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Abstract Cyclones, whether tropical, extratropical, or of Mediterranean origin, play a crucial role in the Earth’s climate system, affecting environments and populations through strong winds, heavy rainfall, and flooding. While much research has focused on tropical and extratropical cyclones, Mediterranean cyclones have received less attention. These cyclones are generally weaker, smaller, and shorter-lived than their tropical or mid-latitude counterparts. However, recent events, such as Mediterranean cyclone Daniel in 2023, which caused severe flooding and thousands of deaths in Libya, underscore the major threat Mediterranean cyclones pose. In this study, we investigate the role of Mediterranean cyclones in triggering floods in Corsica, a region frequently affected by these storms. By analyzing cyclone tracks, streamflow data, and flood-related damage records from Corsica, we reveal a notable rise in river discharge linked to Mediterranean cyclones and show that they contributed to some of the most destructive floods recorded in Corsica between 1979 and 2020.

Abstract Debris-flow activity in the Alps is anticipated to undergo pronounced changes in response to a warming climate. Yet, a fundamental challenge in comprehensively assessing changes in process activity is the systematic lack of long-term observational debris-flow records. Here, we reconstruct the longest, continuous time series (1626-2020) of debris flows at Multetta, a supply-limited torrential system in the Eastern Swiss Alps. Relying on growth-ring records of trees that were damaged by debris flows, we do not detect significant changes in the frequency or magnitude over time. This seeming absence of a direct climatic influence on debris-flow initiation aligns with the regular distribution of repose time patterns, indicating a dependence of local process activity on sediment discharge and recharge. This stark difference in process behavior between our supply-limited site and transport-limited catchments has implications for assessing torrential hazard and risk mitigation in a context of global warming.

Abstract Common Era temperature variability has been a prominent component in Intergovernmental Panel on Climate Change reports over the last several decades and was twice featured in their Summary for Policymakers. A single reconstruction of mean Northern Hemisphere temperature variability was first highlighted in the 2001 Summary for Policymakers, despite other estimates that existed at the time. Subsequent reports assessed many large-scale temperature reconstructions, but the entirety of Common Era temperature history in the most recent Sixth Assessment Report of the Intergovernmental Panel on Climate Change was restricted to a single estimate of mean annual global temperatures. We argue that this focus on a single reconstruction is an insufficient summary of our understanding of temperature variability over the Common Era. We provide a complementary perspective by offering an alternative assessment of the state of our understanding in high-resolution paleoclimatology for the Common Era and call for future reports to present a more accurate and comprehensive assessment of our knowledge about this important period of human and climate history.

Abstract The rock glaciers of the Swiss National Park were the first in the world where in-situ measurements of surface displacement were undertaken, starting with the pioneering work of Chaix in 1918. Our research is focused on the four rock glaciers described by Chaix, bridging the historical data gap that existed between their early 20th-century measurements and the most recent observations. Through the application of photogrammetric techniques, we geomorphologically analyze the spatiotemporal evolution of rock glaciers in the region, and disentangle the interplay with their adjacent glaciers. We show that these rock glaciers are in different phases of degradation with a general trend of deceleration and loss of volume. Our findings reveal historical kinematic changes influenced by the hydrological contributions of adjacent glaciers, which were closely connected since the Little Ice Age but are now severely degraded. The observed hydrological control, suggests that ongoing climate-induced glacier degradation will likely result in a future scenario with limited new accelerations. Instead, a steady water flow from adjacent glaciers may sustain a gradual secondary creep, progressively slowing as permafrost degradation continues, driven by predicted warming and dry climatic conditions in the Alps.

