bluuebunny/crossref_metadata_2025 huggingface dataset:
The Devil and Florentino: Specters of Petro-Populism in Venezuela
Authors: Kappeler Aaron
Published: April 2024

Scholarship on the political economy of natural resources in the Global South has often relied on the concept of the “resource curse” to explain the negative features of extractive economies and their alleged tendency to promote rent capture at the expense of national sovereignty and development. Such theories link the behavior of social actors to an excess of “unearned income,” with little reference to the concrete forms of political and cultural mediation that reproduce this structure of growth. This article explores the role of the devil symbol in populist discourse in Venezuela and how this spectral figure comes to mediate subaltern consciousness. Tracing the origins of this image to colonialism and efforts to grasp the dynamics of the modern petrostate, the analysis shows how use of this symbol to mediate the forecast transition from a rentier to a productive economy has given workers in a state enterprise a potent set of signs to articulate opposition to unjust labor conditions. Venezuelan leaders have deployed figures drawn from local folklore to divide society into two competing power blocs. Yet, while these discourses are effective at forging coalitions and justifying specific reallocations of oil wealth, they do not obviate the tensions of this transition, and a counternarrative using these same figures has arisen in response. The article concludes with an analysis of parallels between global theories of the resource curse and local Venezuelan iterations of this discourse as well as a discussion of the role of translation in theories of culture and modernity.
Conducting Socio-Legal Research in a Conflict Area during a Pandemic: Reflections and Lessons for Future Researchers
Authors: Ezirigwe Jane , Glazewski Jan
Published: April 2024

A “sink or swim” approach has been considered the only way to learn how to conduct empirical research; this should not be the case. Empirical research can be challenging for methodological, practical and ethical reasons; thus there should be detailed and systematic reporting on the methodology adopted. The absence of studies documenting the experiences of researching law implies that important lessons gained by one cohort are not readily accessible in a systematic way for the next. This article presents the methodology of research that was conducted in a conflict area in Nigeria during the pandemic; it aims to provide detailed reporting on the research and highlight the challenges. It offers lessons to future researchers undertaking socio-legal research in a conflict zone, during a pandemic or both. It contributes to the body of knowledge that presents not just what is being done in legal research but how, in order to develop “robust and cumulative scholarly traditions”.
Consumption Growth Persistence and the Stock–Bond Correlation
Authors: Jones Christopher S. , Pyun Sungjune
Published: April 2024

We consider a model in which the correlation between shocks to consumption and to expected future consumption growth is nonzero and varies over time. We validate this assumption empirically using the model’s implication that time variation in consumption growth persistence (CGP) drives the correlation between stock and bond returns. Our model implies that the stock–bond correlation is also related to the predictive relation between bond yields and future stock returns. Finally, we provide suggestive evidence that asset price fluctuations are the primary driver of changes in CGP.
Evolution of Debt Financing Toward Less-Regulated Financial Intermediaries in the United States
Authors: Erel Isil , Inozemtsev Eduard
Published: April 2024

Nonbank lenders have been playing an increasing role in supplying debt, especially after the Great Recession. How important are the distortions in the greater regulation of banks that differentially limit risk-taking across alternative providers of credit? How might the growing role of nonbanks in credit markets affect financial stability? This selective review addresses these questions and discusses how banks and nonbanks helped provide liquidity to the nonfinancial sector during the COVID-19 pandemic shock. We argue that tighter bank regulation has created incentives for nonbanks to increase their participation in credit markets, a trend that creates concerns about financial stability.
Financing Payouts
Authors: Farre-Mensa Joan , Michaely Roni , Schmalz Martin
Published: April 2024

We find that 43% of firms that make payouts also raise capital during the same year, resulting in 31% of aggregate payouts being externally financed, primarily with debt. Most financed payouts cannot be explained by payout smoothing in response to volatile earnings or investment (rather, they are the result of firms persistently setting payouts above free cash flow). In fact, 25% of aggregate payouts could not have been paid without the firms simultaneously raising capital. Profitable firms with moderate growth use debt-financed payouts to jointly manage their leverage and cash, thus highlighting the close relationship between payout and capital structure decisions.
NOTATION AND IMPROVISATION: NOTATIONAL PRAXIS IN THE WORK OF THE ICP, SARAH BRAND AND MOSS FREED
Authors: Zaldua Alistair
Published: April 2024

This article examines the relationship between notation and improvisation and the ways in which notational representation and prescription are extended by para-notation in the work and practice of the improvisers Sarah Brand and Moss Freed and in the work of ethnomusicologist Floris Schuiling, in particular through his research into the Dutch collective, the Instant Composers Pool (ICP). Sarah Brand analyses her own improvisation transcriptions using concepts derived from music therapy to help sharpen awareness for future improvisation. Moss Freed's Micromotives features his own variant of conduction, developed through reflexive and cyclic processes of notation, rehearsals and discussion. Floris Schuiling's ethnomusicological research into the ICP reveals how notation can be used to generate creative challenges, not only for the members of the collective but for musicians in general. A series of interviews reveals that these musicians use notation to render processes visible and to build and develop communities and cultures.
HELMUT LACHENMANN'S SALUT FÜR CAUDWELL (1977) TODAY: BETWEEN STRUCTURE AND ASSEMBLAGE, BETWEEN INTERPRETATION AND EXPERIMENTATION
Authors: Castro Magas Diego
Published: April 2024

