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The North Atlantic sector has been identified as a region where the 11-year solar cycle has small but potentially non-negligible impacts on winter climate, but a debate persists about the robustness of such impacts. This work explores the signatures of the 11-year solar cycle over the North Atlantic in the ERA5 and 20th Century Reanalysis datasets. The results confirm previous studies with a robust positive boreal winter response in mean-sea-level pressure (mslp) in the region of the Azores at lags of three years after solar maximum. The spatial evolution of the response is examined in detail by first decomposing the mslp time series into the dominant modes of North Atlantic winter mslp variability, including the North Atlantic Oscillation (NAO), the East Atlantic (EA) and the Scandinavian patterns, before performing a multilinear regression analysis. We find that the maximum 11-year solar response in the December-January-February (DJF) average does not project directly onto the NAO. However, when the early/late-winter responses are examined separately, a statistically significant NAO response is seen in late winter (January-February) at lag 0-1 years and a statistically significant NAO response is also seen at lag +3 years in early winter (November-December). These results are consistent with predicted responses from previously proposed top-down influences from the stratosphere in late winter followed by the re-emergence of a signal from underlying sea surface temperatures in early winter. However, the NAO response is not the primary contributor to the total DJF response at lag +3 years. A previously unidentified solar-cycle response in the EA pattern is found in late winter at lag +3 years with larger amplitude than the NAO response. The evolution of the DJF mslp response over the Azores region can thus be understood as a summation of the NAO and EA patterns at lag +3 years.
Climate extremes are increasingly shaping both environmental and human health outcomes. Global warming has led to a rise in the frequency, duration, and intensity of extreme temperature events, with heatwaves emerging as one of the most hazardous weather-related threats. Beyond their well-recognized cardiovascular and respiratory effects, heat extremes are now understood to influence immune function. Growing evidence indicates that heat extremes along with air pollution, wildfires, humidity shifts, and ecosystem disruption can impair epithelial barrier integrity and disturb immune regulation. These stressors may promote chronic inflammation, alter adaptive immune responses, and compromise host defense mechanisms. Experimental and epidemiological data suggest that heat stress can reduce effective B-cell responses, modify antigen presentation, and increase inflammatory signaling, while combined exposures to heat and pollutants may further increase susceptibility to infectious, allergic, and autoimmune diseases. Although the physical drivers of climate change are well established, the biological pathways linking environmental stressors to immune dysregulation remain incompletely defined. This review synthesizes current evidence on the mechanisms by which extreme heat events influence immune tolerance and disease risk. We discuss implications for allergy, autoimmunity, and infectious diseases, highlight vulnerable populations, and outline key research priorities needed to inform clinical and public health adaptation.
AbstractNon-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers.
Circular RNAs (circRNAs) have emerged as significant regulators of cancer biology. However, the characterization and the regulatory potential of circRNAs deriving from key apoptotic genes remain poorly understood in breast cancer. We aimed to comprehensively characterize circRNAs originating from the pro-apoptotic BAX gene and predict their regulatory potential in BC signaling. Targeted amplification of circular BAX transcripts was conducted in eleven cancerous and one non-cancerous breast cell lines, followed by third-generation (nanopore) and next-generation sequencing. Finally, extensive bioinformatic analysis was conducted. Therefore, we identified 106 circRNAs, 82 of which were novel. These circRNAs exhibited diverse biogenesis features, including exon skipping, intron retention, and rare inclusion of exon 5. Expression profiling revealed subtype-specific patterns, with several circRNAs being detected only in triple-negative or luminal BC subtypes, while circ-BAX-55b was detected exclusively in the non-cancerous cell line. Many circRNAs were predicted to sponge miRNAs such as miR-152-5p, miR-4802-5p, and miR-3619-5p, potentially modulating signaling pathways including MAPK, PI3K/AKT, and NFκB. Extensive sponging of miR-152-5p, which targets BAX mRNA, suggests a feedback mechanism modulating apoptosis. Several circRNAs also contain binding sites for RNA-binding proteins (RBPs) such as RBM6 and HNRNPF, possibly dictating RNA fate. Overlapping miRNA and RBP-binding sites imply complex competitive or cooperative interactions. Additionally, multiple circRNAs, such as circ-BAX-6c, displayed translation-related features. In conclusion, these findings reveal a novel repertoire of BAX circRNAs with putative roles in BC signaling and apoptosis regulation. Moreover, they constitute a valuable resource for functional studies as well as potential biomarkers or therapeutic targets in breastcancer.
We construct a Bohmian quantum cosmological model for a spatially flat Friedmann-Robertson-Walker universe filled with a single scalar field whose potential provides a unified description of cold dark matter and dark energy at the background level. Starting from the Einstein-Hilbert action supplemented by a scalar field, we derive the minisuperspace Lagrangian and the associated canonical Hamiltonian formulation. By means of a nontrivial canonical transformation, the minisuperspace dynamics is mapped into that of a two-dimensional hyperbolic oscillator with a fixed frequency ratio, rendering the Wheeler-DeWitt equation exactly solvable by separation of variables. The resulting Wheeler-DeWitt solutions are expressed in terms of parabolic cylinder functions and are parametrised by a continuous separation constant, reflecting the constrained nature of the theory and the absence of a standard Schrödinger time parameter. Adopting the de Broglie-Bohm formulation, we derive deterministic guidance equations in minisuperspace and construct a well-defined Bohmian Hubble parameter directly in terms of the pilot-wave phase. Finally, we present a Wheeler-DeWitt-derived toy wave function for which the Bohmian trajectories and the associated cosmological expansion history can be obtained analytically, reproducing the late-time ΛCDM behaviour while exhibiting quantum modifications at earlier epochs.
