bluuebunny/crossref_metadata_2025 huggingface dataset:
Adding human values on the deepfake: co-designing fact-checking solutions to combat misinformation
Authors: Maia C. H. , Ariel P. , Nunes S.
Published: December 2024

The proliferation of misinformation poses a significant challenge to societies, and fact-checking emerges as a critical tool to combat this issue. In this work, we conduct an innovation impact assessment to question the use of technology to combat misinformation, specifically examining the ethical implications of this choice. To address this, we organized a workshop using the value sensitive design (VSD) methodology to explore questions in this context. The workshop introduced participants to the VSD framework, enabling them to critically assess whether specific scenarios align with human values, norms, and requirements. Real-world scenarios were discussed, including approaches implemented by legitimate news outlets and using 3D virtual characters by a Brazilian television employing deep learning. Participants analyzed how technology impacts journalism values, norms, and practices, focusing on aligning synthetic media technologies with automated fact-checking dissemination. In conclusion, the authors prepared recommendations from valuable insights into the complex ethical considerations surrounding synthetic media technologies for automatic fact-checking dissemination. It also facilitated cross-border discussions, with 11 participants from seven countries engaging in fruitful dialogue on this vital topic. The study proposed evaluation criteria for AI-generated content in this diversity, including privacy protection, inclusiveness, transparency, beauty standards conformity, engagement, meaningfulness, and effortlessness.
Safe motion planning and formation control of quadruped robots
Authors: Ji Zongrui , Dong Yi
Published: December 2024

This paper introduces a motion planning and cooperative formation control approach for quadruped robots and multi-agent systems. First, in order to improve the efficiency and safety of quadruped robots navigating in complex environments, this paper proposes a new planning method that combines the dynamic model of quadruped robots and a gradient-optimized obstacle avoidance strategy without Euclidean Signed Distance Field. The framework is suitable for both static and slow dynamic obstacle environments, aiming to achieve multiple goals of obstacle avoidance, minimizing energy consumption, reducing impact, satisfying dynamic constraints, and ensuring trajectory smoothness. This approach differs in that it reduces energy consumption throughout the movement from a new perspective. Meanwhile, this method effectively reduces the impact of the ground on the robot, thus mitigating the damage to its structure. Second, we combine the dynamic control barrier function and the virtual leader-follower model to achieve efficient and safe formation control through model predictive control. Finally, the proposed algorithm is validated through both simulations and real-world scenarios testing.
Criteria for the choice and monitoring of Menopausal Hormone Therapy
Authors: Ruan Xiangyan , Mueck Alfred O.
Published: December 2024

To review the criteria for the selection of estrogens and especially progestogens for optimizing Menopausal Hormone Therapy (MHT). The main criteria are primarily derived from the Women's Health Initiative (WHI)-trial, disclosing the main risks like endometrial cancer, coronary heart disease (CHD), stroke, venous tromboembolism (VTE) and breast cancer. In addition observational studies must be considered for individualizing MHT, because WHI has tested only one preparation and has a lot of problems like early opening of the hormone/placebo-code (i.e., loss of placebo control), in 60% MHT-initiation too late, and in 40% risk factors for cardiovascular diseases and breast cancer. Pharmacological properties should be considered, such as only oral, but not transdermal estradiol increases VTE-risk. The choice of progestogens could be dependent on the different "partial effects" on steroid receptors, e.g., use of anti-androgenic progestogens in metabolic syndrome, Polycystic Ovary Syndrome (PCOS) etc., taking advantage of the anti-mineralocorticoid effect of drospirenone to stabilize blood pressure and reduce the risk of stroke, selection of tibolone for patients with sexual dysfunctions because its androgenic properties etc. Most important for the selection of the progestogen is endometrial efficacy, primary indication for progestogens in MHT. Therefore regular endometrial monitoring is reommended, using sequential or continuous combined regimens; "hormonal curettage" and/or the progestogen challenge text to avoid endometrial hyperproliferation. Levonorgestrel-IUD as progestogen component can reduce progestogen-dependent risks, offering also contraception, but often with longer bleeding problems, in contrast to sequential regimens of MHT, which can be used to treat irregular bleedings. Other main indications are treatment of climacteric complaints and prevention of osteoporosis and possible other preventive options. Regarding contraindications, according to the general rules of "class-labeling", they are the same for every MHT despite there are differences in benefits and risks. Choice of the timing of MHT-initiation is crucial to whether cardiovascular prevention (early start) or (like in WHI) increased risk of CHD and stroke occurs. The increased risk of breast cancer can be reduced using progesterone or its isomer dydrogesterone. Since, however, this risk cannot been excluded with any MHT, recommendations for screening on the possible development of breast cancer are given, on the basis of own recent research. Criteria for the selection of MHT are mainly to reduce possible risks as seen in WHI since for every MHT efficacy is good and essentially the same. Often the best choice is estradiol combined with progesterone or dydrogesterone, but also other progestogens should be considered including LNG-IUD, to optimize and individualize MHT.
Tide-river interaction in the Pechora Delta as revealed by new measurements and numerical modeling
Authors: Panchenko Evgeniya , Krylenko Inna , Alabyan Andrei
Published: December 2024

