bluuebunny/crossref_metadata_2025 huggingface dataset:
Meaning in Life in AI Ethics—Some Trends and Perspectives
Authors: Nyholm Sven , Rüther Markus
Published: March 2023

In this paper, we discuss the relation between recent philosophical discussions about meaning in life (from authors like Susan Wolf, Thaddeus Metz, and others) and the ethics of artificial intelligence (AI). Our goal is twofold, namely, to argue that considering the axiological category of meaningfulness can enrich AI ethics, on the one hand, and to portray and evaluate the small, but growing literature that already exists on the relation between meaning in life and AI ethics, on the other hand. We start out our review by clarifying the basic assumptions of the meaning in life discourse and how it understands the term ‘meaningfulness’. After that, we offer five general arguments for relating philosophical questions about meaning in life to questions about the role of AI in human life. For example, we formulate a worry about a possible meaningfulness gap related to AI on analogy with the idea of responsibility gaps created by AI, a prominent topic within the AI ethics literature. We then consider three specific types of contributions that have been made in the AI ethics literature so far: contributions related to self-development, the future of work, and relationships. As we discuss those three topics, we highlight what has already been done, but we also point out gaps in the existing literature. We end with an outlook regarding where we think the discussion of this topic should go next.
The fractional stochastic heat equation driven by time-space white noise
Authors: Moulay Hachemi Rahma Yasmina , Øksendal Bernt
Published: March 2023

We study the stochastic time-fractional stochastic heat equation$$\begin{aligned} \frac{\partial ^{\alpha }}{\partial t^{\alpha }}Y(t,x)=\lambda \varDelta Y(t,x)+\sigma W(t,x);\; (t,x)\in (0,\infty )\times \mathbb {R}^{d}, \end{aligned}$$∂α∂tαY(t,x)=λΔY(t,x)+σW(t,x);(t,x)∈(0,∞)×Rd,where$$d\in \mathbb {N}=\{1,2,...\}$$d∈N={1,2,...}and$$\frac{\partial ^{\alpha }}{\partial t^{\alpha }}$$∂α∂tαis the Caputo derivative of order$$\alpha \in (0,2)$$α∈(0,2), and$$\lambda >0$$λ>0and$$\sigma \in \mathbb {R}$$σ∈Rare given constants. Here$$\varDelta $$Δdenotes the Laplacian operator,W(t, x) is time-space white noise, defined by$$\begin{aligned} W(t,x)=\frac{\partial }{\partial t}\frac{\partial ^{d}B(t,x)}{\partial x_{1}...\partial x_{d}}, \end{aligned}$$W(t,x)=∂∂t∂dB(t,x)∂x1...∂xd,$$B(t,x)=B(t,x,\omega ); t\ge 0, x \in \mathbb {R}^d, \omega \in \varOmega $$B(t,x)=B(t,x,ω);t≥0,x∈Rd,ω∈Ωbeing time-space Brownian motion with probability law$$\mathbb {P}$$P. We consider the equation (0.1) in the sense of distribution, and we find an explicit expression for the$$\mathcal {S}'$$S′-valued solutionY(t, x), where$$\mathcal {S}'$$S′is the space of tempered distributions. Following the terminology of Y. Hu [11], we say that the solution ismildif$$Y(t,x) \in L^2(\mathbb {P})$$Y(t,x)∈L2(P)for allt, x. It is well-known that in the classical case with$$\alpha = 1$$α=1, the solution is mild if and only if the space dimension$$d=1$$d=1. We prove that if$$\alpha \in (1,2)$$α∈(1,2)the solution is mild if$$d=1$$d=1or$$d=2$$d=2. If$$\alpha < 1$$α<1we prove that the solution is not mild for anyd.
Multi-domain lifestyle intervention in older adults after myocardial infarction: rationale and design of the PIpELINe randomized clinical trial
Authors: Tonet Elisabetta , Raisi Andrea , Zagnoni Silvia , Chiaranda Giorgio , Pavasini Rita , Vitali Francesco , Gibiino Federico , Campana Roberta , Boccadoro Alberto , Scala Antonella , Canovi Luca , Amantea Veronica , Matese Camilla , Berloni Maria Letizia , Piva Tommaso , Zerbini Valentina , Cardelli Laura Sofia , Pasanisi Giovanni , Mazzoni Gianni , Casella Gianni , Grazzi Giovanni , Campo Gianluca
Published: March 2023

Background

Traditional cardiac rehabilitation (CR) is effective in improving physical performance and prognosis after myocardial infarction (MI). Anyway, it is not consistently recommended to older adults, and its attendance rate is low. Previous studies suggested that alternative, early and tailored exercise interventions are feasible and effective in improving physical performance in older MI patients. Anyway, the demonstration that they are associated also with a significant reduction of hard endpoints is lacking.

Aim

To describe rationale and design of the “Physical activity Intervention in Elderly patients with myocardial Infarction” (PIpELINe) trial.

Methods

The PIpELINe trial is a prospective, randomized, multicentre study with a blinded adjudicated evaluation of the outcomes. Patients aged ≥ 65 years, admitted to hospital for MI and with a low physical performance one month after discharge, as defined as short physical performance battery (SPPB) value between 4 and 9, will be randomized to a multi-domain lifestyle intervention (including dietary counselling, strict management of cardiovascular and metabolic risk factors, and exercise training) or health education. The primary endpoint is the one-year occurrence of the composite of cardiovascular death or re-hospitalization for cardiovascular causes.

Results

The recruitment started in March 2020. The estimated sample size is 456 patients. The conclusion of the enrolment is planned for mid-2023. The primary endpoint analysis will be available for the end of 2024.

