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L-asparaginase has been used for more than three decades in acute lymphoblastic leukemia (ALL) patients and remains an essential drug in the treatment of ALL. Poor response to L-asparaginase is associated with increased risk of therapeutic failure in ALL. However, both the metabolic perturbation and molecular context of L-asparaginase-treated ALL cells has not been fully elucidated. Here we identify that treatment with L-asparaginase results in metabolic shutdown via the reduction of both glycolysis and oxidative phosphorylation, accompanied by mitochondrial damage and activation of autophagy. The autophagy is involved in reducing reactive oxygen species (ROS) level by eliminating injured mitochondria. Inhibition of autophagy enhances L-asparaginase-induced cytotoxicity and overcomes the acquired resistance to L-asparaginase in ALL cells. The ROS-p53-positive feedback loop is an essential mechanism of this synergistic cytotoxicity. Thus, our findings provide the rationale for the future development of combined treatment of L-asparaginase and anti-autophagy drug in ALL patients.

Ocean circulation around the Antarctic coastal margins plays a critical role in heat delivery to Antarctica, melting ice shelves. However, until recently, satellite‐based sea‐level observations have been limited by the presence of sea ice. With improved algorithms, it is now possible to monitor sea‐level fluctuations over most of the Southern Ocean, including sea ice‐covered areas. We identified several clockwise gyres along East Antarctic coastal margins in satellite‐derived dynamic ocean topography (DOT). Singular value decomposition analyses revealed that the coastal DOT deepening and anomalous clockwise circulation consistently occur during the positive phase of the southern annular mode (SAM), which is associated with negative wind stress curl anomalies. Shifting of the SAM to a more positive phase since the 20th century and its expected continuation into the coming century could lead to enhanced clockwise gyres along East Antarctica, contributing to increased poleward ocean heat transport. Plain Language Summary The Southern Ocean melts the Antarctic ice sheet. The poleward ocean heat, which controls ice‐ocean interactions, is transported from offshore to coastal margins across the shelf break by ocean circulation. Satellite observations are powerful for monitoring global sea‐level distribution which is closely related to ocean circulation; however, this approach is difficult to apply to polar regions with sea ice. This limitation has been addressed through the development of improved satellite algorithms, enabling monitoring in these regions. In this study, we utilized improved satellite sea‐level data to investigate the relationship between sea‐level variation and atmospheric circulation, with a focus on East Antarctic regions. Using analyses to find interlocking patterns in ocean and atmospheric variables, we found that several clockwise gyres form along the East Antarctic coastal margins along with deepening coastal sea levels during the positive phase of the Southern Annular Mode, the leading mode of the Southern Hemisphere atmospheric circulation. The negative wind stress curl tendency associated with the SAM positive phase is responsible for strengthening the regional ocean gyres. The continuous shift of the SAM to a positive phase, both in the past and near future, is expected to enhance these gyres and increase poleward ocean heat transport. Key Points Variability of the ocean circulation along East Antarctica is investigated using satellite radar altimetry Clockwise ocean circulation varies in response to the negative wind stress curl, which depends on the Southern Annular Mode Expected trend toward the positive phase of SAM will leads to enhanced poleward ocean heat transport in the East Antarctic coastal area

The free fatty acid receptor 2 (FFA2) is a G protein-coupled receptor (GPCR) that selectively recognizes short-chain fatty acids to regulate metabolic and immune functions. As a promising therapeutic target, FFA2 has been the focus of intensive development of synthetic ligands. However, the mechanisms by which endogenous and synthetic ligands modulate FFA2 activity remain unclear. Here, we present the structures of the human FFA2–Gi complex activated by the synthetic orthosteric agonist TUG-1375 and the positive allosteric modulator/allosteric agonist 4-CMTB, along with the structure of the inactive FFA2 bound to the antagonist GLPG0974. Structural comparisons with FFA1 and mutational studies reveal how FFA2 selects specific fatty acid chain lengths. Moreover, our structures reveal that GLPG0974 functions as an allosteric antagonist by binding adjacent to the orthosteric pocket to block agonist binding, whereas 4-CMTB binds the outer surface of transmembrane helices 6 and 7 to directly activate the receptor. Supported by computational and functional studies, these insights illuminate diverse mechanisms of ligand action, paving the way for precise GPCR-targeted drug design. The authors present structures of FFA2 bound to TUG-1375/4-CMTB or GLPG0974, revealing how the receptor selects lipid chain lengths and is allosterically regulated by synthetic ligands.

