bluuebunny/crossref_metadata_2025 huggingface dataset:
Leveraging a Sturdy Norm: How Ethicists Really Argue
Authors: DeGrazia David
Published: December 2023

Rarely do everyday discussions of ethical issues invoke ethical theories. Even ethicists deploy ethical theories less frequently than one might expect. In my experience, the most powerful ethical arguments rarely appeal to an ethical theory. How is this possible? I contend that ethical argumentation can proceed successfully without invoking any ethical theory because the structure of good ethical argumentation involves leveraging a sturdy norm, where the norm is usually far more specific than a complete ethical theory. To illustrate this idea, I present the argumentative structure of five powerful articles in the ethics literature. I further argue that the present model of ethical argumentation is consistent with the coherence model of ethical justification, but the former need not--and usually should not--invoke the latter explicitly for various practical reasons.
Living Freedom: The Heautonomy of the Judgement of Taste
Authors: Zhouhuang Zhengmi
Published: December 2023

Different from the autonomy of understanding in cognition and the autonomy of practical reason in praxis, the heautonomy in the judgement of taste is reflexive. The reflexivity consists not only in the fact that the power of judgement legislates to its own usage but also, and more importantly, it legislates to itself through its own operative process. This normativity, based on the self-referential structure of pure aesthetic judgement and the a priori principle of subjective, internal purposiveness, can be regarded as a self-discovering and self-flourishing principle that organically grows out of the aesthetic experience and, at the same time, regulates its growth in return. In this scenario, aesthetic freedom can be identified as a third kind of freedom different from Kant’s transcendental freedom and practical freedom – a flexible and living freedom with spontaneous legislation, but not bound by any determinate laws.
Law and politics from the sea
Authors: Mann Itamar
Published: December 2023

Recent scholarship in law and society has engaged in novel ways with maritime spaces, articulating how they inform legal theory more broadly. This essay builds on such scholarship, and on a broad-brushed survey of maritime history, to make two basic arguments. First, a look at political and legal processes regarding maritime spaces reveals that law is transnational ‘all the way down’. Legal theorists often assume that transnational legal processes are an added layer beyond domestic and international law. But the maritime perspective reveals that transnationalism comes first, both analytically and historically, as a constant negotiation of the relationship between what is ‘inside’ and what is ‘outside’ a polity. Second, the maritime space begins, at least in dominant legal traditions, as an absolute exteriority – imagined as outside or beyond polities and jurisdictions. But with the climate crisis and the emergence of the Anthropocene we may observe an inversion, the sea now appears as a record of harmful human activity; a mirror showing a troublesome collective portrait of humanity. The inversion from a maritime exteriority to the intimacy of ubiquitous environmental harm defines the parameters of law and politics today. The essay concludes with reflections on how the maritime perspective may best be engaged today in responding to that image through political action. It conceptualizes what I call the ‘commonist lifeboat’ – a model of bottom-up universalism for tumultuous times.
A Log‐Ratio‐Based Algorithm for Petrologic Mass‐Balance Problems and Uncertainty Assessment
Authors: Prissel Kelsey , Olive Jean‐Arthur , Krawczynski Michael J.
Published: December 2023

We provide a new algorithm for mass‐balance calculations in petrology and geochemistry based on the log‐ratio approach championed initially by John Aitchison (e.g., Aitchison, 1982, https://doi.org/10.1111/j.2517-6161.1982.tb01195.x; Aitchison, 1984, https://doi.org/10.1007/bf01029316) along with the underlying principles, mathematical frameworks, and data requirements. Log‐ratio Inversion of Mixed End‐members (LIME) is written in MATLAB and calculates phase proportions in an experiment or rock given a bulk composition, the composition of each phase, and the associated compositional uncertainties. An important advantage of LIME is that performing the mass‐balance calculation in inverse log‐ratio space constrains phase proportions to be between 0 and 100 wt.%. Further, the resulting LIME phase proportions provide realistic estimates of uncertainty regardless of data distribution. These two characteristics of LIME improve upon standard multiple linear regression techniques, which may yield negative values for phase proportions if non‐constrained or report oversimplified symmetric errors. Primary applications of LIME include estimating phase abundances, calculating melting and metamorphic reaction stoichiometries, and checking for open system behavior in phase equilibria experiments. The technique presented here covers whole‐rock analysis, mineralogy, and phase abundance, but could be extended to isotopic tracers, trace element modeling, and regolith component un‐mixing. We highlight the importance of uncertainty estimations for phase abundances to the fields of petrology and geochemistry by comparing our results from LIME to previously published mass‐balance calculations. Furthermore, we present case studies that demonstrate the role of mass‐balance calculations in determining magma crystallinity and defining melting reactions.
Probing the Magnetospheric Generator of Quiet Electrostatic Auroral Arcs From Ground Based Optical Observations and Magnetosphere‐ionosphere Coupling Modeling
Authors: Echim M. , Lamy H. , Simon‐Wedlund C. , De Keyser J. , Cessateur G.
Published: December 2023

