuels in energy systems” in order to reach net zero GHG emissions (i.e., carbon neutrality) by 2050, and to triple renewable energy capacity and double energy efficiency by 2030. The present assessment sets out the background to what needs to be achieved at future annual COP summits, including the next GST at COP30 to beheld in the Brazilian city of Belém later in 2025

Stocktaking Global Warming:The outcomes of the 2023 Dubai Climate Summit (COP28)

This briefing reviews outcomes of the 28th United Nations Climate Change Conference of the Parties (COP28)held in Dubai, United Arab Emirates in late 2023. In particular, it considered the first Global Stocktake [GST] of actions taken by signatory nations to the 2015 Paris Agreement on Climate Change. The GST examined the potential impact of bottom-up national pledges on ‘greenhouse gas’ [GHG] mitigation required to limit global warming to 1.5°C above pre-industrial levels by the end of the 21st Century. The achievements at COP28 were mixed, and disappointed many from the climate-vulnerable states at high risk from extreme weather events and rising sea levels. There is a significant GHG emissions gap between that needed to “keep 1.5°C alive” and climate actions identified in the GST. Nonetheless, the Parties agreed to “transition away from fossil fuels in energy systems” in order to reach net zero GHG emissions (i.e., carbon neutrality) by 2050, and to triple renewable energy capacity and double energy efficiency by 2030. The present assessment sets out the background to what needs to be achieved at future annual COP summits, including the next GST at COP30 to beheld in the Brazilian city of Belém later in 2025

Machine learning on cardiotocography data to classify fetal outcomes: A scoping review

Introduction: Uterine contractions during labour constrict maternal blood flow and oxygen delivery to the developing baby, causing transient hypoxia. While most babies are physiologically adapted to withstand such intrapartum hypoxia, those exposed to severe hypoxia or with poor physiological reserves may experience neurological injury or death during labour. Cardiotocography (CTG) monitoring was developed to identify babies at risk of hypoxia by detecting changes in fetal heart rate (FHR) patterns. CTG monitoring is in widespread use in intrapartum care for the detection of fetal hypoxia, but the clinical utility is limited by a relatively poor positive predictive value (PPV) of an abnormal CTG and significant inter and intra observer variability in CTG interpretation. Clinical risk and human factors may impact the quality of CTG interpretation. Misclassification of CTG traces may lead to both under-treatment (with the risk of fetal injury or death) or over-treatment (which may include unnecessary operative interventions that put both mother and baby at risk of complications). Machine learning (ML) has been applied to this problem since early 2000 and has shown potential to predict fetal hypoxia more accurately than visual interpretation of CTG alone. To consider how these tools might be translated for clinical practice, we conducted a review of ML techniques already applied to CTG classification and identified research gaps requiring investigation in order to progress towards clinical implementation. Materials and method: We used identified keywords to search databases for relevant publications on PubMed, EMBASE and IEEE Xplore. We used Preferred Reporting Items for Systematic Review and Meta-Analysis for Scoping Reviews (PRISMA-ScR). Title, abstract and full text were screened according to the inclusion criteria. Results: We included 36 studies that used signal processing and ML techniques to classify CTG. Most studies used an open-access CTG database and predominantly used fetal metabolic acidosis as the benchmark for hypoxia with varying pH levels. Various methods were used to process and extract CTG signals and several ML algorithms were used to classify CTG. We identified significant concerns over the practicality of using varying pH levels as the CTG classification benchmark. Furthermore, studies needed to be more generalised as most used the same database with a low number of subjects for an ML study. Conclusion: ML studies demonstrate potential in predicting fetal hypoxia from CTG. However, more diverse datasets, standardisation of hypoxia benchmarks and enhancement of algorithms and features are needed for future clinical implementation.</p

Dual isotope evidence for sedimentary integration of plant wax biomarkers across an Andes-Amazon elevation transect