The recent new edition of Helmut Lachenmann's Salut für Caudwell (1977) published in Breitkopf & Härtel (2020) by guitarist-researcher Seth Josel has renewed public attention on this seminal work from contemporary guitar literature. As a performer myself, I first performed the piece in 2008 (its Chilean premiere) and have recently premiered the new edition. Performing this piece in a concert situation is always a big event for both performers and listeners; the score seems to age well and its multivalence urges a rethink about how to approach it today. The purpose of this article is threefold: to consider the contribution of the new edition, to examine the relation of notation and performance through the analysis of selected recordings and to interrogate the possible futures for Salut, given recent developments in research into contemporary performing practice.
REHEARSING TIME
Authors: Sikau Lea Luka
Published: April 2024

This article explores the times and datedness of new opera. When referring to an opera (20**) the bracketed number that follows the composition title usually refers to the date of composition or the first performance. When asked how many times an opera was played, its interpreters tend to refer to the number of performances, not the number of instances of rehearsal and individual practice. These times often remain unmentioned by performers, composers, production teams and institutions. But what do we make invisible when we exclude the main act of collective labour in the production of a new staged work? How do new operas structure their times and, in turn, how do these various times restructure new opera? I call for an inclusion of the rehearsal in the temporal narratives that new opera tells through its dates and times, emerging from collaborative processes in compound temporalities. With ethnographic glimpses into different operatic rehearsal studios, I examine the process that takes up most of new opera's time – rehearsal time – rather than audiences’ or performers’ lived experiences during the performance. This article maps the times inside rehearsal time – from daily schedules, call times and deep times of props to computational time and the timing of time itself – for better understanding new opera's ontology.
Migration in Austria after the Fall of the Iron Curtain
Authors: Biffl Gudrun
Published: April 2024

This article addresses the impact of the fall of the Iron Curtain on migration and migration policy in Austria. The introduction explains Austria's reasoning for prioritizing trade over migration policy relative to the Central and Eastern European countries after the fall of the Iron Curtain. This decision was a paradigm shift, abandoning the guest worker model of migration and introducing immigration legislation with family migration as a core element. The legislative reforms brought about changes in all areas of migration governance. Despite the restrictive policy stance toward migration, in-migration gained momentum to the extent that, by 2022, Austria had one of the highest shares of migrants in its population in the European Union. As the official understanding of Austria is to be an immigration country by chance rather than by choice, it has consequently been unable to develop the necessary instruments to promote innovation and economic growth with the help of migrants. Instead, restrictive policies that guide the settlement and integration of migrants in general, and of asylum seekers in particular, may jeopardize social cohesion and the sustainability of economic growth.
Worker-led Unionization Sweeps the US
Authors: Blanc Eric
Published: April 2024

Over the last half-decade, worker-led struggles have spread across US cafes, warehouses, universities, media outlets, and beyond. Reviving the bottom-up spirit that enabled unions to make their big breakthrough in the 1930s, recent worker-to-worker initiatives have shown how this can be done in our sprawled out, economically decentralized conditions. Building off the best traditions of left trade unionism, and leaning on the novel affordances of digital tools, they’ve pioneered new forms of organizing that can extend widely enough to confront the systemic ills plaguing working people.
Music-making for music teacher identity: perspectives from novice music teachers in South Korea
Authors: Shin Jihae
Published: April 2024

Music teacher identity is constructed at the intersection between musician and teacher. This study investigated the meaning of music-making among Korean novice music teachers and its role in constructing music teacher identity. Five music teachers participated in this study, and I used two data collection methods, reflective journaling and individual interviews. The results showed that while playing their instruments outside the classroom, several music teachers understood the importance of music in their lives, which was essential in constructing music teacher identities. In addition, playing outside the classroom allowed these participants to demonstrate their musical abilities to students, parents and other teachers and gain credibility as music teachers. However, other participants did not appear to recognise the importance of the intersection between music-making outside the classroom and teaching, which was an obstacle to music-making. Music-making inside the classroom was an important pedagogical tool to teach low-level students effectively. Importantly, regardless of their level of music-making inside the classroom, novice music teachers commonly viewed professional playing skills with primary and secondary instruments as important for teaching.
A genetically informed longitudinal study of early-life temperament and childhood aggression
Authors: Penichet Eric N. , Beam Christopher R. , Luczak Susan E. , Davis Deborah W.
Published: April 2024