The Arctic is warming at more than twice the rate of the global average. This warming is influenced by clouds, which modulate the solar and terrestrial radiative fluxes and, thus, determine the surface energy budget. However, the interactions among clouds, aerosols, and radiative fluxes in the Arctic are still poorly understood. To address these uncertainties, the Ny-Ålesund Aerosol Cloud Experiment (NASCENT) study was conducted from September 2019 to August 2020 in Ny-Ålesund, Svalbard. The campaign’s primary goal was to elucidate the life cycle of aerosols in the Arctic and to determine how they modulate cloud properties throughout the year. In situ and remote sensing observations were taken on the ground at sea level, at a mountaintop station, and with a tethered balloon system. An overview of the meteorological and the main aerosol seasonality encountered during the NASCENT year is introduced, followed by a presentation of first scientific highlights. In particular, we present new findings on aerosol physicochemical and molecular properties. Further, the role of cloud droplet activation and ice crystal nucleation in the formation and persistence of mixed-phase clouds, and the occurrence of secondary ice processes, are discussed and compared to the representation of cloud processes within the regional Weather Research and Forecasting Model. The paper concludes with research questions that are to be addressed in upcoming NASCENT publications.

Microtubule-associated protein 1 light chain 3 has an important role in autophagy. The human LC3 gene family has five members, LC3A ( variant-1: v1 and -2: v2 ), LC3B, LC3B2 and LC3C . Although a form of LC3B modified by phosphatidylethanolamine (form-II) is localized in autophagosomes, it is not clear whether other LC3 proteins also function in autophagy. Here, we examined the association between autophagy and human LC3 proteins during starvation- or p53-induced autophagy in Saos-2 cells. In an analysis of the intracellular distribution of each LC3 protein fused with GFP, GFP-LC3Av1 was frequently localized in autophagosomes with a punctate pattern, similar to GFP-LC3B. Further, endogenous LC3Av1 generated form-II and mostly localized in LC3B-positive autophagosomes during the induced autophagy. Interestingly, LC3Av1 , not LC3B , was frequently inactivated at the transcriptional level in various human cancer cell lines (111/244 cell lines, 45.5%) and its inactivation was due to aberrant DNA methylation in esophageal squamous cell carcinoma (ESCC) cell lines and primary tumors. Restoration of LC3Av1 expression in KYSE170 cells, an LC3Av1 -inactivated ESCC cell line, showed the inhibition of tumor growth in vivo . These results suggest that LC3Av1, not only LC3B, functions in autophagy and further, LC3Av1 may be crucial in carcinogenesis.

Dihydroartemisinin-piperaquine (DHA-PPQ) is being recommended in Africa for the management of uncomplicated Plasmodium falciparum malaria and for chemoprevention strategies, based on the ability of piperaquine to delay re-infections. Although therapeutic resistance to piperaquine has been linked to increased copy number in plasmepsin-coding parasite genes ( pfpm ), their effect on the duration of the post-treatment prophylactic period remains unclear. Here, we retrospectively analyzed data from a randomized clinical trial, where patients received either DHA-PPQ or artesunate-amodiaquine for recurrent malaria episodes over two years. We observed an increase in the relative risk of re-infection among patients receiving DHA-PPQ compared to artesunate-amodiaquine after the first malaria season. This was driven by shorter average times to reinfection and coincided with an increased frequency of infections comprising pfpm3 multi-copy parasites. The decline in post-treatment protection of DHA-PPQ upon repeated use in a high transmission setting raises concerns for its wider use for chemopreventive strategies in Africa. Authors analyzed a large dihydroartemisinin–piperaquine (DHA-PPQ) repetitive treatment efficacy trial including a 2-year follow-up period, monitoring the evolution of the protective effect of this antimalarial over time.