The Pechora is the greatest river of the European Russian Arctic, flowing into the Barents Sea. Its estuarine area includes a vast delta, represented by extensive lowlands that are dissected by the complicated network of arms and branches. Despite the Pechora Delta is considered to be microtidal, tides with a range of 0.5–1 m during the low water period have a significant impact on the nature of currents in the main branches and the distribution of runoff among them during the tidal cycle. Tidal sea level fluctuations as well as storm surges determine the reversing pattern of currents over a significant extent of the delta branches. The modern field equipment combined with 2D hydrodynamic modeling has allowed to understand the contemporary flow features and evaluate their possible alterations under climate changes. The climate impact under considered scenarios is more pronounced during the low flow period, and this can lead to the propagation of tidal currents and an increase in water levels in the city of Naryan-Mar (100 km upstream from the mouth). From a flood risk perspective, sea level rise can be offset by a reduction in flood runoff.
Regulators of Last Resort
Authors: Kenny Kate
Published: December 2024

How do public whistleblowers prevail despite employers' attempts to silence them? Whistleblowing is essential for raising awareness of extreme wrongdoing within organizations yet, despite changing laws designed to offer more protection, workers exposed for public disclosures frequently find themselves the targets of extreme retaliation. Featuring high-profile cases from Amazon, Facebook and Theranos, Kate Kenny reveals the critical - and often unseen - role that skilled allies play in supporting whistleblowers when official channels fail. Novel and sophisticated means of silencing require new strategies for whistleblowing – and supportive partners are key. In this new era of whistleblowing, oppressive lawfare is used against truth-telling workers, and official channels can be weaponized. Yet powerful employers can still make mistakes. Regulators of Last Resort shows how aggressive reprisals can yield surprising advantages for dissenters. Working in partnership with advocates, public whistleblowers can find strategies to survive, persist and bring their disclosures to light.
Relocating Development Economics
Authors: Bach Maria
Published: December 2024

Originating in the Nineteenth Century, the European idea of development was shaped around the premise that the West possessed progressive characteristics that the East lacked. As a result of this perspective, many alternative development discourses originating in the East were often overlooked and forgotten. Indian Economics is but one example. By recovering thought from the margins, Relocating Development Economics exposes useful new ways of viewing development. It looks at how an Indian tradition in economic thought emerged from a group of Indian economists in the late Nineteenth Century who questioned dominant European economic ideas on development and agricultural economics. This book shows how the first generation of modern Indian economists pushed at the boundaries of existing theories to produce reformulations that better fit their subcontinent and opens up discursive space to find new ways of thinking about regress, progress and development.
Money, Value, and the State
Authors: Donovan Kevin P.
Published: December 2024

Decolonization in East Africa was more than a political event: it was a step towards economic self-determination. In this innovative book, historian and anthropologist Kevin Donovan analyses the contradictions of economic sovereignty and citizenship in Tanzania, Kenya and Uganda, placing money, credit, and smuggling at the center of the region's shifting fortunes. Using detailed archival and ethnographic research undertaken across the region, Donovan reframes twentieth century statecraft and argues that self-determination was, at most, partially fulfilled, with state monetary infrastructures doing as much to produce divisions and inequality as they did to produce nations. A range of dissident practices, including smuggling and counterfeiting, arose as people produced value on their own terms. Weaving together discussions of currency controls, bank nationalizations and coffee smuggling with wider conceptual interventions, Money, Value and the State traces the struggles between bankers, bureaucrats, farmers and smugglers that shaped East Africa's postcolonial political economy.
Behaviour Beyond the Text and the Morality Clause in Twenty-First-Century Publishing
Authors: Bullen Chiara
Published: December 2024

A morality clause allows contracting parties to terminate a contractual agreement with those who exhibit behaviour deemed unacceptable. Established in 1920s Hollywood, these contractual clauses are now found in twenty-first-century publishing agreements. This Element investigates the presence of the morality clause in the UK book publishing industry in relation to an increased focus on author behaviour beyond the text in the twenty-first-century, examining the way it operates within the publishing field in the context of behaviour perceived to be 'problematic'. It asserts the clause is perceived to be needed due to the emergence of social media and twenty-first-century social contexts combining to impact the author-reader relationship which, in turn, leads to author behaviour acting as a paratextual threshold to their work. This Element presents an analysis of the morality clause in practice, concluding the clause has the potential to further the power imbalance between author and publisher.
Reboundless design: towards the prevention of rebound effects by design
Authors: Pigosso Daniela C. A.
Published: December 2024