The present study examined the longitudinal associations between three dimensions of temperament – activity, affect-extraversion, and task orientation – and childhood aggression. Using 131 monozygotic and 173 dizygotic (86 same-sex) twin pairs from the Louisville Twin Study, we elucidated the ages, from 6 to 36 months, at which each temperament dimension began to correlate with aggression at age 7. We employed latent growth modeling to show that developmental increases (i.e., slopes) in activity were positively associated with aggression, whereas increases in affect-extraversion and task orientation were negatively associated with aggression. Genetically informed models revealed that correlations between temperament and aggression were primarily explained by common genetic variance, with nonshared environmental variance accounting for a small proportion of each correlation by 36 months. Genetic variance explained the correlations of the slopes of activity and task orientation with aggression. Nonshared environmental variance accounted for almost half of the correlation between the slopes of affect-extraversion and aggression. Exploratory analyses revealed quantitative sex differences in each temperament-aggression association. By establishing which dimensions of temperament correlate with aggression, as well as when and how they do so, our work informs the development of future child and family interventions for children at highest risk of aggression.
‘In Itself’: A New Investigation of Kant’s Adverbial Wording of Transcendental Idealism
Authors: Rosefeldt Tobias
Published: April 2024

This article offers the first systematic investigation of the linguistic forms in which Kant expresses his transcendental idealism since Gerold Prauss’ seminal book Kant und das Problem der Dinge an sich. It is argued that Prauss’ own argument for the claim that ‘in itself’ is an adverbial expression that standardly modifies verbs of philosophical reflection is flawed and that there is hence very poor exegetical evidence for so-called ‘methodological two-aspect’ interpretations of Kant’s transcendental idealism. A comprehensive investigation of Kant’s adverbial uses of ‘in itself’ rather reveals that there are various groups of verbs that ‘in itself’ modifies, which can more or less all be reduced to a standard use in which ‘in itself’ modifies verbs of predicative being such as the copula. It is also discussed how these findings can be accommodated by the two main alternative kinds of interpretations, that is, two-object and ontological two-aspect interpretations.
A panacea to unsustainable consumption? A review of resource caps
Authors: Kelly Adam
Published: April 2024

Non-technical summary

Many of the most pressing issues of today, such as climate change, habitat destruction, and conflict, are linked to our growing economies and the increasing amount of natural resources needed to maintain them. Current resource management policies focus on using resources more efficiently while maintaining economic growth. However, these policies have been insufficient and alternatives are needed. Resource caps are one such alternative which would directly limit resource consumption and extraction. This first review on the topic covers existing research on resource caps, the practical issues of implementation, and suggests a way forward for future policy and research.

Technical summary

Increasingly unsustainable rates of resource consumption and extraction have led to a growing discussion among researchers and environmental advocates on introducing caps on resource use. Research suggests that a reliance on efficiency-based approaches and a focus on decoupling are not sufficient to reduce ecosystem pressures, and instead alternatives such as resource caps may be needed. This article therefore provides the first comprehensive review of research on resource caps, linking them to major social science debates on resource scarcity, social metabolism, decoupling, and degrowth. Resource caps have been increasingly proposed in contemporary degrowth research, but this review found that resource caps are compatible with the agendas of those who endorse ‘green growth’ or ‘ecomodernist’ positions. Although resource caps are commonly proposed at a global level, it was found that enacting national or regional level caps is more viable, and that such caps should be developed through post-normal science and with democratic governance. However, current research does not show how resource caps can be implemented in practice, despite there being a detailed discussion on the political and social factors surrounding implementation. Future research will need to consider how, and even if, caps can function, and in what situations they are effective.

Social media summary

Capping consumption and extraction of natural resources is an alternative to current efficiency-based resource policies.
Is there a place for new herbicides targeting photosynthetic electron transport?
Authors: Twitty Alyssa , Dayan Franck E.
Published: April 2024

Due to increased food demand, the use of herbicides is both necessary and on the rise. Several herbicide classes target photosynthetic electron transport: Herbicide Resistance Action Committee (HRAC) Groups 5, 6, and 22. These herbicides are used in large amounts in many different cropping systems to control several species of broadleaf and grass weeds. This article provides a comprehensive review of what these photosynthesis inhibitors are, how they are used, and their modes of action. Presently, commercial herbicides only inhibit electron flow at two different sites: photosystem II (PSII) and photosystem I (PSI). Herbicides that inhibit electron flow at PSII block the movement of electrons down the electron transport chain, while those that inhibit electron flow at PSI accept electrons. Necrosis developing on the leaves of plants treated with PSII and PSI inhibitors is due to the accumulation of reactive oxygen species. Evolution of resistance, toxicity concerns, and other limitations of these herbicides call for the exploration of new chemistries that can be used to target this pathway.
A Computationally Efficient Method for Parameter Sensitivity Analysis of Microbially Explicit Biogeochemical Models Accounting for Long‐Term Behavior
Authors: Li Wanyu , Wang Gangsheng , Xiang Daifeng
Published: April 2024