Conclusions

The PIpELINe trial will show if a multi-domain lifestyle intervention is able to reduce adverse events in older patients with reduced physical performance after hospitalization for MI.

Trial registration

ClinicalTrials.gov NCT04183465.
Looking China Youth film project: untold stories a small handbook on documentary or how to shooting successfully in unknown circumstances
Authors: Velinovic Predrag
Published: March 2023

Theoretical and practical work in the education of students of film and television directing are important and somehow go hand in hand. The choice of the topic, the director’s attitude, the question of the concept, are themes that are thought about more and more as the level of knowledge and understanding increases. What happens when a student faces with an unexpected challenge, with an unknown topic, in a new environment? How much education, and how much coping, intuitiveness, talent, are important for making the decisions?
Reinforcement-learning-based parameter adaptation method for particle swarm optimization
Authors: Yin Shiyuan , Jin Min , Lu Huaxiang , Gong Guoliang , Mao Wenyu , Chen Gang , Li Wenchang
Published: March 2023

Particle swarm optimization (PSO) is a well-known optimization algorithm that shows good performances in solving different optimization problems. However, the PSO usually suffers from slow convergence. In this article, a reinforcement-learning-based parameter adaptation method (RLAM) is developed to enhance the PSO convergence by designing a network to control the coefficients of the PSO. Moreover, based on the RLAM, a new reinforcement-learning-based PSO (RLPSO) algorithm is designed. To investigate the performance of the RLAM and RLPSO, experiments on 28 CEC 2013 benchmark functions were carried out to compare with other adaptation methods and PSO variants. The reported computational results showed that the proposed RLAM is efficient and effective and that the proposed RLPSO is superior to several state-of-the-art PSO variants.
Promises and partner-switch
Authors: Di Bartolomeo Giovanni , Dufwenberg Martin , Papa Stefano
Published: March 2023

Building on a partner-switching mechanism, we experimentally test two theories that posit different reasons why promises breed trust and cooperation. The expectation-based explanation (EBE) operates via belief-dependent guilt aversion, while the commitment-based explanation (CBE) suggests that promises offer commitment power via a (belief-independent) preference to keep one’s word. Previous research performed a similar test, which we argue should be interpreted as concerning informal agreements rather than (unilateral) promises.
Leibniz on Purely Extrinsic Denominations
Authors: Plaisted Dennis
Published: March 2023

An examination of the philosopher Gottfried Leibniz's views on extrinsic denominations (relational properties), which argues that they are in fact the properties of the things they denominate.
The Correspondence of Dante Gabriel Rossetti
Authors: Fredeman William E.
Published: March 2023

Major edition revealing key ideas and events in the lives and work of the Pre-Raphaelite brotherhood and Victorian literary circles: 5,800 letters (including 2,000 previously unpublished letters) to 330 recipients.
Solar Cycle and Solar Wind Dependence of the Occurrence of Large dB/dt Events at High Latitudes
Authors: Milan S. E. , Imber S. M. , Fleetham A. L. , Gjerloev J.
Published: March 2023

We investigate sharp changes in magnetic field that can produce Geomagnetically Induced Currents (GICs) which damage pipelines and power grids. We use one‐minute cadence SuperMAG observations to find the occurrence distribution of magnetic field “spikes.” Recent studies have determined recurrence statistics for extreme events and charted the local time distribution of spikes; however, their relation to solar activity and conditions in the solar wind is poorly understood. We study spike occurrence during solar cycles 23 and 24, roughly 1995 to 2020. We find three local time hotspots in occurrence: the pre‐midnight region associated with substorm onsets, the dawn sector often associated with omega band activity, and the pre‐noon sector associated with the Kelvin‐Helmholtz instability (KHI) occurring at the magnetopause. Magnetic field perturbations are mainly North‐South for substorms and KHI, and East‐West for omega bands. Substorm spikes occur at all phases of the solar cycle, but maximize in the declining phase. Omega‐band and KHI spikes are confined to solar maximum and the declining phase. Substorm spikes occur during moderate solar wind driving, omega band spikes during strong driving, and KHI spikes during quiet conditions but with high solar wind speed. We show that the shapes of these distributions do not depend on the magnitude of the spikes, so it appears that our results can be extrapolated to extreme events.
Stress‐Based and Convolutional Forecasting of Injection‐Induced Seismicity: Application to the Otaniemi Geothermal Reservoir Stimulation
Authors: Kim Taeho , Avouac Jean‐Philippe
Published: March 2023

Induced seismicity observed during Enhanced Geothermal Stimulation at Otaniemi, Finland is modeled using both statistical and physical approaches. The physical model produces simulations closest to the observations when assuming rate‐and‐state friction for shear failure with diffusivity matching the pressure build‐up at the well‐head at onset of injections. Rate‐and‐state friction implies a time‐dependent earthquake nucleation process which is found to be essential in reproducing the spatial pattern of seismicity. This implies that permeability inferred from the expansion of the seismicity triggering front (Shapiro et al., 1997, https://doi.org/10.1111/j.1365-246x.1997.tb01215.x) can be biased. We suggest a heuristic method to account for this bias that is independent of the earthquake magnitude detection threshold. Our modeling suggests that the Omori law decay during injection shut‐ins results mainly from stress relaxation by pore pressure diffusion. During successive stimulations, seismicity should only be induced where the previous maximum of Coulomb stress changes is exceeded. This effect, commonly referred to as the Kaiser effect, is not clearly visible in the data from Otaniemi. The different injection locations at the various stimulation stages may have resulted in sufficiently different effective stress distributions that the effect was muted. We describe a statistical model whereby seismicity rate is estimated from convolution of the injection history with a kernel which approximates earthquake triggering by fluid diffusion. The statistical method has superior computational efficiency to the physical model and fits the observations as well as the physical model. This approach is applicable provided the Kaiser effect is not strong, as was the case in Otaniemi.
New Insights Into the Rift‐To‐Drift Process of the Northern South China Sea Margin Constrained by a Three‐Dimensional Wide‐Angle Seismic Velocity Model
Authors: Zhang Jiazheng , Zhao Minghui , Ding Weiwei , Ranero César R. , Sallares Valenti , Gao Jinwei , Zhang Cuimei , Qiu Xuelin
Published: March 2023