Observations of a quiet electrostatic auroral arc by the ALIS network on 5 March 2008 are used to infer a two‐dimensional map of the flux of precipitating energy. Among a family of numerical solutions of a stationary magnetosphere—ionosphere coupling model in which the origin of the arc is a magnetospheric generator interface, we find which generator interface properties best fit the observed precipitating energy flux. The procedure finds that the plasma populations in the generator are colder and more rarefied on one side of the interface and warmer and denser on the other side, similar to a transition between plasma trough and plasma sheet plasmas. The increase of the arc's brightness, the decrease of its thickness and its slight spatial undulation may be driven by an increase of plasma sheet electron temperature in the tailward direction, tangential to the interface, and a local spatial indentation in the dawn‐ward direction.
Exploring Background Noise With a Large‐N Infrasound Array: Waterfalls, Thunderstorms, and Earthquakes
Authors: Scamfer L. T. , Anderson J. F.
Published: December 2023

Ambient infrasound noise contains an abundance of information that is typically overlooked due to limitations of typical infrasound arrays. To evaluate the ability of large‐N infrasound arrays to identify weak signals hidden in background noise, we examine data from a 22‐element array in central Idaho, USA, spanning 58 days using a standard beamforming method. Our results include nearly continuous detections of diverse weak signals from infrasonic radiators, sometimes at surprising distances. We observe infrasound from both local (8 km) and distant (195 km) waterfalls. Thunderstorms and earthquakes are also notable sources, with distant thunderstorm infrasound observed from ∼800 to 900 km away. Our findings show that large‐N infrasound arrays can detect very weak signals below instrument and environmental noise floors, including from multiple simultaneous sources, enabling new infrasound monitoring applications and helping map the composition of background noise wavefields.
Similarities and Differences in Arctic Sea‐Ice Loss During the Solar‐Forced Last Interglacial Warming (127 Kyr BP) and CO2‐Forced Future Warming
Authors: Sicard Marie , de Boer Agatha M. , Coxall Helen K. , Koenigk Torben , Karami Mehdi Pasha , Jakobsson Martin , O’Regan Matt
Published: December 2023

Based on a 7‐member global circulation model ensemble from CMIP6/PMIP4, we compare the regional distribution of Arctic sea ice between a simulation representing the Last Interglacial (LIG) climate, with solar‐forced warming, and an idealized future CO2‐forced simulation with a similar annual sea‐ice volume. The two simulations feature small but robust differences in the Central Arctic and Baffin Bay during summer, and larger differences at the sea‐ice margins in the sub‐Arctic Atlantic and North Pacific sectors during winter. Our results indicate that, under both forcings, sea ice persists north of Greenland until late summer, suggesting that the assumption that this region is the “Last Ice Area” is robust and holds for other climate states. However, we show that processes influencing sea‐ice distribution in winter, such as Atlantification and sea‐ice drift, differ and need to be further investigated.
Open Water in Sea Ice Causes High Bias in Polar Low‐Level Clouds in GFDL CM4
Authors: Li Xia , Tan Zhihong , Zheng Youtong , Bushuk Mitchell , Donner Leo J.
Published: December 2023

Global climate models (GCMs) struggle to simulate polar clouds, especially low‐level clouds that contain supercooled liquid and closely interact with both the underlying surface and large‐scale atmosphere. Here we focus on GFDL's latest coupled GCM–CM4–and find that polar low‐level clouds are biased high compared to observations. The CM4 bias is largely due to moisture fluxes that occur within partially ice‐covered grid cells, which enhance low cloud formation in non‐summer seasons. In simulations where these fluxes are suppressed, it is found that open water with an areal fraction less than 5% dominates the formation of low‐level clouds and contributes to more than 50% of the total low‐level cloud response to open water within sea ice. These findings emphasize the importance of accurately modeling open water processes (e.g., sea ice lead‐atmosphere interactions) in the polar regions in GCMs.
Snow Avalanches as a Driver of Large Wood Dynamics in Mountain Streams
Authors: Kemper John T. , Scamardo Julianne
Published: December 2023

Snow avalanches are thought to influence large wood dynamics within mountain streams, but studies that explicitly quantify their impact are minimal. In three headwater catchments of the Frying Pan River, Colorado, USA, we found that wood loads in stream reaches intersected by avalanche pathways ranged from 220 to 8,500 m3/ha and were significantly greater than in non‐avalanched reaches. Inter‐catchment differences in the number of avalanche occurrences were not reflected in control reach wood loads, suggesting that elevated loads may be restricted to the general vicinity of the avalanche pathway. However, the sizable wood volumes in avalanche reaches generated notable geomorphic impacts, indicating that avalanches can create hotspots of in‐stream geomorphic complexity and influence the overall habitat mosaic of the stream ecosystem. Loads in avalanche reaches were moreover significantly greater than literature values for similar streams and recruitment processes, emphasizing the importance of snow avalanches as a wood recruitment mechanism.
Nitrogen‐Containing Functional Groups Dominate the Molecular Absorption of Water‐Soluble Humic‐Like Substances in Air From Nanjing, China Revealed by the Machine Learning Combined FT‐ICR‐MS Technique
Authors: Hong Yihang , Zhang Yan‐Lin , Bao Mengying , Fan Mei‐Yi , Lin Yu‐Chi , Xu Rongshuang , Shu Zhiyang , Wu Ji‐Yan , Cao Fang , Jiang Hongxing , Cheng Zhineng , Li Jun , Zhang Gan
Published: December 2023