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 242 (2018): 64-81, doi:10.1016/j.gca.2018.09.007.Tropical montane regions tend to have high rates of precipitation, biological production, erosion, and sediment export, which together move material off the landscape and toward sedimentary deposits downstream. Plant wax biomarkers can be used to investigate sourcing of organic matter and are often used as proxies to reconstruct past climate and environment in sedimentary deposits. To understand how plant waxes are sourced within a wet, tropical montane catchment, we measure the stable C and H isotope composition (δ13C and δD) of n-alkanes and n-alkanoic acids in soils along an elevation transect and from sediments within the Madre de Dios River network along the eastern flank of the Peruvian Andes, draining an area of 75,400 km2 and 6 km of elevation. Soils yield systematic trends in plant wax δ13C (+1.75 and +1.31‰ km−1, for the C29n-alkanes and C30n-alkanoic acids respectively in the mineral horizon) and δD values (−10 and −12‰ km−1, respectively) across a 3.5 km elevation transect, which approximates trends previously reported from canopy leaves, though we find offsets between δ13C values in plants and soils. River suspended sediments generally follow soil isotopic gradients defined by catchment elevations (δ13C: +1.03 and +0.99‰ km−1 and δD: −10 to −7‰ km−1, for the C29n-alkanes and C30n-alkanoic acids respectively) in the wet season, with a lowering in the dry season that is less well-constrained. In a few river suspended sediments, petrogenic contributions and depth-sorting influence the n-alkane δ13C signal. Our dual isotope, dual compound class and seasonal sampling approach reveals no Andean-dominance in plant wax export, and instead that the sourcing of plant waxes in this very wet, forested catchment approximates that expected for spatial integration of the upstream catchment, thus with a lowland dominance on areal basis, guiding paleoenvironmental reconstructions in tropical montane regions. The dual isotope approach provides a cross-check on the altitudinal signals and can resolve ambiguity such as might be associated with vegetation change or aridity in paleoclimate records. Further, the altitude effect encoded within plant waxes presents a novel dual-isotope biomarker approach to paleoaltimetry.This material is based upon work supported by the US National Science Foundation under Grant No. EAR-1227192 to A.J.W and S.J.F for the river work

Hit and run versus long-term activation of PARP-1 by its different domains fine-tunes nuclear processes.

Poly(ADP-ribose) polymerase 1 (PARP-1) is a multidomain multifunctional nuclear enzyme involved in the regulation of the chromatin structure and transcription. PARP-1 consists of three functional domains: the N-terminal DNA-binding domain (DBD) containing three zinc fingers, the automodification domain (A), and the C-terminal domain, which includes the protein interacting WGR domain (W) and the catalytic (Cat) subdomain responsible for the poly(ADP ribosyl)ating reaction. The mechanisms coordinating the functions of these domains and determining the positioning of PARP-1 in chromatin remain unknown. Using multiple deletional isoforms of PARP-1, lacking one or another of its three domains, as well as consisting of only one of those domains, we demonstrate that different functions of PARP-1 are coordinated by interactions among these domains and their targets. Interaction between the DBD and damaged DNA leads to a short-term binding and activation of PARP-1. This hit and run activation of PARP-1 initiates the DNA repair pathway at a specific point. The long-term chromatin loosening required to sustain transcription takes place when the C-terminal domain of PARP-1 binds to chromatin by interacting with histone H4 in the nucleosome. This long-term activation of PARP-1 results in a continuous accumulation of pADPr, which maintains chromatin in the loosened state around a certain locus so that the transcription machinery has continuous access to DNA. Cooperation between the DBD and C-terminal domain occurs in response to heat shock (HS), allowing PARP-1 to scan chromatin for specific binding sites

Longitudinal genome-wide methylation study of Roux-en-Y gastric bypass patients reveals novel CpG sites associated with essential hypertension

Background: Essential hypertension is a significant risk factor for cardiovascular diseases. Emerging research suggests a role of DNA methylation in blood pressure physiology. We aimed to investigate epigenetic associations of promoter related CpG sites to essential hypertension in a genome-wide methylation approach. Methods: The genome-wide methylation pattern in whole blood was measured in 11 obese patients before and six months after Roux-en-Y gastric bypass surgery using the Illumina 450 k beadchip. CpG sites located within 1500 bp of the transcriptional start site of adjacent genes were included in our study, resulting in 124 199 probes investigated in the subsequent analysis. Percent changes in methylation states and SBP measured before and six months after surgery were calculated. These parameters were correlated to each other using the Spearman's rank correlation method (Edgeworth series approximation). To further investigate the detected relationship between candidate CpG sites and systolic blood pressure levels, binary logistic regression analyses were performed in a larger and independent cohort of 539 individuals aged 19-101 years to elucidate a relationship between EH and the methylation state in candidate CpG sites. Results: We identified 24 promoter associated CpG sites that correlated with change in SBP after RYGB surgery (p &lt; 10-16). Two of these CpG loci (cg00875989, cg09134341) were significantly hypomethylated in dependency of EH (p &lt; 10-03). These results were independent of age, BMI, ethnicity and sex. Conclusions: The identification of these novel CpG sites may contribute to a further understanding of the epigenetic regulatory mechanisms underlying the development of essential hypertension