A three‐dimensional (3D) P‐wave seismic velocity (Vp) model of the crust in the northern South China Sea margin drilled by IODP Expeditions 367/368/368X has been obtained with first‐arrival travel‐time tomography using wide‐angle seismic data from a network of 49 OBSs and 11 air‐gun shot lines. The 3D Vp distribution constrains the extent, structure and nature of the continental, continent to ocean transition (COT), and oceanic domains. Continental crust laterally ranges in thickness from ∼8 to 20 km, a ∼20 km‐width COT contains no evidence of exhumed mantle, and crust with clear oceanic seismic structure ranges in thickness from ∼4.5 to 9 km. A high‐velocity (7.0–7.5 km/s) lower crust (HVLC) ranges in thickness from ∼1 to 9 km across the continental and COT domains, which is interpreted as a proxy of syn‐rift and syn‐breakup magma associated to underplating and/or intrusions. Continental crust thinning style is abrupter in the NE segment and gradual in the SW segment. Abrupter continental thinning exhibits thicker HVLC at stretching factor (β) < ∼3, whereas gentler thinning associates to thinner HVLC at β > ∼4. Opening of the NE segment thus occurred by comparatively increased magmatism, whereas tectonic extension was more important in the SW segment. The Vp distribution shows the changes in deformation and magmatism are abrupt along the strike of the margin, with the segments possibly bounded by a transfer fault system. No conventional model explains the structure and segmentation of tectonic and magmatic processes. Local inherited lithospheric heterogeneities during rifting may have modulated the contrasting opening styles.
Equation of State and Spin Crossover of (Al, Fe)‐Phase H
Authors: Strozewski Benjamin , Buchen Johannes , Sturhahn Wolfgang , Ishii Takayuki , Ohira Itaru , Chariton Stella , Lavina Barbara , Zhao Jiyong , Toellner Thomas S. , Jackson Jennifer M.
Published: March 2023

The transport of hydrogen into Earth's deep interior may have an impact on lower mantle dynamics as well as on the seismic signature of subducted material. Due to the stability of the hydrous phases δ‐AlOOH (delta phase), MgSiO2(OH)2 (phase H), and ε‐FeOOH at high temperatures and pressures, their solid solutions may transport significant amounts of hydrogen as deep as the core‐mantle boundary. We have constrained the equation of state, including the effects of a spin crossover in the Fe3+ atoms, of (Al, Fe)‐phase H: Al0.84Fe3+ 0.07Mg0.02Si0.06OOH, using powder X‐ray diffraction measurements to 125 GPa, supported by synchrotron Mössbauer spectroscopy measurements on (Al, Fe)‐phase H and δ‐(Al, Fe)OOH. The changes in spin state of Fe3+ in (Al, Fe)‐phase H results in a significant decrease in bulk sound velocity and occurs over a different pressure range (48–62 GPa) compared with δ‐(Al, Fe)OOH (32–40 GPa). Changes in axial compressibilities indicate a decrease in the compressibility of hydrogen bonds in (Al, Fe)‐phase H near 30 GPa, which may be associated with hydrogen bond symmetrization. The formation of (Al, Fe)‐phase H in subducted oceanic crust may contribute to scattering of seismic waves in the mid‐lower mantle (∼1,100–1,550 km). Accumulation of 1–4 wt.% (Al, Fe)‐phase H could reproduce some of the seismic signatures of large, low seismic‐velocity provinces. Our results suggest that changes in the electronic structure of phases in the (δ‐AlOOH)‐(MgSiO2(OH)2)‐(ε‐FeOOH) solid solution are sensitive to composition and that the presence of these phases in subducted oceanic crust could be seismically detectable throughout the lower mantle.
Synoptic Drivers of Atmospheric River Induced Precipitation Near Dronning Maud Land, Antarctica
Authors: Baiman Rebecca , Winters Andrew C. , Lenaerts Jan , Shields Christine A.
Published: March 2023

Atmospheric rivers (ARs) that reach the Antarctic Ice Sheet (AIS) transport anomalous moisture from lower latitudes and can impact the AIS via extreme precipitation and increased downward longwave radiation. ARs contribute significantly to the interannual variability of precipitation over the AIS and thus are likely to play a key role in understanding future changes in the surface mass balance of the AIS. Dronning Maud Land (DML) is one of four maxima in AR frequency over coastal East Antarctica, with AR precipitation explaining 77% of the interannual variability in precipitation for this region. We employ a 16‐node self‐organizing map (SOM) trained with MERRA‐2 sea‐level pressure anomalies to identify synoptic‐scale environments associated with landfalling ARs in and around DML. Node composites of atmospheric variables reveal common drivers of precipitation associated with ARs reaching DML including anomalous high‐low surface pressure couplets, anomalously high integrated water vapor, and coastal barrier jets. Using a quasi‐geostrophic framework, we find that upward vertical motion associated with the occlusion process of attendant cyclones dominates atmospheric lift in AR environments. We further identify mechanisms that explain the variability in AR precipitation intensity across nodes, such as the lift associated with the occlusion process of attendant cyclones and the spatial coincidence of ascent induced by the occlusion process and frontogenesis. The latter suggests that ARs making landfall during the mature phase of cyclogenesis result in higher precipitation intensity compared to landfalling ARs that occur during the occluded phase.
Complexity and Predictability of Daily Actual Evapotranspiration Across Climate Regimes
Authors: Di Chongli , Wang Tiejun , Han Qiong , Mai Mai , Wang Lichun , Chen Xi
Published: March 2023