The light absorption capacity of water‐soluble humic‐like substances (HULISWS) at the molecular level is crucial for reducing the uncertainties in modeling the radiative forcing. This study proposed a machine learning approach to allocate the light absorption coefficient at 365 nm (Abs365) of HULISWS into 8084 Fourier transform‐ion cyclotron resonance mass spectrometry (FT‐ICR‐MS) detached molecular markers and their potential functional groups. The ML model showed an acceptable uncertainty (<5%) to the whole Abs365 value based on the prediction errors. The results showed that five critical light‐absorbing molecules (C4H6O4NS, C8H6O4NS, C11H15O3N2, C12H15O3N2, and C19H21O6) could explain 74% (±3%) of the variation of Abs365 in the winter, whereas no crucial light‐absorbing molecules were found in the summer. Besides, the nitrogen‐containing functional groups were found to dominate (61% ± 8%) the molecular absorption near the 365 nm of the spectrum. This work illustrated how functional groups affect the absorption of HULISWS, providing critical information for future research of HULISWS on the molecular level.
The Missing Craters and Basin Rings Beneath the Lunar Maria
Authors: Liang Weigang , Andrews‐Hanna Jeffrey C. , Evans Alexander J.
Published: December 2023

Evidence for a population of craters buried beneath the nearside lunar maria has been found in the gravity data returned from the Gravity Recovery and Interior Laboratory mission. Although the total population of buried and visible craters within maria is comparable to the crater population in non‐mare regions at large diameters, a deficit was observed for craters less than ∼90 km in diameter. This deficit is surprising because the data can resolve craters down to 10 km in diameter. Similarly, the Imbrium basin only has a partially exposed ring system, with individual ring widths of up to ∼100 km, but where those rings should be buried beneath the mare surface, we find the gravitational signature mostly non‐existent. In this study, we test a series of mechanisms and scenarios that may explain the observed deficits in the buried crater populations by comparing localized Bouguer gravity power spectra and recovered crater size‐frequency distributions from models of a simulated volcanically flooded cratered surface to the observed data. Our results indicate that the observed crater deficit and missing rings of Imbrium are best explained by a smoothing of the pre‐mare surface. We represent this smoothing as a diffusional process, as might occur with thermomechanical erosion during the earliest stages of the mare eruptions. The removal of the missing craters and Imbrium rings was a massive and unprecedented event that sheds light on the early evolution of the mare region, possibly supporting high temperature voluminous floods of lava early during mare formation.
Integrating the Spatial Configurations of Green and Gray Infrastructure in Urban Stormwater Networks
Authors: Chen Xiating , Davitt‐Liu Indigo , Erickson Andrew J. , Feng Xue
Published: December 2023

Green infrastructure (GI) practices improve stormwater quality and reduce urban flooding, but as urban hydrology is highly controlled by its associated gray infrastructure (e.g., stormwater pipe network), GI's watershed‐scale performance depends on its siting within its associated watershed. Although many stormwater practitioners have begun considering GI's spatial configuration within a larger watershed, few approaches allow for flexible scenario exploration, which can untangle GI's interaction with gray infrastructure network and assess its effects on watershed hydrology. To address the gap in integrated gray‐green infrastructure planning, we used an exploratory model to examine gray‐green infrastructure performance using synthetic stormwater networks with varying degrees of flow path meandering, informed by analysis on stormwater networks from the Minneapolis‐St. Paul Metropolitan Area, MN, USA. Superimposed with different coverage and placements of GI (e.g., bioretention cells), these gray‐green stormwater networks are then subjected to different rainfall intensities within Environmental Protection Agency's Storm Water Management Model to simulate their hydrological benefits (e.g., peak flow reduction, flood reduction). Although only limited choices of green and gray infrastructure were explored, the results show that the gray infrastructure's spatial configuration can introduce tradeoffs between increased peak flow and increased flooding, and further interacts with GI coverage and placement to reduce peak flow and flooding at low rainfall intensity. However, as rainfall intensifies, GI ceases to reduce peak flow. For integrated gray‐green infrastructure planning, our results suggest that physical constraints of the stormwater networks and the range of rainfall intensities must be considered when implementing GI.
Exploring the Critical Zone Heterogeneity and the Hydrological Diversity Using an Integrated Ecohydrological Model in Three Contrasted Long‐Term Observatories
Authors: Ackerer J. , Kuppel S. , Braud I. , Pasquet S. , Fovet O. , Probst A. , Pierret M. C. , Ruiz L. , Tallec T. , Lesparre N. , Weill S. , Flechard C. , Probst J. L. , Marçais J. , Riviere A. , Habets F. , Anquetin S. , Gaillardet J.
Published: December 2023