Microbial ecological models become increasingly complex owing to the incorporation of many parameters and multiple biotic and abiotic processes. However, little attention has been paid to the variations in the parameter sensitivity during long‐term versus short‐term simulations. Here, we developed a Multi‐Objective Parameter Sensitivity Analysis (MOPSA) method to efficiently identify the important parameters in complex microbial ecological models with multiple response variables of interest in terms of short‐ and long‐term model simulations. We found that MOPSA was more computationally efficient for complex microbial ecological models than Sobol's method because of MOPSA's reliability and low computational sample size. In addition, we address the increased significance of microbial physiology in mediating long‐term than short‐term soil C‐N cycling, indicating that experiment‐model integration practices should examine model behaviors beyond the conventional short‐term experimental period. The outcomes of this study provide an efficient global sensitivity analysis method for parameterization and the scientific foundation for microbial physiology in mediating long‐term microbial ecological processes.
Assimilating Space‐Based Thermospheric Neutral Density (TND) Data Into the TIE‐GCM Coupled Model During Periods With Low and High Solar Activity
Authors: Kosary Mona , Farzaneh Saeed , Schumacher Maike , Forootan Ehsan
Published: April 2024

The global estimation of Thermospheric Neutral Density (TND) and electron density (Ne) on various altitudes are provided by upper atmosphere models, however, the quality of their forecasts needs to be improved. In this study, we present the impact of assimilating space‐based TNDs, measured along Low Earth Orbit (LEO) mission, into the NCAR Thermosphere‐Ionosphere‐Electrodynamics General Circulation Model (TIE‐GCM). In these experiments, the Ensemble Kalman Filter (EnKF) merger of the Data Assimilation Research Testbed (DART) community software is applied. To cover various space‐based TND data and both low and high solar activity periods, we used the measurements of CHAMP (Challenging Minisatellite Payload) and Swarm‐C as assimilated observations. The TND forecasts are then validated against independent TNDs of GRACE (Gravity Recovery and Climate Experiment mission) and Swarm‐B, respectively. To introduce the impact of the thermosphere on estimating ionospheric parameters, the outputs of Ne are validated against the radio occultation data. The Data Assimilation (DA) results indicate that TIE‐GCM overestimates (underestimates) TND and Ne during low (high) solar activity. Considerable improvements are found in forecasting TNDs after DA, that is, the Root Mean Squared Error (RMSE) is reduced by 79% and 51% during low and high solar activity periods, respectively. The reduction values for Ne are found to be 52.3% and 40.4%, respectively.
Estimation of Sediment Transport Parameters From Measured Suspended Concentration Time Series Under Waves and Currents With a New Conceptual Model
Authors: Zhang Shaotong , Zhao Zixi , Li Guangxue , Wu Jinran , Wang You‐Gan , Nielsen Peter , Jeng Dong‐Sheng , Qiao Lulu , Wang Chenghao , Li Sanzhong
Published: April 2024

In‐situ observations of hydrodynamics and suspended sediment concentrations (SSCs) were conducted on an abandoned lobe in the northern part of the modern Yellow River Delta, China. The SSC record at the site is found to be the superposition of a general trend (fast increase and slow decrease cycle) caused by storm waves (SubSSC1) and relatively smaller fluctuations caused by tidal currents (SubSSC2). Physically, this indicates that storm waves eroded the bottom sediments while tidal currents then re‐suspended and advected the suspended sediments in the study area. To further obtain the suspended sediment transport parameters, first, SubSSC1 is modeled with significant wave height which incorporates a “memory curve” to consider the remaining impacts of historical waves. It is detected that waves in the past 75 hr still influence the present SSC which is reasonable because 75 hr is roughly the typical duration of a normal storm. Second, SubSSC2 is modeled with tidal excursion and trigonometric functions with measured periodicities. Finally, some sediment transport parameters, for example, the background SSC, the horizontal SSC gradient, the tidal constituents that advect it, and their relative time lags are optimized from the best fits of the measured and modeled SSC time series. The proposed framework for model construction and parameter optimization can be extended to other sea areas for inferring sediment transport parameters from field SSC time series at a specific station.
Roles of Hydrology and Transport Processes in Denitrification at Watershed Scale
Authors: Wen Y. , Lin J.‐S. , Plaza F. , Liang X.
Published: April 2024

Rainfall runoff and leaching are the main driving forces that nitrogen, an important non‐point source (NPS) pollutant, enters streams, lakes, and groundwater. Hydrological and transport processes thus play a pivotal role in NPS nitrogen pollution. Existing hydro‐environmental models for nitrogen pollution often over‐simplify the within‐watershed processes. It is unclear how such simplification affects the pollution assessment regarding the formation and distribution of denitrification hot spots—which is important for the design of land‐based countermeasures. To study this problem, we developed a model, DHSVM‐N, and its variant, DHSVM‐N_alt. DHSVM‐N is developed by integrating nitrogen‐related processes of SWAT into a comprehensive process‐based hydrological model, the Distributed Hydrology Soil and Vegetation Model (DHSVM). DHSVM‐N includes detailed representations of nitrate transport process at a fine spatial resolution with good landscape connectivity to accommodate interactions between hydrological and biogeochemical processes along the flow travel pathways. Because of the lack of spatially distributed observational data for validation, a model‐to‐model comparison study is conducted. Through comparison studies on a representative catchment using SWAT, DHSVM‐N and DHSVM‐N_alt, we quantify the critical roles of hydrological processes and nitrate transport processes in modeling the denitrification process. That is, the capabilities to give reasonable soil moisture estimates and to account for essential processes that take place along flow pathways are keys to simulate denitrification hot spots and their spatial variation. Furthermore, DHSVM‐N results show that terrestrial denitrification from hotspots alone can reach as high as 36% of the annual stream nitrate export of the watershed.
Impact of Mass‐Loading Effect on the Competition in the Energy Conversion Rate During Magnetic Reconnection
Authors: Xiong Q. Y. , Huang S. Y. , Yuan Z. G. , Jiang K. , Lin R. T. , Yu L.
Published: April 2024