Estimation of actual evapotranspiration (ETa) is challenging due to its complex interactions with surrounding environments; thus, understanding the complexity and predictability of ETa along with its influencing factors is essential to improve ETa estimation. Based on the FLUXNET and ChinaFLUX datasets, we first examined whether daily ETa exhibited chaotic behaviors, and then investigated how daily ETa complexity and predictability varied across climate regimes and ecosystems using the chaos theory. The results of recurrence plot and correlation dimension (CD) analysis suggested the existence of chaotic behaviors in daily ETa, implying the system controlling ETa processes was deterministic with a limited number of controlling variables. The recurrence quantification analysis further revealed a varying degree of complexity for ETa processes (e.g., determinism‐DET with a range from 0.01% to 40.7%) across the sites. Specifically, daily ETa featured stronger deterministic properties (e.g., higher DET and lower CD values) and thus higher predictability in humid and arid regions; whereas, higher degrees of daily ETa complexity emerged in sub‐humid and semi‐arid regions due to more complex interactions with environmental factors. Moreover, primary environmental controls on daily ETa complexity varied with climatic and land surface conditions. Results showed that energy and water supplies along with average daily temperature and relative humidity were the primary controls on the ETa complexity across the sites, while leaf area index also played an important role at drier sites. As a first attempt, this study provides additional avenues to understand the complexity of ETa processes from a global perspective using the chaos theory.
Is It Possible to Quantify Irrigation Water‐Use by Assimilating a High‐Resolution Satellite Soil Moisture Product?
Authors: Jalilvand Ehsan , Abolafia‐Rosenzweig Ronnie , Tajrishy Masoud , Kumar Sujay V. , Mohammadi Mohammad Reza , Das Narendra N.
Published: March 2023

Irrigation is the largest human intervention in the water cycle that can modulate climate extremes, yet irrigation water use (IWU) remains largely unknown in most regions. Microwave remote sensing offers a practical way to quantify IWU by monitoring changes in soil moisture caused by irrigation. However, high‐resolution satellite soil moisture data is typically infrequent (e.g., 6–12 days) and thus may miss irrigation events. This study evaluates the ability to quantify IWU by assimilating high‐resolution (1 km) SMAP‐Sentinel 1 remotely sensed soil moisture with a physically based land surface model (LSM) using a particle batch smoother (PBS). A suite of synthetic experiments is devised to evaluate different error sources. Results from the synthetic experiments show that unbiased simulations with known irrigation timing can produce an accurate irrigation estimate with a mean annual bias of 0.45% and a mean R2 of 0.97, relative to observed IWU. Unknown irrigation timing can significantly deteriorate the model performance, resulting in an increased mean annual bias to 23% and decreased mean R2 to 0.36. Adding random noise to synthetic observations does not significantly decrease model performance except for the experiments with low observation frequency (>12 days). In real‐world experiments, the PBS data assimilation approach underestimates observed IWU by 18.6% when the timing of IWU is known. IWU estimates are consistently significantly higher over irrigated pixels compared to the non‐irrigated pixels, indicating data assimilation skillfully conveys irrigation signals to the LSM.
Underestimated Interannual Variability of Terrestrial Vegetation Production by Terrestrial Ecosystem Models
Authors: Lin Shangrong , Hu Zhongmin , Wang Yingping , Chen Xiuzhi , He Bin , Song Zhaoliang , Sun Shaobo , Wu Chaoyang , Zheng Yi , Xia Xiaosheng , Liu Liyang , Tang Jing , Sun Qing , Joos Fortunat , Yuan Wenping
Published: March 2023

Vegetation gross primary production (GPP) is the largest terrestrial carbon flux and plays an important role in regulating the carbon sink. Current terrestrial ecosystem models (TEMs) are indispensable tools for evaluating and predicting GPP. However, to which degree the TEMs can capture the interannual variability (IAV) of GPP remains unclear. With large data sets of remote sensing, in situ observations, and predictions of TEMs at a global scale, this study found that the current TEMs substantially underestimate the GPP IAV in comparison to observations at global flux towers. Our results also showed the larger underestimations of IAV in GPP at nonforest ecosystem types than forest types, especially in arid and semiarid grassland and shrubland. One cause of the underestimation is that the IAV in GPP predicted by models is strongly dependent on canopy structure, that is, leaf area index (LAI), and the models underestimate the changes of canopy physiology responding to climate change. On the other hand, the simulated interannual variations of LAI are much less than the observed. Our results highlight the importance of improving TEMs by precisely characterizing the contribution of canopy physiological changes on the IAV in GPP and of clarifying the reason for the underestimated IAV in LAI. With these efforts, it may be possible to accurately predict the IAV in GPP and the stability of the global carbon sink in the context of global climate change.
Non-steroidal anti-inflammatory drug target gene associations with major depressive disorders: a Mendelian randomisation study integrating GWAS, eQTL and mQTL Data
Authors: He Qian , Wu Kevin Chun Hei , Bennett Adam N. , Fan Beifang , Liu Jundong , Huang Ruixuan , Kong Alice P. S. , Tian Xiaoyu , Kwok Man Ki Maggie , Chan Kei Hang Katie
Published: March 2023