An integrated ecohydrological modeling approach was deployed in three long‐term critical zone (CZ) observatories of the French CZ network (CZ Observatories—Application and Research) to better understand how the CZ heterogeneity modulates the water cycle within territories. Ecohydrological simulations with the physically based model EcH2O‐iso constrained by a wide range of observations crossing several disciplines (meteorology, hydrology, geomorphology, geophysics, soil sciences, and satellite imagery) are able to capture stream water discharges, evapotranspiration fluxes, and piezometric levels in the Naizin, Auradé, and Strengbach watersheds. In Naizin, an agricultural watershed in northwestern France with a schist bedrock underlying deep weathered materials (5–15 m) along gentle slopes, modeling results reveal a deep aquifer with a large total water storage (1,080–1,150 mm), an important fraction of inactive water storage (94%), and relatively long stream water transit times (0.5–2.5 years). In the Auradé watershed, representative of agricultural landscapes of the southwestern France developed on molasse, a relatively shallow regolith (1–8 m) is observed along hilly slopes. Simulations indicate a shallow aquifer with moderate total water storage (590–630 mm), an important fraction of inactive water storage (91%), and shorter stream water transit times (0.1–1.3 years). In the Strengbach watershed, typical of mid‐mountain forested landscapes developed on granite, CZ evolution implies a shallow regolith (1–5 m) along steep slopes. Modeling results infer a shallow aquifer with the smallest total water storage (475–575 mm), the shortest stream water transit times (0.1–0.7 years), but also the highest fraction of active water storage (18%).
Molecular mapping of a core transcriptional signature of microglia-specific genes in schizophrenia
Authors: Fiorito Anna M. , Fakra Eric , Sescousse Guillaume , Ibrahim El Chérif , Rey Romain
Published: December 2023

Besides playing a central role in neuroinflammation, microglia regulate synaptic development and is involved in plasticity. Converging lines of evidence suggest that these different processes play a critical role in schizophrenia. Furthermore, previous studies reported altered transcription of microglia genes in schizophrenia, while microglia itself seems to be involved in the etiopathology of the disease. However, the regional specificity of these brain transcriptional abnormalities remains unclear. Moreover, it is unknown whether brain and peripheral expression of microglia genes are related. Thus, we investigated the expression of a pre-registered list of 10 genes from a core signature of human microglia both at brain and peripheral levels. We included 9 independent Gene Expression Omnibus datasets (764 samples obtained from 266 individuals with schizophrenia and 237 healthy controls) from 8 different brain regions and 3 peripheral tissues. We report evidence of a widespread transcriptional alteration of microglia genes both in brain tissues (we observed a decreased expression in the cerebellum, associative striatum, hippocampus, and parietal cortex of individuals with schizophrenia compared with healthy controls) and whole blood (characterized by a mixed altered expression pattern). Our results suggest that brain underexpression of microglia genes may represent a candidate transcriptional signature for schizophrenia. Moreover, the dual brain-whole blood transcriptional alterations of microglia/macrophage genes identified support the model of schizophrenia as a whole-body disorder and lend weight to the use of blood samples as a potential source of biological peripheral biomarkers.
Spatiotemporal expression patterns of anxiety disorder-associated genes
Authors: Karunakaran Kalyani B. , Amemori Ken-ichi
Published: December 2023

Anxiety disorders (ADs) are the most common form of mental disorder that affects millions of individuals worldwide. Although physiological studies have revealed the neural circuits related to AD symptoms, how AD-associated genes are spatiotemporally expressed in the human brain still remains unclear. In this study, we integrated genome-wide association studies of four human AD subtypes—generalized anxiety disorder, social anxiety disorder, panic disorder, and obsessive-compulsive disorder—with spatial gene expression patterns. Our investigation uncovered a novel division among AD-associated genes, marked by significant and distinct expression enrichments in the cerebral nuclei, limbic, and midbrain regions. Each gene cluster was associated with specific anxiety-related behaviors, signaling pathways, region-specific gene networks, and cell types. Notably, we observed a significant negative correlation in the temporal expression patterns of these gene clusters during various developmental stages. Moreover, the specific brain regions enriched in each gene group aligned with neural circuits previously associated with negative decision-making and anxious temperament. These results suggest that the two distinct gene clusters may underlie separate neural systems involved in anxiety. As a result, our findings bridge the gap between genes and neural circuitry, shedding light on the mechanisms underlying AD-associated behaviors.
Elovanoid-N34 modulates TXNRD1 key in protection against oxidative stress-related diseases
Authors: Calandria Jorgelina M. , Bhattacharjee Surjyadipta , Kala-Bhattacharjee Sayantani , Mukherjee Pranab K. , Feng Yuehan , Vowinckel Jakob , Treiber Tobias , Bazan Nicolas G.
Published: December 2023