Society’s most well-intended efforts to solve sustainability challenges have not yet achieved the expected gains due to rebound effects (i.e., negative consequences of interventions arising from induced changes in system behaviour). Rebound effects offset about 40% of potential sustainability gains, but the understanding of design as a key leverage point for preventing rebound effects is still untapped. In this position paper, three fundamental scientific gaps hampering the prevention of rebound effects are discussed: (1) limited knowledge about the rebound effects triggered by efficiency–effectiveness–sufficiency strategies; (2) the influence of the counterintuitive behaviour of complex socio-technical systems in giving rise to rebound effects is not yet understood and (3) the bounded rationality within design limits the understanding of rebound effects at a broader systemic level. To address the aforementioned gaps, novel methodologies, simulation models and strategies to enable the design of reboundless interventions (i.e., products, product/service-systems and socio-technical systems that are resilient to rebound effects) are required. Building on the strong foundation of systems and design theory, this position paper argues for the need to bridge the interdisciplinary gap in the interplay of design and rebound effects, qualitative and quantitative models, engineering and social sciences, and theory and practice.
Identifying species traits that predict vulnerability to climate change
Authors: Fordham Damien A.
Published: December 2024

Accurately predicting the vulnerabilities of species to climate change requires a more detailed understanding of the functional and life-history traits that make some species more susceptible to declines and extinctions in shifting climates. This is because existing trait-based correlates of extinction risk from climate and environmental disturbances vary widely, often being idiosyncratic and context dependent. A powerful solution is to analyse the growing volume of biological data on changes in species ranges and abundances using process-explicit ecological models that run at fine temporal and spatial scales and across large geographical extents. These simulation-based approaches can unpack complex interactions between species’ traits and climate and other threats. This enables species-responses to climatic change to be contextualised and integrated into future biodiversity projections and to be used to formulate and assess conservation policy goals. By providing a more complete understanding of the traits and contexts that regulate different responses of species to climate change, these process-driven approaches are likely to result in more certain predictions of the species that are most vulnerable to climate change.
Functional stasis and changing habitat preferences among mammalian communities from the PETM of the Bighorn Basin, Wyoming
Authors: Whittingham Misha A.J.B. , Korasidis Vera A. , Fraser Danielle
Published: December 2024

The transition between the Paleocene and Eocene epochs (ca. 56 Ma) was marked by a period of rapid global warming of 5 °C to 8 °C following a carbon isotope excursion (CIE) lasting 200 ky or less referred to as the Paleocene-Eocene Thermal Maximum (PETM). The PETM precipitated a significant shift in the composition of North American floral communities and major mammalian turnover. We explored the ecological impacts of this phenomenon by analyzing 173 mammal species from the Bighorn Basin, Wyoming, USA, including their associated body alongside a database of 30 palynofloral localities as proxies for habitat. For each time bin, we calculated mean and median differences in body mass and habitat preference between significantly aggregated and segregated mammal species. Aggregated species showed significant similarity in habitat preference only prior to the PETM, after which habitat preference ceased to be a significant factor in community assembly. Our measures of differences in body mass space provide no evidence of a significant impact of competitive interactions on community assembly across the PETM, aligning with previous work. Our results indicate the persistence of a stable mammalian functional community structure despite taxonomic turnover, climate change and broadening habitat preferences.
The de-ideologization of welfare politics: Political governments’ social policy measures in eight welfare states during the COVID-19 pandemic
Authors: Peltoniemi Johanna , Ketonen Eeva-Leena , Hiilamo Heikki
Published: December 2024

During the global COVID-19 pandemic, many countries have expanded the level and coverage of current social insurance and social assistance programs as well as implemented new programs. Based on three separate datasets, V-Dem V-Party dataset; fourteen structured expert interviews; and a dataset of 114 social security measures, we study the link between the welfare regime, pandemic-related social policy measures, and incumbents’ ideological stand. Does the pandemic-related social policy measures mirror the political attitudes of the incumbents? What role did the welfare regime play? We scrutinise eight OECD countries (Denmark, Finland, Germany, Netherlands, Norway, Sweden, UK, and the US) representing three different welfare regimes: corporatist-conservative countries, liberal countries, and socio-democratic countries. The key findings of this article show that the pandemic-related social policy measures did not mirror the political attitudes of the incumbents.
Constrained Precipitation Extremes Reveal Unequal Future Socioeconomic Exposure
Authors: Liu Ziyi , Yue Yao , Slater Louise , Borthwick Alistair G. L. , Chai Yuanfang , Luan Xiaofan , Miao Chiyuan , Yang Zhonghua
Published: December 2024