Previous observational studies reported associations between non-steroidal anti-inflammatory drugs (NSAIDs) and major depressive disorder (MDD), however, these associations are often inconsistent and underlying biological mechanisms are still poorly understood. We conducted a two-sample Mendelian randomisation (MR) study to examine relationships between genetic variants and NSAID target gene expression or DNA methylation (DNAm) using publicly available expression, methylation quantitative trait loci (eQTL or mQTL) data and genetic variant-disease associations from genome-wide association studies (GWAS of MDD). We also assessed drug exposure using gene expression and DNAm levels of NSAID targets as proxies. Genetic variants were robustly adjusted for multiple comparisons related to gene expression, DNAm was used as MR instrumental variables and GWAS statistics of MDD as the outcome. A 1-standard deviation (SD) lower expression of NEU1 in blood was related to lower C-reactive protein (CRP) levels of −0.215 mg/L (95% confidence interval (CI): 0.128–0.426) and a decreased risk of MDD (odds ratio [OR] = 0.806; 95% CI: 0.735–0.885; p = 5.36 × 10−6). A concordant direction of association was also observed for NEU1 DNAm levels in blood and a risk of MDD (OR = 0.886; 95% CI: 0.836–0.939; p = 4.71 × 10−5). Further, the genetic variants associated with MDD were mediated by NEU1 expression via DNAm (β = −0.519; 95% CI: −0.717 to −0.320256; p = 3.16 × 10−7). We did not observe causal relationships between inflammatory genetic marker estimations and MDD risk. Yet, we identified a concordant association of NEU1 messenger RNA and an adverse direction of association of higher NEU1 DNAm with MDD risk. These results warrant increased pharmacovigilance and further in vivo or in vitro studies to investigate NEU1 inhibitors or supplements for MDD.
Targeted DNA demethylation of the ZNF334 promoter inhibits colorectal cancer growth
Authors: Yang Bin , Tang Haiyu , Wang Nan , Gu Jian , Wang Qin
Published: March 2023

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Aberrant regulation of DNA methylation in promoters of tumor suppressor genes or proto-oncogenes is one of the fundamental processes driving the initiation and progression of CRC. Zinc-finger proteins (ZNFs) are one of the most abundant groups of proteins and function in many important biological processes related to tumorigenesis. Herein, we detected abnormal hypermethylation of the ZNF334 gene in CRC tissues compared with normal tissues, and this modification downregulated the expression of ZNF334. Furthermore, ten-eleven translocation 1 (TET1) was identified to be involved in regulating the methylation level of ZNF334. Next, a dCas9-multiGCN4/scFv-TET1CD-sgZNF334-targeted demethylation system was constructed to reverse the expression of ZNF334 through sgRNA targeting the ZNF334 promoter. Both in vitro and in vivo experiments demonstrated the targeted demethylation system upregulated ZNF334 expression and inhibited CRC growth. Collectively, targeted DNA demethylation of the ZNF334 promoter sheds light on the precise treatment of CRC.
ZNF582 overexpression restrains the progression of clear cell renal cell carcinoma by enhancing the binding of TJP2 and ERK2 and inhibiting ERK2 phosphorylation
Authors: Yang Wuping , Zhang Zedan , Li Lei , Zhang Kenan , Xu Yawei , Xia Mancheng , Zhou Jingcheng , Gong Yanqing , Chen Jinchao , Gong Kan
Published: March 2023

Recent evidences have suggested that Zinc finger protein 582 (ZNF582) plays different important roles in various tumors, but its clinical role, biological function and regulatory mechanism in clear cell renal cell carcinoma (ccRCC) are still vague. Through analyzing GEO and TCGA-KIRC data and validation with local samples, we identified the low expression pattern of ZNF582 in ccRCC. Decreased ZNF582 expression is correlated with higher tumor stage and grade, distant metastasis and poor prognosis. By analyzing the DNA methylation data of ccRCC in TCGA-KIRC and using Massarray DNA methylation and demethylation analysis, we confirmed the hypermethylation status of ZNF582 in ccRCC and its negative regulation on ZNF582 expression. Using cell phenotype experiments and orthotopic kidney tumor growth models, we determined the inhibitory effect of ZNF582 overexpression on ccRCC growth and metastasis in vivo and in vitro. Mechanistically, using TMT (Tandem mass tags) quantitative proteomics test, Co-IP (Co-immunoprecipitation) and Western Blot experiments, we clarified that ZNF582 binds to TJP2 and up-regulates TJP2 protein expression. Increased TJP2 protein combines with ERK2 to promote ERK2 protein expression and suppresses the phosphorylation of ERK2, thereby inhibiting the growth and metastasis of ccRCC. In general, our findings provide the first solid theoretical rationale for targeting ZNF582/TJP2/ERK2 axis to improve ccRCC treatment.
The endocannabinoid system promotes hepatocyte progenitor cell proliferation and maturation by modulating cellular energetics
Authors: Mukhopadhyay Bani , Holovac Kellie , Schuebel Kornel , Mukhopadhyay Partha , Cinar Resat , Iyer Sindhu , Marietta Cheryl , Goldman David , Kunos George
Published: March 2023