The thioredoxin (TXN) system is an NADPH + H+/FAD redox-triggered effector that sustains homeostasis, bioenergetics, detoxifying drug networks, and cell survival in oxidative stress-related diseases. Elovanoid (ELV)-N34 is an endogenously formed lipid mediator in neural cells from omega-3 fatty acid precursors that modulate neuroinflammation and senescence gene programming when reduction-oxidation (redox) homeostasis is disrupted, enhancing cell survival. Limited proteolysis (LiP) screening of human retinal pigment epithelial (RPE) cells identified TXNRD1 isoforms 2, 3, or 5, the reductase of the TXN system, as an intracellular target of ELV-N34. TXNRD1 silencing confirmed that the ELV-N34 target was isoform 2 or 3. This lipid mediator induces TXNRD1 structure changes that modify the FAD interface domain, leading to its activity modulation. The addition of ELV-N34 decreased membrane and cytosolic TXNRD1 activity, suggesting localizations for the targeted reductase. These results show for the first time that the lipid mediator ELV-N34 directly modulates TXNRD1 activity, underling its protection in several pathologies when uncompensated oxidative stress (UOS) evolves.
N6-methyladenosine demethylase FTO regulates synaptic and cognitive impairment by destabilizing PTEN mRNA in hypoxic-ischemic neonatal rats
Authors: Deng Jianhui , Liao Yanling , Chen Jianghu , Chen Andi , Wu Shuyan , Huang Yongxin , Qian Haitao , Gao Fei , Wu Guixi , Chen Yisheng , Chen Xiaohui , Zheng Xiaochun
Published: December 2023

Hypoxic-ischemic brain damage (HIBD) can result in significant global rates of neonatal death or permanent neurological disability. N6-methyladenosine (m6A) modification of RNA influences fundamental aspects of RNA metabolism, and m6A dysregulation is implicated in various neurological diseases. However, the biological roles and clinical significance of m6A in HIBD remain unclear. We currently evaluated the effect of HIBD on cerebral m6A methylation in RNAs in neonatal rats. The m6A dot blot assay showed a global augmentation in RNA m6A methylation post-HI. Herein, we also report on demethylase FTO, which is markedly downregulated in the hippocampus and is the main factor involved with aberrant m6A modification following HI. By conducting a comprehensive analysis of RNA-seq data and m6A microarray results, we found that transcripts with m6A modifications were more highly expressed overall than transcripts without m6A modifications. The overexpression of FTO resulted in the promotion of Akt/mTOR pathway hyperactivation, while simultaneously inhibiting autophagic function. This is carried out by the demethylation activity of FTO, which selectively demethylates transcripts of phosphatase and tensin homolog (PTEN), thus promoting its degradation and reduced protein expression after HI. Moreover, the synaptic and neurocognitive disorders induced by HI were effectively reversed through the overexpression of FTO in the hippocampus. Cumulatively, these findings demonstrate the functional importance of FTO-dependent hippocampal m6A methylome in cognitive function and provides novel mechanistic insights into the therapeutic potentials of FTO in neonatal HIBD.
The TRIM21-FOXD1-BCL-2 axis underlies hyperglycaemic cell death and diabetic tissue damage
Authors: Cheng Wenwen , Cai Cifeng , Xu Yifan , Xiao Xueqi , Shi Tiantian , Liao Yueling , Wang Xiaoyi , Chen Shasha , Zhou Meiliang , Liao Zhiyong
Published: December 2023

Chronic hyperglycaemia is a devastating factor that causes diabetes-induced damage to the retina and kidney. However, the precise mechanism by which hyperglycaemia drives apoptotic cell death is incompletely known. Herein, we found that FOXD1, a FOX family transcription factor specifically expressed in the retina and kidney, regulated the transcription of BCL-2, a master regulator of cell survival. Intriguingly, the protein level of FOXD1, which responded negatively to hyperglycaemic conditions, was controlled by the TRIM21-mediated K48-linked polyubiquitination and subsequent proteasomal degradation. The TRIM21-FOXD1-BCL-2 signalling axis was notably active during diabetes-induced damage to murine retinal and renal tissues. Furthermore, we found that tartary buckwheat flavonoids effectively reversed the downregulation of FOXD1 protein expression and thus restored BCL-2 expression and facilitated the survival of retinal and renal tissues. In summary, we identified a transcription factor responsible for BCL-2 expression, a signalling axis (TRM21-FOXD1-BCL-2) underlying hyperglycaemia-triggered apoptosis, and a potential treatment for deleterious diabetic complications.
Jagged1 intracellular domain/SMAD3 complex transcriptionally regulates TWIST1 to drive glioma invasion
Authors: Kim Jung Yun , Hong Nayoung , Park Sehyeon , Ham Seok Won , Kim Eun-Jung , Kim Sung-Ok , Jang Junseok , Kim Yoonji , Kim Jun-Kyum , Kim Sung-Chan , Park Jong-Whi , Kim Hyunggee
Published: December 2023