Heavy particles are extensively detected in the space environment, especially in the solar wind and interplanetary magnetosphere. Various physical processes can be affected by the physical dynamics of heavy particles. One of the processes is magnetic reconnection, which converts the energy from the magnetic field to the particles. In the present study, we investigate the impact of heavy particles with increasing mass (i.e., mass‐loading effect) on energy conversion rate during magnetic reconnection. The declined reconnection rate and energy conversion rates by this effect are captured as reported previously. After considering three major regions in reconnection, it reveals that the mass‐loading effect decreases more energy conversion rate of positive species at the separatrix, affects the heavier species less in the inner electron diffusion region (EDR), and propels the formation of a non‐zero electric field at reconnection front (RF). Our results provide a more comprehensive understanding of the magnetic reconnection with complicated plasma components.
The acute phase reactant orosomucoid-2 directly promotes rheumatoid inflammation
Authors: Kim Ki-Myo , Lee Kang-Gu , Lee Saseong , Hong Bong-Ki , Yun Heejae , Park Yune-Jung , Yoo Seung-Ah , Kim Wan-Uk
Published: April 2024

Acute phase proteins involved in chronic inflammatory diseases have not been systematically analyzed. Here, global proteome profiling of serum and urine revealed that orosomucoid-2 (ORM2), an acute phase reactant, was differentially expressed in rheumatoid arthritis (RA) patients and showed the highest fold change. Therefore, we questioned the extent to which ORM2, which is produced mainly in the liver, actively participates in rheumatoid inflammation. Surprisingly, ORM2 expression was upregulated in the synovial fluids and synovial membranes of RA patients. The major cell types producing ORM2 were synovial macrophages and fibroblast-like synoviocytes (FLSs) from RA patients. Recombinant ORM2 robustly increased IL-6, TNF-α, CXCL8 (IL-8), and CCL2 production by RA macrophages and FLSs via the NF-κB and p38 MAPK pathways. Interestingly, glycophorin C, a membrane protein for determining erythrocyte shape, was the receptor for ORM2. Intra-articular injection of ORM2 increased the severity of arthritis in mice and accelerated the infiltration of macrophages into the affected joints. Moreover, circulating ORM2 levels correlated with RA activity and radiographic progression. In conclusion, the acute phase protein ORM2 can directly increase the production of proinflammatory mediators and promote chronic arthritis in mice, suggesting that ORM2 could be a new therapeutic target for RA.
Methyl-CpG binding domain protein 2 (Mbd2) drives breast cancer progression through the modulation of epithelial-to-mesenchymal transition
Authors: Mahmood Niaz , Arakelian Ani , Szyf Moshe , Rabbani Shafaat A.
Published: April 2024

Methyl-CpG-binding domain protein 2 (Mbd2), a reader of DNA methylation, has been implicated in different types of malignancies, including breast cancer. However, the exact role of Mbd2 in various stages of breast cancer growth and progression in vivo has not been determined. To test whether Mbd2 plays a causal role in mammary tumor growth and metastasis, we performed genetic knockout (KO) of Mbd2 in MMTV-PyMT transgenic mice and compared mammary tumor progression kinetics between the wild-type (PyMT-Mbd2+/+) and KO (PyMT-Mbd2−/−) groups. Our results demonstrated that deletion of Mbd2 in PyMT mice impedes primary tumor growth and lung metastasis at the experimental endpoint (postnatal week 20). Transcriptomic and proteomic analyses of primary tumors revealed that Mbd2 deletion abrogates the expression of several key determinants involved in epithelial-to-mesenchymal transition, such as neural cadherin (N-cadherin) and osteopontin. Importantly, loss of the Mbd2 gene impairs the activation of the PI3K/AKT pathway, which is required for PyMT-mediated oncogenic transformation, growth, and survival of breast tumor cells. Taken together, the results of this study provide a rationale for further development of epigenetic therapies targeting Mbd2 to inhibit the progression of breast cancer.
Recent advances in CRISPR-based functional genomics for the study of disease-associated genetic variants
Authors: Kim Heon Seok , Kweon Jiyeon , Kim Yongsub
Published: April 2024