The proliferation and differentiation of hepatic progenitor cells (HPCs) drive the homeostatic renewal of the liver under diverse conditions. Liver regeneration is associated with an increase in Axin2+Cnr1+ HPCs, along with a marked increase in the levels of the endocannabinoid anandamide (AEA). But the molecular mechanism linking AEA signaling to HPC proliferation and/or differentiation has not been explored. Here, we show that in vitro exposure of HPCs to AEA triggers both cell cycling and differentiation along with increased expression of Cnr1, Krt19, and Axin2. Mechanistically, we found that AEA promotes the nuclear localization of the transcription factor β-catenin, with subsequent induction of its downstream targets. Systemic analyses of cells after CRISPR-mediated knockout of the β-catenin-regulated transcriptome revealed that AEA modulates β-catenin-dependent cell cycling and differentiation, as well as interleukin pathways. Further, we found that AEA promotes OXPHOS in HPCs when amino acids and glucose are readily available as substrates, but AEA inhibits it when the cells rely primarily on fatty acid oxidation. Thus, the endocannabinoid system promotes hepatocyte renewal and maturation by stimulating the proliferation of Axin2+Cnr1+ HPCs via the β-catenin pathways while modulating the metabolic activity of their precursor cells.
Genomic characterization of DICER1-associated neoplasms uncovers molecular classes
Authors: Kommoss Felix K. F. , Chong Anne-Sophie , Chong Anne-Laure , Pfaff Elke , Jones David T. W. , Hiemcke-Jiwa Laura S. , Kester Lennart A. , Flucke Uta , Gessler Manfred , Schrimpf Daniel , Sahm Felix , Clarke Blaise A. , Stewart Colin J. R. , Wang Yemin , Gilks C. Blake , Kommoss Friedrich , Huntsman David G. , Schüller Ulrich , Koelsche Christian , McCluggage W. Glenn , von Deimling Andreas , Foulkes William D.
Published: March 2023

DICER1 syndrome is a tumor predisposition syndrome that is associated with up to 30 different neoplastic lesions, usually affecting children and adolescents. Here we identify a group of mesenchymal tumors which is highly associated with DICER1 syndrome, and molecularly distinct from other DICER1-associated tumors. This group of DICER1-associated mesenchymal tumors encompasses multiple well-established clinicopathological tumor entities and can be further divided into three clinically meaningful classes designated “low-grade mesenchymal tumor with DICER1 alteration” (LGMT DICER1), “sarcoma with DICER1 alteration” (SARC DICER1), and primary intracranial sarcoma with DICER1 alteration (PIS DICER1). Our study not only provides a combined approach to classify DICER1-associated neoplasms for improved clinical management but also suggests a role for global hypomethylation and other recurrent molecular events in sarcomatous differentiation in mesenchymal tumors with DICER1 alteration. Our results will facilitate future investigations into prognostication and therapeutic approaches for affected patients.
Coastal El Niño triggers rapid marine silicate alteration on the seafloor
Authors: Geilert Sonja , Frick Daniel A. , Garbe-Schönberg Dieter , Scholz Florian , Sommer Stefan , Grasse Patricia , Vogt Christoph , Dale Andrew W.
Published: March 2023

Marine silicate alteration plays a key role in the global carbon and cation cycles, although the timeframe of this process in response to extreme weather events is poorly understood. Here we investigate surface sediments across the Peruvian margin before and after extreme rainfall and runoff (coastal El Niño) using Ge/Si ratios and laser-ablated solid and pore fluid Si isotopes (δ30Si). Pore fluids following the rainfall show elevated Ge/Si ratios (2.87 µmol mol−1) and δ30Si values (3.72‰), which we relate to rapid authigenic clay formation from reactive terrigenous minerals delivered by continental runoff. This study highlights the direct coupling of terrestrial erosion and associated marine sedimentary processes. We show that marine silicate alteration can be rapid and highly dynamic in response to local weather conditions, with a potential impact on marine alkalinity and CO2-cycling on short timescales of weeks to months, and thus element turnover on human time scales.
Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics
Authors: Zhang Danyang , Lape Remigijus , Shaikh Saher A. , Kohegyi Bianka K. , Watson Jake F. , Cais Ondrej , Nakagawa Terunaga , Greger Ingo H.
Published: March 2023

AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.
Unnatural activities and mechanistic insights of cytochrome P450 PikC gained from site-specific mutagenesis by non-canonical amino acids
Authors: Pan Yunjun , Li Guobang , Liu Ruxin , Guo Jiawei , Liu Yunjie , Liu Mingyu , Zhang Xingwang , Chi Luping , Xu Kangwei , Wu Ruibo , Zhang Yuzhong , Li Yuezhong , Gao Xiang , Li Shengying
Published: March 2023

Cytochrome P450 enzymes play important roles in the biosynthesis of macrolide antibiotics by mediating a vast variety of regio- and stereoselective oxidative modifications, thus improving their chemical diversity, biological activities, and pharmaceutical properties. Tremendous efforts have been made on engineering the reactivity and selectivity of these useful biocatalysts. However, the 20 proteinogenic amino acids cannot always satisfy the requirement of site-directed/random mutagenesis and rational protein design of P450 enzymes. To address this issue, herein, we practice the semi-rational non-canonical amino acid mutagenesis for the pikromycin biosynthetic P450 enzyme PikC, which recognizes its native macrolide substrates with a 12- or 14-membered ring macrolactone linked to a deoxyamino sugar through a unique sugar-anchoring mechanism. Based on a semi-rationally designed substrate binding strategy, non-canonical amino acid mutagenesis at the His238 position enables the unnatural activities of several PikC mutants towards the macrolactone precursors without any sugar appendix. With the aglycone hydroxylating activities, the pikromycin biosynthetic pathway is rewired by the representative mutant PikCH238pAcF carrying a p-acetylphenylalanine residue at the His238 position and a promiscuous glycosyltransferase. Moreover, structural analysis of substrate-free and three different enzyme-substrate complexes of PikCH238pAcF provides significant mechanistic insights into the substrate binding and catalytic selectivity of this paradigm biosynthetic P450 enzyme.
Quantum structural fluxion in superconducting lanthanum polyhydride
Authors: Wang Hui , Salzbrenner Pascal T. , Errea Ion , Peng Feng , Lu Ziheng , Liu Hanyu , Zhu Li , Pickard Chris J. , Yao Yansun
Published: March 2023