Jagged1 (JAG1) is a Notch ligand that correlates with tumor progression. Not limited to its function as a ligand, JAG1 can be cleaved, and its intracellular domain translocates to the nucleus, where it functions as a transcriptional cofactor. Previously, we showed that JAG1 intracellular domain (JICD1) forms a protein complex with DDX17/SMAD3/TGIF2. However, the molecular mechanisms underlying JICD1-mediated tumor aggressiveness remains unclear. Here, we demonstrate that JICD1 enhances the invasive phenotypes of glioblastoma cells by transcriptionally activating epithelial-to-mesenchymal transition (EMT)-related genes, especially TWIST1. The inhibition of TWIST1 reduced JICD1-driven tumor aggressiveness. Although SMAD3 is an important component of transforming growth factor (TGF)-β signaling, the JICD1/SMAD3 transcriptional complex was shown to govern brain tumor invasion independent of TGF-β signaling. Moreover, JICD1-TWIST1-MMP2 and MMP9 axes were significantly correlated with clinical outcome of glioblastoma patients. Collectively, we identified the JICD1/SMAD3-TWIST1 axis as a novel inducer of invasive phenotypes in cancer cells.
Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma
Authors: Nomura Miyuki , Ohuchi Mai , Sakamoto Yoshimi , Kudo Kei , Yaku Keisuke , Soga Tomoyoshi , Sugiura Yuki , Morita Mami , Hayashi Kayoko , Miyahara Shuko , Sato Taku , Yamashita Yoji , Ito Shigemi , Kikuchi Naohiko , Sato Ikuro , Saito Rintaro , Yaegashi Nobuo , Fukuhara Tatsuro , Yamada Hidekazu , Shima Hiroshi , Nakayama Keiichi I. , Hirao Atsushi , Kawasaki Kenta , Arai Yoichi , Akamatsu Shusuke , Tanuma Sei-ichi , Sato Toshiro , Nakagawa Takashi , Tanuma Nobuhiro
Published: December 2023

Nicotinamide phosphoribosyltransferase (NAMPT) plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells is associated with down-regulation of genes relevant to quinolinate phosphoribosyltransferase-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also report that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but nicotinamide riboside kinase 1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations is synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.
Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis
Authors: Muta Yu , Linares Juan F. , Martinez-Ordoñez Anxo , Duran Angeles , Cid-Diaz Tania , Kinoshita Hiroto , Zhang Xiao , Han Qixiu , Nakanishi Yuki , Nakanishi Naoko , Cordes Thekla , Arora Gurpreet K. , Ruiz-Martinez Marc , Reina-Campos Miguel , Kasashima Hiroaki , Yashiro Masakazu , Maeda Kiyoshi , Albaladejo-Gonzalez Ana , Torres-Moreno Daniel , García-Solano José , Conesa-Zamora Pablo , Inghirami Giorgio , Metallo Christian M. , Osborne Timothy F. , Diaz-Meco Maria T. , Moscat Jorge
Published: December 2023

The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.
Anti-VEGFR2 F(ab′)2 drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy
Authors: Liu Di , Song Yanling , Chen Hui , You Yuchan , Zhu Luwen , Zhang Jucong , Xu Xinyi , Hu Jiahao , Huang Xiajie , Wu Xiaochuan , Xu Xiaoling , Jiang Saiping , Du Yongzhong
Published: December 2023

Poor renal distribution of antibody-based drugs is the key factor contributing to low treatment efficiency for renal diseases and side effects. Here, we prepare F(ab′)2 fragmented vascular endothelial growth factor receptor 2 antibody (anti-VEGFR2 (F(ab′)2) to block VEGFR2 overactivation in diabetic nephropathy (DN). We find that the anti-VEGFR2 F(ab′)2 has a higher accumulation in DN male mice kidneys than the intact VEGFR2 antibody, and simultaneously preserves the binding ability to VEGFR2. Furthermore, we develop an antibody fragment drug conjugate, anti-VEGFR2 F(ab′)2-SS31, comprising the anti-VEGFR2 F(ab′)2 fragment linked to the mitochondria-targeted antioxidant peptide SS31. We find that introduction of SS31 potentiates the efficacy of anti-VEGFR2 F(ab′)2. These findings provide proof of concept for the premise that antibody fragment drug conjugate improves renal distribution and merits drug validation in renal disease therapy.
Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology
Authors: Hu Thomas , Allam Mayar , Cai Shuangyi , Henderson Walter , Yueh Brian , Garipcan Aybuke , Ievlev Anton V. , Afkarian Maryam , Beyaz Semir , Coskun Ahmet F.
Published: December 2023

Metabolic reprogramming in cancer and immune cells occurs to support their increasing energy needs in biological tissues. Here we propose Single Cell Spatially resolved Metabolic (scSpaMet) framework for joint protein-metabolite profiling of single immune and cancer cells in male human tissues by incorporating untargeted spatial metabolomics and targeted multiplexed protein imaging in a single pipeline. We utilized the scSpaMet to profile cell types and spatial metabolomic maps of 19507, 31156, and 8215 single cells in human lung cancer, tonsil, and endometrium tissues, respectively. The scSpaMet analysis revealed cell type-dependent metabolite profiles and local metabolite competition of neighboring single cells in human tissues. Deep learning-based joint embedding revealed unique metabolite states within cell types. Trajectory inference showed metabolic patterns along cell differentiation paths. Here we show scSpaMet’s ability to quantify and visualize the cell-type specific and spatially resolved metabolic-protein mapping as an emerging tool for systems-level understanding of tissue biology.
Embedding security into ferroelectric FET array via in situ memory operation
Authors: Xu Yixin , Xiao Yi , Zhao Zijian , Müller Franz , Vardar Alptekin , Gong Xiao , George Sumitha , Kämpfe Thomas , Narayanan Vijaykrishnan , Ni Kai
Published: December 2023