Abstract The trade winds cause strong upwelling in the eastern equatorial Pacific, and create the eastern Pacific Cold Tongue (EPCT) that has far‐reaching impacts on global climate. However, large discrepancies persist in quantifying 20th‐century EPCT sea surface temperature (SST) changes across different instrumental data sets. Here we synthesize four coral Sr/Ca‐SST records from the tropical central‐eastern Pacific to develop a Cold Tongue Index (CTI) reconstruction for 1887–1997. The coral CTI record shows a rapid 20th century warming of the EPCT, suggesting an underestimation of warming trends in instrumental CTI records. The decadal to multidecadal changes in reconstructed EPCT SST show an association with the Walker Circulation. Our reconstruction indicates that recent EPCT cooling during the global warming hiatus is not unusual in the context of the 20th century. Our results provide new evidence for 20th century EPCT SST changes and an observational constraint for predicting future tropical climate changes.

Summary: Brain functionality relies on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7 (also known as CDR1as), the microRNA miR-7, and the long ncRNA Cyrano. We describe ischemia-induced alterations in the ncRNA network both in vitro and in vivo and in transgenic mice lacking ciRS-7 or miR-7. Our data show that cortical neurons downregulate ciRS-7 and Cyrano and upregulate miR-7 expression during ischemia. Mice lacking ciRS-7 exhibit reduced lesion size and motor impairment, while the absence of miR-7 alone results in increased ischemia-induced neuronal death. Moreover, miR-7 levels in pyramidal excitatory neurons regulate neurite morphology and glutamatergic signaling, suggesting a potential molecular link to the in vivo phenotype. Our data reveal the role of ciRS-7 and miR-7 in modulating ischemic stroke outcome, shedding light on the pathophysiological function of intracellular ncRNA networks in the brain.

Abstract System-wide cross-linking and immunoprecipitation (CLIP) approaches have unveiled regulatory mechanisms of RNA-binding proteins (RBPs) mainly in cultured cells due to limitations in the cross-linking efficiency of tissues. Here, we describe viP-CLIP (in vivo PAR-CLIP), a method capable of identifying RBP targets in mammalian tissues, thereby facilitating the functional analysis of RBP-regulatory networks in vivo. We applied viP-CLIP to mouse livers and identified Insig2 and ApoB as prominent TIAL1 target transcripts, indicating an important role of TIAL1 in cholesterol synthesis and secretion. The functional relevance of these targets was confirmed by showing that TIAL1 influences their translation in hepatocytes. Mutant Tial1 mice exhibit altered cholesterol synthesis, APOB secretion and plasma cholesterol levels. Our results demonstrate that viP-CLIP can identify physiologically relevant RBP targets by finding a factor implicated in the negative feedback regulation of cholesterol biosynthesis.

Nonalcoholic steatohepatitis (NASH) is a leading cause for chronic liver diseases. Current therapeutic options are limited due to an incomplete mechanistic understanding of how steatosis transitions to NASH. Here we show that the TRIM21 E3 ubiquitin ligase is induced by the synergistic actions of proinflammatory TNF-α and fatty acids in livers of humans and mice with NASH. TRIM21 ubiquitinates and degrades ChREBP, SREBP1, ACC1, and FASN, key regulators of de novo lipogenesis, and A1CF, an alternative splicing regulator of the high-activity ketohexokinase-C (KHK-C) isoform and rate-limiting enzyme of fructose metabolism. TRIM21-mediated degradation of these lipogenic activators improved steatosis and hyperglycemia as well as fructose and glucose tolerance. Our study identifies TRIM21 as a negative regulator of liver steatosis in NASH and provides mechanistic insights into an immunometabolic crosstalk that limits fatty acid synthesis and fructose metabolism during metabolic stress. Thus, enhancing this natural counteracting force of steatosis through inhibition of key lipogenic activators via TRIM21-mediated ubiquitination may provide a therapeutic opportunity to treat NASH.