Advances in sequencing technology have greatly increased our ability to gather genomic data, yet understanding the impact of genetic mutations, particularly variants of uncertain significance (VUSs), remains a challenge in precision medicine. The CRISPR‒Cas system has emerged as a pivotal tool for genome engineering, enabling the precise incorporation of specific genetic variations, including VUSs, into DNA to facilitate their functional characterization. Additionally, the integration of CRISPR‒Cas technology with sequencing tools allows the high-throughput evaluation of mutations, transforming uncertain genetic data into actionable insights. This allows researchers to comprehensively study the functional consequences of point mutations, paving the way for enhanced understanding and increasing application to precision medicine. This review summarizes the current genome editing tools utilizing CRISPR‒Cas systems and their combination with sequencing tools for functional genomics, with a focus on point mutations.
Advances in Engineered Macrophages: A New Frontier in Cancer Immunotherapy
Authors: Yang Shuaixi , Wang Yuhang , Jia Jiachi , Fang Yingshuai , Yang Yabing , Yuan Weitang , Hu Junhong
Published: April 2024

Macrophages, as pivotal cells within the tumour microenvironment, significantly influence the impact of and reactions to treatments for solid tumours. The rapid evolution of bioengineering technology has revealed the vast potential of engineered macrophages in immunotherapy, disease diagnosis, and tissue engineering. Given this landscape, the goal of harnessing and innovating macrophages as a novel strategy for solid tumour immunotherapy cannot be overstated. The diverse strategies for engineered macrophages in the realm of cancer immunotherapy, encompassing macrophage drug delivery systems, chimeric antigen receptor macrophage therapy, and synergistic treatment approaches involving bacterial outer membrane vesicles and macrophages, are meticulously examined in this review. These methodologies are designed to enhance the therapeutic efficacy of macrophages against solid tumours, particularly those that are drug-resistant and metastatic. Collectively, these immunotherapies are poised to supplement and refine current solid tumour treatment paradigms, thus heralding a new frontier in the fight against malignant tumours.
Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2
Authors: Zhuang Mingzhi , Li Fengyue , Liang Hong , Su Yongfu , Cheng Lei , Lin Bingkai , Zhou Jun , Deng Runzhi , Chen Linying , Lyu Peng , Lu Zhonglei
Published: April 2024

Soft-tissue sarcomas (STS) emerges as formidable challenges in clinics due to the complex genetic heterogeneity, high rates of local recurrence and metastasis. Exploring specific targets and biomarkers would benefit the prognosis and treatment of STS. Here, we identified RCC1, a guanine-nucleotide exchange factor for Ran, as an oncogene and a potential intervention target in STS. Bioinformatics analysis indicated that RCC1 is highly expressed and correlated with poor prognosis in STS. Functional studies showed that RCC1 knockdown significantly inhibited the cell cycle transition, proliferation and migration of STS cells in vitro, and the growth of STS xenografts in mice. Mechanistically, we identified Skp2 as a downstream target of RCC1 in STS. Loss of RCC1 substantially diminished Skp2 abundance by compromising its protein stability, resulting in the upregulation of p27Kip1 and G1/S transition arrest. Specifically, RCC1 might facilitate the nucleo-cytoplasmic trafficking of Skp2 via direct interaction. As a result, the cytoplasmic retention of Skp2 would further protect it from ubiquitination and degradation. Notably, recovery of Skp2 expression largely reversed the phenotypes induced by RCC1 knockdown in STS cells. Collectively, this study unveils a novel RCC1-Skp2-p27Kip1 axis in STS oncogenesis, which holds promise for improving prognosis and treatment of this formidable malignancy.
Data-driven identification of predictive risk biomarkers for subgroups of osteoarthritis using interpretable machine learning
Authors: Nielsen Rikke Linnemann , Monfeuga Thomas , Kitchen Robert R. , Egerod Line , Leal Luis G. , Schreyer August Thomas Hjortshøj , Gade Frederik Steensgaard , Sun Carol , Helenius Marianne , Simonsen Lotte , Willert Marianne , Tahrani Abd A. , McVey Zahra , Gupta Ramneek
Published: April 2024

Osteoarthritis (OA) is increasing in prevalence and has a severe impact on patients’ lives. However, our understanding of biomarkers driving OA risk remains limited. We developed a model predicting the five-year risk of OA diagnosis, integrating retrospective clinical, lifestyle and biomarker data from the UK Biobank (19,120 patients with OA, ROC-AUC: 0.72, 95%CI (0.71–0.73)). Higher age, BMI and prescription of non-steroidal anti-inflammatory drugs contributed most to increased OA risk prediction ahead of diagnosis. We identified 14 subgroups of OA risk profiles. These subgroups were validated in an independent set of patients evaluating the 11-year OA risk, with 88% of patients being uniquely assigned to one of the 14 subgroups. Individual OA risk profiles were characterised by personalised biomarkers. Omics integration demonstrated the predictive importance of key OA genes and pathways (e.g., GDF5 and TGF-β signalling) and OA-specific biomarkers (e.g., CRTAC1 and COL9A1). In summary, this work identifies opportunities for personalised OA prevention and insights into its underlying pathogenesis.
CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer
Authors: Cheng Maosheng , Chen Shuang , Li Kang , Wang Ganping , Xiong Gan , Ling Rongsong , Zhang Caihua , Zhang Zhihui , Han Hui , Chen Zhi , Wang Xiaochen , Liang Yu , Tian Guoli , Zhou Ruoxing , Zhu Yan , Ma Jieyi , Liu Jiahong , Lin Shuibin , Xu Hao , Chen Demeng , Li Yang , Peng Liang
Published: April 2024

Interplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated macrophages (TAM), play a role in diminishing the immune response against tumors. Using a model of tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in BLCA male mice we show that genetic ablation of CD276 in TAMs blocks efferocytosis and enhances the expression of the major histocompatibility complex class II (MHCII) of TAMs. This in turn increases CD4 + and cytotoxic CD8 + T cell infiltration of the tumor. Combined single cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN to regulate the expression of AXL and MerTK, resulting in enhanced efferocytosis in TAMs. Proving the principle, we show that simultaneous blockade of CD276 and PD-1 restrain tumor growth better than any of the components as a single intervention. Taken together, our study supports a role for CD276 in efferocytosis by TAMs, which is potentially targetable for combination immune therapy.
Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma
Authors: Zhou Yang , Ray Partho Sarothi , Zhu Jianguo , Stein Frank , Rettel Mandy , Sekaran Thileepan , Sahadevan Sudeep , Perez-Perri Joel I. , Roth Eva K. , Myklebost Ola , Meza-Zepeda Leonardo A. , von Deimling Andreas , Fu Chuli , Brosig Annika N. , Boye Kjetil , Nathrath Michaela , Blattmann Claudia , Lehner Burkhard , Hentze Matthias W. , Kulozik Andreas E.
Published: April 2024

Osteosarcoma is the most common primary malignant bone tumor with a strong tendency to metastasize, limiting the prognosis of affected patients. Genomic, epigenomic and transcriptomic analyses have demonstrated the exquisite molecular complexity of this tumor, but have not sufficiently defined the underlying mechanisms or identified promising therapeutic targets. To systematically explore RNA-protein interactions relevant to OS, we define the RNA interactomes together with the full proteome and the transcriptome of cells from five malignant bone tumors (four osteosarcomata and one malignant giant cell tumor of the bone) and from normal mesenchymal stem cells and osteoblasts. These analyses uncover both systematic changes of the RNA-binding activities of defined RNA-binding proteins common to all osteosarcomata and individual alterations that are observed in only a subset of tumors. Functional analyses reveal a particular vulnerability of these tumors to translation inhibition and a positive feedback loop involving the RBP IGF2BP3 and the transcription factor Myc which affects cellular translation and OS cell viability. Our results thus provide insight into potentially clinically relevant RNA-binding protein-dependent mechanisms of osteosarcoma.
Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer
Authors: Croizer Hugo , Mhaidly Rana , Kieffer Yann , Gentric Geraldine , Djerroudi Lounes , Leclere Renaud , Pelon Floriane , Robley Catherine , Bohec Mylene , Meng Arnaud , Meseure Didier , Romano Emanuela , Baulande Sylvain , Peltier Agathe , Vincent-Salomon Anne , Mechta-Grigoriou Fatima
Published: April 2024

Although heterogeneity of FAP+ Cancer-Associated Fibroblasts (CAF) has been described in breast cancer, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute spatial transcriptomics at single-cell level and perform functional assays to generate a high-resolution integrated map of breast cancer (BC), with a focus on inflammatory and myofibroblastic (iCAF/myCAF) FAP+ CAF clusters. We identify 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. Consistent with their spatial organization, cancer cells drive the transition of detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myCAF (ECM-myCAF) via a DPP4- and YAP-dependent mechanism. In turn, ECM-myCAF polarize TREM2+ macrophages, regulatory NK and T cells to induce immunosuppressive EcoCellTypes, while Detox-iCAF are associated with FOLR2+ macrophages in an immuno-protective EcoCellType. FAP+ CAF subpopulations accumulate differently according to the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation.
Bacteria contribute exopolysaccharides to an algal-bacterial joint extracellular matrix
Authors: Lipsman Valeria , Shlakhter Olesia , Rocha Jorge , Segev Einat
Published: April 2024

Marine ecosystems are influenced by phytoplankton aggregation, which affects processes like marine snow formation and harmful events such as marine mucilage outbreaks. Phytoplankton secrete exopolymers, creating an extracellular matrix (ECM) that promotes particle aggregation. This ECM attracts heterotrophic bacteria, providing a nutrient-rich and protective environment. In terrestrial environments, bacterial colonization near primary producers relies on attachment and the formation of multidimensional structures like biofilms. Bacteria were observed attaching and aggregating within algal-derived exopolymers, but it is unclear if bacteria produce an ECM that contributes to this colonization. This study, using Emiliania huxleyi algae and Phaeobacter inhibens bacteria in an environmentally relevant model system, reveals a shared algal-bacterial ECM scaffold that promotes algal-bacterial aggregation. Algal exudates play a pivotal role in promoting bacterial colonization, stimulating bacterial exopolysaccharide (EPS) production, and facilitating a joint ECM formation. A bacterial biosynthetic pathway responsible for producing a specific EPS contributing to bacterial ECM formation is identified. Genes from this pathway show increased expression in algal-rich environments. These findings highlight the underestimated role of bacteria in aggregate-mediated processes in marine environments, offering insights into algal-bacterial interactions and ECM formation, with implications for understanding and managing natural and perturbed aggregation events.
Magnetically tunable supercurrent in dilute magnetic topological insulator-based Josephson junctions
Authors: Mandal Pankaj , Mondal Soumi , Stehno Martin P. , Ilić Stefan , Bergeret F. Sebastian , Klapwijk Teun M. , Gould Charles , Molenkamp Laurens W.
Published: April 2024