Non-volatile memories (NVMs) have the potential to reshape next-generation memory systems because of their promising properties of near-zero leakage power consumption, high density and non-volatility. However, NVMs also face critical security threats that exploit the non-volatile property. Compared to volatile memory, the capability of retaining data even after power down makes NVM more vulnerable. Existing solutions to address the security issues of NVMs are mainly based on Advanced Encryption Standard (AES), which incurs significant performance and power overhead. In this paper, we propose a lightweight memory encryption/decryption scheme by exploiting in-situ memory operations with negligible overhead. To validate the feasibility of the encryption/decryption scheme, device-level and array-level experiments are performed using ferroelectric field effect transistor (FeFET) as an example NVM without loss of generality. Besides, a comprehensive evaluation is performed on a 128 × 128 FeFET AND-type memory array in terms of area, latency, power and throughput. Compared with the AES-based scheme, our scheme shows ~22.6×/~14.1× increase in encryption/decryption throughput with negligible power penalty. Furthermore, we evaluate the performance of our scheme over the AES-based scheme when deploying different neural network workloads. Our scheme yields significant latency reduction by 90% on average for encryption and decryption processes.
Remote transport of high-dimensional orbital angular momentum states and ghost images via spatial-mode-engineered frequency conversion
Authors: Qiu Xiaodong , Guo Haoxu , Chen Lixiang
Published: December 2023

The efficient transport and engineering of photonic orbital angular momentum (OAM) lie at the heart of various related classical and quantum applications. Here, by leveraging the spatial-mode-engineered frequency conversion, we realize the remote transport of high-dimensional orbital angular momentum (OAM) states between two distant parties without direct transmission of information carriers. We exploit perfect vortices for preparing high-dimensional yet maximal O AM entanglement. Based on nonlinear sum-frequency generation working with a strong coherent wave packet and a single photon, we conduct the Bell-like state measurements for high-dimensional perfect vortices. We experimentally achieve an average transport fidelity 0.879 ± 0.048 and 0.796 ± 0.066 for a complete set of 3-dimensional and 5-dimensional OAM mutually unbiased bases, respectively. Furthermore, by exploring the full transverse entanglement, we construct another strategy of quantum imaging with interaction-free light. It is expected that, with the future advances in nonlinear frequency conversion, our scheme will pave the way for realizing truly secure high-dimensional quantum teleportation in the upcoming quantum network.
A coherent phonon-induced hidden quadrupolar ordered state in Ca2RuO4
Authors: Ning Honglie , Mehio Omar , Li Xinwei , Buchhold Michael , Driesse Mathias , Zhao Hengdi , Cao Gang , Hsieh David
Published: December 2023

Ultrafast laser excitation provides a means to transiently realize long-range ordered electronic states of matter that are hidden in thermal equilibrium. Recently, this approach has unveiled a variety of thermally inaccessible ordered states in strongly correlated materials, including charge density wave, ferroelectric, magnetic, and intertwined charge-orbital ordered states. However, more exotic hidden states exhibiting higher multipolar ordering remain elusive owing to the challenge of directly manipulating and detecting them with light. Here we demonstrate a method to induce a dynamical transition from a thermally allowed to a thermally forbidden spin-orbit entangled quadrupolar ordered state in Ca2RuO4 by coherently exciting a phonon that is strongly coupled to the order parameter. Combining probe photon energy-resolved coherent phonon spectroscopy measurements with model Hamiltonian calculations, we show that the dynamical transition is manifested through anomalies in the temperature, pump excitation fluence, and probe photon energy dependence of the strongly coupled phonon. With this procedure, we introduce a general pathway to uncover hidden multipolar ordered states and to control their re-orientation on ultrashort timescales.
Phase-dependent Andreev molecules and superconducting gap closing in coherently-coupled Josephson junctions
Authors: Matsuo Sadashige , Imoto Takaya , Yokoyama Tomohiro , Sato Yosuke , Lindemann Tyler , Gronin Sergei , Gardner Geoffrey C. , Nakosai Sho , Tanaka Yukio , Manfra Michael J. , Tarucha Seigo
Published: December 2023

The Josephson junction (JJ) is an essential element of superconducting (SC) devices for both fundamental and applied physics. The short-range coherent coupling of two adjacent JJs forms Andreev molecule states (AMSs), which provide a new ingredient to engineer exotic SC phenomena such as topological SC states and Andreev qubits. Here we provide tunneling spectroscopy measurements on a device consisting of two electrically controllable planar JJs sharing a single SC electrode. We discover that Andreev spectra in the coupled JJ are highly modulated from those in the single JJs and possess phase-dependent AMS features reproduced in our numerical calculation. Notably, the SC gap closing due to the AMS formation is experimentally observed. Our results help in understanding SC transport derived from the AMS and promoting the use of AMS physics to engineer topological SC states and quantum information devices.
Uncertainties in deforestation emission baseline methodologies and implications for carbon markets
Authors: Teo Hoong Chen , Tan Nicole Hui Li , Zheng Qiming , Lim Annabel Jia Yi , Sreekar Rachakonda , Chen Xiao , Zhou Yuchuan , Sarira Tasya Vadya , De Alban Jose Don T. , Tang Hao , Friess Daniel A. , Koh Lian Pin
Published: December 2023