The Arctic climate system is rapidly transitioning into a new regime with a reduction in the extent of sea ice, enhanced mixing in the ocean and atmosphere, and thus enhanced coupling within the ocean–ice–atmosphere system; these physical changes are leading to ecosystem changes in the Arctic Ocean. In this review paper, we assess one of the critically important aspects of this new regime, the variability of Arctic freshwater, which plays a fundamental role in the Arctic climate system by impacting ocean stratification and sea ice formation or melt. Liquid and solid freshwater exports also affect the global climate system, notably by impacting the global ocean overturning circulation. We assess how freshwater budgets have changed relative to the 2000–2010 period. We include discussions of processes such as poleward atmospheric moisture transport, runoff from the Greenland Ice Sheet and Arctic glaciers, the role of snow on sea ice, and vertical redistribution. Notably, sea ice cover has become more seasonal and more mobile; the mass loss of the Greenland Ice Sheet increased in the 2010s (particularly in the western, northern, and southern regions) and imported warm, salty Atlantic waters have shoaled. During 2000–2010, the Arctic Oscillation and moisture transport into the Arctic are in-phase and have a positive trend. This cyclonic atmospheric circulation pattern forces reduced freshwater content on the Atlantic–Eurasian side of the Arctic Ocean and freshwater gains in the Beaufort Gyre. We show that the trend in Arctic freshwater content in the 2010s has stabilized relative to the 2000s, potentially due to an increased compensation between a freshening of the Beaufort Gyre and a reduction in freshwater in the rest of the Arctic Ocean. However, large inter-model spread across the ocean reanalyses and uncertainty in the observations used in this study prevent a definitive conclusion about the degree of this compensation.

Climate is an important control on biomass burning, but the sensitivity of fire to changes in temperature and moisture balance has not been quantified. We analyze sedimentary charcoal records to show that the changes in fire regime over the past 21,000 yrs are predictable from changes in regional climates. Analyses of paleo‐ fire data show that fire increases monotonically with changes in temperature and peaks at intermediate moisture levels, and that temperature is quantitatively the most important driver of changes in biomass burning over the past 21,000 yrs. Given that a similar relationship between climate drivers and fire emerges from analyses of the interannual variability in biomass burning shown by remote‐sensing observations of month‐by‐month burnt area between 1996 and 2008, our results signal a serious cause for concern in the face of continuing global warming. Key Points Sedimentary charcoal records were analyzed over the past 21 kyr Changes in fire regime are predictable from changes in regional climates Temperature is the most important driver of fire over the last 21 kyr

With our increasing ability for generating whole-genome sequences, comparative analysis of whole genomes has become a powerful tool for understanding the structure, function, and evolutionary history of human and other vertebrate genomes. By virtue of their position basal to bony vertebrates, cartilaginous fishes (class Chondrichthyes) are a valuable outgroup in comparative studies of vertebrates. Recently, a holocephalan cartilaginous fish, the elephant shark, Callorhinchus milii (Subclass Holocephali: Order Chimaeriformes), has been proposed as a model genome, and low-coverage sequence of its genome has been generated. Despite such an increasing interest, the evolutionary history of the modern holocephalans—a previously successful and diverse group but represented by only 39 extant species—and their relationship with elasmobranchs and other jawed vertebrates has been poorly documented largely owing to a lack of well-preserved fossil materials after the end-Permian about 250 Ma. In this study, we assembled the whole mitogenome sequences for eight representatives from all the three families of the modern holocephalans and investigated their phylogenetic relationships and evolutionary history. Unambiguously aligned sequences from these holocephalans together with 17 other vertebrates (9,409 nt positions excluding entire third codon positions) were subjected to partitioned maximum likelihood analysis. The resulting tree strongly supported a single origin of the modern holocephalans and their sister-group relationship with elasmobranchs. The mitogenomic tree recovered the most basal callorhinchids within the chimaeriforms, which is sister to a clade comprising the remaining two families (rhinochimaerids and chimaerids). The timetree derived from a relaxed molecular clock Bayesian method suggests that the holocephalans originated in the Silurian about 420 Ma, having survived from the end-Permian (250 Ma) mass extinction and undergoing familial diversifications during the late Jurassic to early Cretaceous (170–120 Ma). This postulated evolutionary scenario agrees well with that based on the paleontological observations.