A superconductor, when exposed to a spin-exchange field, can exhibit spatial modulation of its order parameter, commonly referred to as the Fulde–Ferrell–Larkin–Ovchinnikov state. Such a state can be induced by controlling the spin-splitting field in Josephson junction devices, allowing access to a wide range of the phase diagram. Here we demonstrate that a Fulde–Ferrell–Larkin–Ovchinnikov state can be induced in Josephson junctions based on the two-dimensional dilute magnetic topological insulator (Hg,Mn)Te. We do this by observing the dependence of the critical current on the magnetic field and temperature. The substitution of Mn dopants induces an enhanced Zeeman effect, which can be controlled with high precision by using a small external magnetic field. We observe multiple re-entrant behaviours of the critical current as a response to an in-plane magnetic field, which we assign to transitions between ground states with a phase shifted by π. This will enable the study of the Fulde–Ferrell–Larkin–Ovchinnikov state in much more accessible experimental conditions.
Complexity of avian evolution revealed by family-level genomes
Authors: Stiller Josefin , Feng Shaohong , Chowdhury Al-Aabid , Rivas-González Iker , Duchêne David A. , Fang Qi , Deng Yuan , Kozlov Alexey , Stamatakis Alexandros , Claramunt Santiago , Nguyen Jacqueline M. T. , Ho Simon Y. W. , Faircloth Brant C. , Haag Julia , Houde Peter , Cracraft Joel , Balaban Metin , Mai Uyen , Chen Guangji , Gao Rongsheng , Zhou Chengran , Xie Yulong , Huang Zijian , Cao Zhen , Yan Zhi , Ogilvie Huw A. , Nakhleh Luay , Lindow Bent , Morel Benoit , Fjeldså Jon , Hosner Peter A. , da Fonseca Rute R. , Petersen Bent , Tobias Joseph A. , Székely Tamás , Kennedy Jonathan David , Reeve Andrew Hart , Liker Andras , Stervander Martin , Antunes Agostinho , Tietze Dieter Thomas , Bertelsen Mads F. , Lei Fumin , Rahbek Carsten , Graves Gary R. , Schierup Mikkel H. , Warnow Tandy , Braun Edward L. , Gilbert M. Thomas P. , Jarvis Erich D. , Mirarab Siavash , Zhang Guojie
Published: April 2024

Despite tremendous efforts in the past decades, relationships among main avian lineages remain heavily debated without a clear resolution. Discrepancies have been attributed to diversity of species sampled, phylogenetic method and the choice of genomic regions1–3. Here we address these issues by analysing the genomes of 363 bird species4 (218 taxonomic families, 92% of total). Using intergenic regions and coalescent methods, we present a well-supported tree but also a marked degree of discordance. The tree confirms that Neoaves experienced rapid radiation at or near the Cretaceous–Palaeogene boundary. Sufficient loci rather than extensive taxon sampling were more effective in resolving difficult nodes. Remaining recalcitrant nodes involve species that are a challenge to model due to either extreme DNA composition, variable substitution rates, incomplete lineage sorting or complex evolutionary events such as ancient hybridization. Assessment of the effects of different genomic partitions showed high heterogeneity across the genome. We discovered sharp increases in effective population size, substitution rates and relative brain size following the Cretaceous–Palaeogene extinction event, supporting the hypothesis that emerging ecological opportunities catalysed the diversification of modern birds. The resulting phylogenetic estimate offers fresh insights into the rapid radiation of modern birds and provides a taxon-rich backbone tree for future comparative studies.
Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity
Authors: Hamid Megat H. B. A. , Cespedes Pablo F. , Jin Chen , Chen Ji-Li , Gileadi Uzi , Antoun Elie , Liang Zhu , Gao Fei , Teague Renuka , Manoharan Nikita , Maldonado-Perez David , Khalid-Alham Nasullah , Cerundolo Lucia , Ciaoca Raul , Hester Svenja S. , Pinto-Fernández Adán , Draganov Simeon D. , Vendrell Iolanda , Liu Guihai , Yao Xuan , Kvalvaag Audun , Dominey-Foy Delaney C. C. , Nanayakkara Charunya , Kanellakis Nikolaos , Chen Yi-Ling , Waugh Craig , Clark Sally-Ann , Clark Kevin , Sopp Paul , Rahman Najib M. , Verrill Clare , Kessler Benedikt M. , Ogg Graham , Fernandes Ricardo A. , Fisher Roman , Peng Yanchun , Dustin Michael L. , Dong Tao
Published: April 2024

Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.