Carbon credits generated through jurisdictional-scale avoided deforestation projects require accurate estimates of deforestation emission baselines, but there are serious challenges to their robustness. We assessed the variability, accuracy, and uncertainty of baselining methods by applying sensitivity and variable importance analysis on a range of typically-used methods and parameters for 2,794 jurisdictions worldwide. The median jurisdiction’s deforestation emission baseline varied by 171% (90% range: 87%-440%) of its mean, with a median forecast error of 0.778 times (90% range: 0.548-3.56) the actual deforestation rate. Moreover, variable importance analysis emphasised the strong influence of the deforestation projection approach. For the median jurisdiction, 68.0% of possible methods (90% range: 61.1%-85.6%) exceeded 15% uncertainty. Tropical and polar biomes exhibited larger uncertainties in carbon estimations. The use of sensitivity analyses, multi-model, and multi-source ensemble approaches could reduce variabilities and biases. These findings provide a roadmap for improving baseline estimations to enhance carbon market integrity and trust.
A corrosion inhibiting layer to tackle the irreversible lithium loss in lithium metal batteries
Authors: Jin Chengbin , Huang Yiyu , Li Lanhang , Wei Guoying , Li Hongyan , Shang Qiyao , Ju Zhijin , Lu Gongxun , Zheng Jiale , Sheng Ouwei , Tao Xinyong
Published: December 2023

Reactive negative electrodes like lithium (Li) suffer serious chemical and electrochemical corrosion by electrolytes during battery storage and operation, resulting in rapidly deteriorated cyclability and short lifespans of batteries. Li corrosion supposedly relates to the features of solid-electrolyte-interphase (SEI). Herein, we quantitatively monitor the Li corrosion and SEI progression (e.g., dissolution, reformation) in typical electrolytes through devised electrochemical tools and cryo-electron microscopy. The continuous Li corrosion is validated to be positively correlated with SEI dissolution. More importantly, an anti-corrosion and interface-stabilizing artificial passivation layer comprising low-solubility polymer and metal fluoride is designed. Prolonged operations of Li symmetric cells and Li | |LiFePO4 cells with reduced Li corrosion by ~74% are achieved (0.66 versus 2.5 μAh h−1). The success can further be extended to ampere-hour-scale pouch cells. This work uncovers the SEI dissolution and its correlation with Li corrosion, enabling the durable operation of Li metal batteries by reducing the Li loss.
A physics informed bayesian optimization approach for material design: application to NiTi shape memory alloys
Authors: Khatamsaz Danial , Neuberger Raymond , Roy Arunabha M. , Zadeh Sina Hossein , Otis Richard , Arróyave Raymundo
Published: December 2023

The design of materials and identification of optimal processing parameters constitute a complex and challenging task, necessitating efficient utilization of available data. Bayesian Optimization (BO) has gained popularity in materials design due to its ability to work with minimal data. However, many BO-based frameworks predominantly rely on statistical information, in the form of input-output data, and assume black-box objective functions. In practice, designers often possess knowledge of the underlying physical laws governing a material system, rendering the objective function not entirely black-box, as some information is partially observable. In this study, we propose a physics-informed BO approach that integrates physics-infused kernels to effectively leverage both statistical and physical information in the decision-making process. We demonstrate that this method significantly improves decision-making efficiency and enables more data-efficient BO. The applicability of this approach is showcased through the design of NiTi shape memory alloys, where the optimal processing parameters are identified to maximize the transformation temperature.
Spread in climate policy scenarios unravelled
Authors: Dekker Mark M. , Hof Andries F. , van den Berg Maarten , Daioglou Vassilis , van Heerden Rik , van der Wijst Kaj-Ivar , van Vuuren Detlef P.
Published: December 2023

Analysis of climate policy scenarios has become an important tool for identifying mitigation strategies, as shown in the latest Intergovernmental Panel on Climate Change Working Group III report1. The key outcomes of these scenarios differ substantially not only because of model and climate target differences but also because of different assumptions on behavioural, technological and socio-economic developments2–4. A comprehensive attribution of the spread in climate policy scenarios helps policymakers, stakeholders and scientists to cope with large uncertainties in this field. Here we attribute this spread to the underlying drivers using Sobol decomposition5, yielding the importance of each driver for scenario outcomes. As expected, the climate target explains most of the spread in greenhouse gas emissions, total and sectoral fossil fuel use, total renewable energy and total carbon capture and storage in electricity generation. Unexpectedly, model differences drive variation of most other scenario outcomes, for example, in individual renewable and carbon capture and storage technologies, and energy in demand sectors, reflecting intrinsic uncertainties about long-term developments and the range of possible mitigation strategies. Only a few scenario outcomes, such as hydrogen use, are driven by other scenario assumptions, reflecting the need for more scenario differentiation. This attribution analysis distinguishes areas of consensus as well as strong model dependency, providing a crucial step in correctly interpreting scenario results for robust decision-making.