The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1K700E on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1K700E alone is insufficient to induce malignant transformation of the murine pancreas, but that it increases aggressiveness of PDAC if it co-occurs with mutated KRAS and p53. We further show that Sf3b1K700E already plays a role during early stages of pancreatic tumor progression and reduces the expression of TGF-β1-responsive epithelial–mesenchymal transition (EMT) genes. Moreover, we found that SF3B1K700E confers resistance to TGF-β1-induced cell death in pancreatic organoids and cell lines, partly mediated through aberrant splicing of Map3k7. Overall, our findings demonstrate that SF3B1K700E acts as an oncogenic driver in PDAC, and suggest that it promotes the progression of early stage tumors by impeding the cellular response to tumor suppressive effects of TGF-β.

Global tree abundance is demonstrated to correlate with latitudinal variables, with tree size and self-thinning strategies impacting current estimates of tree count.

The hypothalamus controls systemic energy homeostasis. Here, the authors show that loss of microRNA-7 in hypothalamic neurons causes obesity, increased growth and endocrine dysfunction in mice, and report genetic evidence that links microRNA-7 to height and adiposity in humans.

Summary: Pancreatic β cells display functional and transcriptional heterogeneity in health and disease. The sequence of events leading to β cell heterogeneity during metabolic stress is poorly understood. Here, we characterize β cell responses to early metabolic stress in vivo by employing RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), single-cell RNA-seq (scRNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and real-time imaging to decipher temporal events of chromatin remodeling and gene expression regulating the unfolded protein response (UPR), protein synthesis, mitochondrial function, and cell-cycle progression. We demonstrate that a subpopulation of β cells with active UPR, decreased protein synthesis, and insulin secretary capacities is more susceptible to proliferation after insulin depletion. Alleviation of endoplasmic reticulum (ER) stress precedes the progression of the cell cycle and mitosis and ensures appropriate insulin synthesis. Furthermore, metabolic stress rapidly activates key transcription factors including FoxM1, which impacts on proliferative and quiescent β cells by regulating protein synthesis, ER stress, and mitochondrial activity via direct repression of mitochondrial-encoded genes.

Summary: Although dietary fructose is associated with an elevated risk for pancreatic cancer, the underlying mechanisms remain elusive. Here, we report that ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, is a driver of PDAC development. We demonstrate that fructose triggers KHK and induces fructolytic gene expression in mouse and human PDAC. Genetic inactivation of KhkC enhances the survival of KPC-driven PDAC even in the absence of high fructose diet. Furthermore, it decreases the viability, migratory capability, and growth of KPC cells in a cell autonomous manner. Mechanistically, we demonstrate that genetic ablation of KHKC strongly impairs the activation of KRAS-MAPK pathway and of rpS6, a downstream target of mTORC signaling. Moreover, overexpression of KHKC in KPC cells enhances the downstream KRAS pathway and cell viability. Our data provide new insights into the role of KHK in PDAC progression and imply that inhibiting KHK could have profound implications for pancreatic cancer therapy.

Climate warming has pronounced impacts on high-elevation regions, including arid Central Asia, and has multiple impacts on the environment. Forests in these mountainous areas provide essential services by regulating regional climate, sequestering carbon, and supporting soil and water conservation. However, trends in forest productivity and their response to climate change remain unclear. To address this knowledge gap, we collected tree cores from five sample plots in the western Tianshan region. We used tree-ring widths to reconstruct net primary productivity (NPP) and investigated the sensitivity of forest NPP to climate change by analysing weather station data and employing LASSO regression to identify climatic factors influencing forest growth. Our results demonstrate that the reconstructed forest NPP effectively captured significant carbon shifts and revealed a non-significant increase in forest productivity associated with climate warming and higher precipitation between 1970 and 2020 at low and middle elevations in the Tianshan mountains. Humidity is the primary limiting factor affecting forest growth in this region. Conversely, the relationship between temperature and forest growth is not consistent as precipitation increases. Our findings suggest that continued warming will exacerbate water stress in forests.

A 7,638 yr summer temperature reconstruction based on subfossil trees buried in the Siberian Arctic shows that recent warming is unprecedented and interrupted a multi-millennial cooling trend.