The discovery of 250-kelvin superconducting lanthanum polyhydride under high pressure marked a significant advance toward the realization of a room‐temperature superconductor. X-ray diffraction (XRD) studies reveal a nonstoichiometric LaH9.6 or LaH10±δ polyhydride responsible for the superconductivity, which in the literature is commonly treated as LaH10 without accounting for stoichiometric defects. Here, we discover significant nuclear quantum effects (NQE) in this polyhydride, and demonstrate that a minor amount of stoichiometric defects will cause quantum proton diffusion in the otherwise rigid lanthanum lattice in the ground state. The diffusion coefficient reaches ~10−7 cm2/s in LaH9.63 at 150 gigapascals and 240 kelvin, approaching the upper bound value of interstitial hydrides at comparable temperatures. A puzzling phenomenon observed in previous experiments, the positive pressure dependence of the superconducting critical temperature Tc below 150 gigapascals, is explained by a modulation of the electronic structure due to a premature distortion of the hydrogen lattice in this quantum fluxional structure upon decompression, and resulting changes of the electron-phonon coupling. This finding suggests the coexistence of the quantum proton fluxion and hydrogen-induced superconductivity in this lanthanum polyhydride, and leads to an understanding of the structural nature and superconductivity of nonstoichiomectric hydrogen-rich materials.
An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
Authors: Lau Victor , Ramer Leanne , Tremblay Marie-Ève
Published: March 2023

Alzheimer’s disease (AD) predominantly occurs as a late onset (LOAD) form involving neurodegeneration and cognitive decline with progressive memory loss. Risk factors that include aging promote accumulation of AD pathologies, such as amyloid-beta and tau aggregates, as well as inflammation and oxidative stress. Homeostatic glial states regulate and suppress pathology buildup; inflammatory states exacerbate pathology by releasing pro-inflammatory cytokines. Multiple stresses likely induce glial senescence, which could decrease supportive functions and reinforce inflammation. In this perspective, we hypothesize that aging first drives AD pathology burden, whereafter AD pathology putatively induces glial senescence in LOAD. We hypothesize that increasing glial senescence, particularly local senescent microglia accumulation, sustains and drives perpetuating buildup and spread of AD pathologies, glial aging, and further senescence. We predict that increasing glial senescence, particularly local senescent microglia accumulation, also transitions individuals from healthy cognition into mild cognitive impairment and LOAD diagnosis. These pathophysiological underpinnings may centrally contribute to LOAD onset, but require further mechanistic investigation.
Continuous Spatiotemporal Therapy of A Full-API Nanodrug via Multi-Step Tandem Endogenous Biosynthesis
Authors: Fang Fang , Wang Sa , Song Yueyue , Sun Meng , Chen Wen-Cheng , Zhao Dongxu , Zhang Jinfeng
Published: March 2023

Nanomedicine holds great promise to enhance cancer therapy. However, low active pharmaceutical ingredient (API) loading content, unpredictable drug release, and potential toxicity from excipients limit their translational capability. We herein report a full-API nanodrug composed of FDA-approved 5-aminolevulinic acid (ALA), human essential element Fe3+, and natural bioactive compound curcumin with an ideal API content and pH-responsive release profile for continuous spatiotemporal cancer therapy achieved by multi-step tandem endogenous biosynthesis. First, ALA enzymatically converts into photosensitizer protoporphyrin IX (PpIX). Afterward, multiple downstream products including carbon monoxide (CO), Fe2+, biliverdin (BV), and bilirubin (BR) are individually biosynthesized through the PpIX-heme-CO/Fe2+/BV-BR metabolic pathway, further cooperating with released Fe3+ and curcumin, ultimately eliciting mitochondria damage, membrane disruption, and intracytoplasmic injury. This work not only provides a paradigm for exploiting diversified metabolites for tumor suppression, but also presents a safe and efficient full-API nanodrug, facilitating the practical translation of nanodrugs.
Lacking mechanistic disease definitions and corresponding association data hamper progress in network medicine and beyond
Authors: Sadegh Sepideh , Skelton James , Anastasi Elisa , Maier Andreas , Adamowicz Klaudia , Möller Anna , Kriege Nils M. , Kronberg Jaanika , Haller Toomas , Kacprowski Tim , Wipat Anil , Baumbach Jan , Blumenthal David B.
Published: March 2023

A long-term objective of network medicine is to replace our current, mainly phenotype-based disease definitions by subtypes of health conditions corresponding to distinct pathomechanisms. For this, molecular and health data are modeled as networks and are mined for pathomechanisms. However, many such studies rely on large-scale disease association data where diseases are annotated using the very phenotype-based disease definitions the network medicine field aims to overcome. This raises the question to which extent the biases mechanistically inadequate disease annotations introduce in disease association data distort the results of studies which use such data for pathomechanism mining. We address this question using global- and local-scale analyses of networks constructed from disease association data of various types. Our results indicate that large-scale disease association data should be used with care for pathomechanism mining and that analyses of such data should be accompanied by close-up analyses of molecular data for well-characterized patient cohorts.
Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia
Authors: Woodward Eleanor L. , Yang Minjun , Moura-Castro Larissa H. , van den Bos Hilda , Gunnarsson Rebeqa , Olsson-Arvidsson Linda , Spierings Diana C. J. , Castor Anders , Duployez Nicolas , Zaliova Marketa , Zuna Jan , Johansson Bertil , Foijer Floris , Paulsson Kajsa
Published: March 2023

High hyperdiploid acute lymphoblastic leukemia (HeH ALL), one of the most common childhood malignancies, is driven by nonrandom aneuploidy (abnormal chromosome numbers) mainly comprising chromosomal gains. In this study, we investigate how aneuploidy in HeH ALL arises. Single cell whole genome sequencing of 2847 cells from nine primary cases and one normal bone marrow reveals that HeH ALL generally display low chromosomal heterogeneity, indicating that they are not characterized by chromosomal instability and showing that aneuploidy-driven malignancies are not necessarily chromosomally heterogeneous. Furthermore, most chromosomal gains are present in all leukemic cells, suggesting that they arose early during leukemogenesis. Copy number data from 577 primary cases reveals selective pressures that were used for in silico modeling of aneuploidy development. This shows that the aneuploidy in HeH ALL likely arises by an initial tripolar mitosis in a diploid cell followed by clonal evolution, in line with a punctuated evolution model.
Neutron-encoded diubiquitins to profile linkage selectivity of deubiquitinating enzymes
Authors: van Tol Bianca D. M. , van Doodewaerd Bjorn R. , Lageveen-Kammeijer Guinevere S. M. , Jansen Bas C. , Talavera Ormeño Cami M. P. , Hekking Paul J. M. , Sapmaz Aysegul , Kim Robbert Q. , Moutsiopoulou Angeliki , Komander David , Wuhrer Manfred , van der Heden van Noort Gerbrand J. , Ovaa Huib , Geurink Paul P.
Published: March 2023

Deubiquitinating enzymes are key regulators in the ubiquitin system and an emerging class of drug targets. These proteases disassemble polyubiquitin chains and many deubiquitinases show selectivity for specific polyubiquitin linkages. However, most biochemical insights originate from studies of single diubiquitin linkages in isolation, whereas in cells all linkages coexist. To better mimick this diubiquitin substrate competition, we develop a multiplexed mass spectrometry-based deubiquitinase assay that can probe all ubiquitin linkage types simultaneously to quantify deubiquitinase activity in the presence of all potential diubiquitin substrates. For this, all eight native diubiquitins are generated and each linkage type is designed with a distinct molecular weight by incorporating neutron-encoded amino acids. Overall, 22 deubiquitinases are profiled, providing a three-dimensional overview of deubiquitinase linkage selectivity over time and enzyme concentration.
Atmospheric CO2 forcing on Mediterranean biomes during the past 500 kyrs
Authors: Koutsodendris Andreas , Dakos Vasilis , Fletcher William J. , Knipping Maria , Kotthoff Ulrich , Milner Alice M. , Müller Ulrich C. , Kaboth-Bahr Stefanie , Kern Oliver A. , Kolb Laurin , Vakhrameeva Polina , Wulf Sabine , Christanis Kimon , Schmiedl Gerhard , Pross Jörg
Published: March 2023

There is growing concern on the survival of Mediterranean forests under the projected near-future droughts as a result of anthropogenic climate change. Here we determine the resilience of Mediterranean forests across the entire range of climatic boundary conditions realized during the past 500 kyrs based on continuous pollen and geochemical records of (sub)centennial-scale resolution from drillcores from Tenaghi Philippon, Greece. Using convergent cross-mapping we provide empirical confirmation that global atmospheric carbon dioxide (CO2) may affect Mediterranean vegetation through forcing on moisture availability. Our analysis documents two stable vegetation regimes across the wide range of CO2and moisture levels realized during the past four glacial-interglacial cycles, with abrupt shifts from forest to steppe biomes occurring when a threshold in precipitation is crossed. Our approach highlights that a CO2-driven moisture decrease in the near future may bear an impending risk for abrupt vegetation regime shifts prompting forest loss in the Mediterranean region.
The genomic landscape of reference genomes of cultivated human gut bacteria
Authors: Lin Xiaoqian , Hu Tongyuan , Chen Jianwei , Liang Hewei , Zhou Jianwei , Wu Zhinan , Ye Chen , Jin Xin , Xu Xun , Zhang Wenwei , Jing Xiaohuan , Yang Tao , Wang Jian , Yang Huanming , Kristiansen Karsten , Xiao Liang , Zou Yuanqiang
Published: March 2023

Culture-independent metagenomic studies have revolutionized our understanding of the gut microbiota. However, the lack of full genomes from cultured species is still a limitation for in-depth studies of the gut microbiota. Here we present a substantially expanded version of our Cultivated Genome Reference (CGR), termed CGR2, providing 3324 high-quality draft genomes from isolates selected from a large-scale cultivation of bacterial isolates from fecal samples of healthy Chinese individuals. The CGR2 classifies 527 species (179 previously unidentified species) from 8 phyla, and uncovers a genomic and functional diversity of Collinsella aerofaciens. The CGR2 genomes match 126 metagenome-assembled genomes without cultured representatives in the Unified Human Gastrointestinal Genome (UHGG) collection and harbor 3767 unidentified secondary metabolite biosynthetic gene clusters, providing a source of natural compounds with pharmaceutical potentials. We uncover accurate phage–bacterium linkages providing information on the evolutionary characteristics of interaction between bacteriophages and bacteria at the strain level.