Extreme precipitation can lead to major flooding, impacting human health and safety. Thus, reliable projections of population and GDP exposure to future extreme precipitation are imperative. Here, we quantify future precipitation characteristics from robust emergent constraint relationships between historical and future monthly precipitation extremes (99th percentile) across 19 CMIP6 models (r2 > 0.7 in 74–84% of 0.5° global land grids), and narrow uncertainty by 37.0–39.5% (absolute reduction being 0.753–0.774 mm/day). The constrained grid‐averaged future 99th percentile extreme is 6.96 ± 0.0059, 7.03 ± 0.0061, 7.11 ± 0.0063, and 7.29 ± 0.0067 mm/day, under SSP126, SSP245, SSP370, and SSP585, respectively, which exceeds historical extremes substantially in terms of intensity (12.9–19.7%) and frequency (1.6–2.3 times more). Future population and GDP exposed to 99th percentile extreme precipitation grow quickly, and are projected to exceed 1 million people in 27–40 countries and 10 billion USD (2005 Purchasing‐Power Parity) in 48–77 countries. Growth of future population exposure is dominated by an increase in extreme precipitation frequency rather than a rise in population, especially in developed countries. GDP exposure is controlled by the coupled effects of rapid socio‐economic development and significant shifts in precipitation frequency. Using indices of socio‐economic vulnerability, government effectiveness and economic freedom, we identify the unequal situation that high‐risk countries with high exposure are commonly characterized by low GDP per capita and high sociopolitical instability.
Characterization of Reflectance Signatures Within Above Anvil Cirrus Plumes in GOES‐16 Infrared and Visible Imagery
Authors: Murphy Kelley M. , Mecikalski John R. , Bedka Kristopher M. , Cooney John W. , Homeyer Cameron R.
Published: December 2024

Above anvil cirrus plumes (AACPs) form atop deep convective storm anvils. Storms containing AACPs are closely associated with surface severe weather. AACPs often reside in the lower stratosphere, and their microphysics are thought to be characterized by smaller ice particles with increased reflectance in shortwave infrared (SWIR) satellite imagery. This study aimed to determine which SWIR channels exhibit the strongest unique signatures over AACP lifetimes, assess how NEXRAD GridRad radar‐derived fields associated with severe weather relate to AACP presence and evolution, and take steps toward a red‐green‐blue (RGB) recipe to identify AACPs. AACPs and non‐plume anvil regions were labeled and analyzed using 5‐min resolution Geostationary Operational Environmental Satellites (GOES)‐16 Advanced Baseline Imager observations for five storms between 2019 and 2021. Considered were 0.64, 1.37, 1.6, 2.24, 3.9 μm reflectances, and 10.3 μm brightness temperatures (BTs). Results show: (a) higher median reflectance of accumulated AACPs in the 0.64, 1.37, and 2.24 μm channels compared to non‐plumes, (b) the 60−79° solar zenith angle bin contained the most data, corresponded with an afternoon peak in storm intensity, and contained a large plume to non‐plume pixel ratio, (c) increased lower stratosphere water vapor associated with AACPs impacted the 1.37 μm reflectance, leading to smaller, more reflective cloud ice particles than non‐plume regions, (d) GridRad radar 10‐ and 40‐dBZ echo heights and column maximum reflectivity (CMR) show AACPs coinciding with a secondary maximum in CMR, and (e) an RGB combining 1.37 μm, 0.64 μm + 3.9 μm reflectance, and 10.3 μm BT visually revealed AACPs.
Adaptively Implicit Advection for Atmospheric Flows
Authors: Weller Hilary , Kühnlein Christian , Smolarkiewicz Piotr K.
Published: December 2024

Implicit time‐stepping for advection is applied locally in space and time where Courant numbers are large, but standard explicit time‐stepping is used for the remaining solution which is typically the majority. This adaptively implicit advection scheme facilitates efficient and robust integrations with long time‐steps while having negligible impact on the overall accuracy, and achieving monotonicity and local conservation on general meshes. A novel and important aspect for the efficiency of the approach is that only one iteration is needed each time the linear equation solver is called for solving the advection equation. The demonstration in this paper uses the second‐order Runge‐Kutta implicit/explicit time integration in combination with a second/third‐order finite‐volume spatial discretization and is tested using deformation flow tracer advection on the sphere and a fully compressible model for atmospheric flows. Tracers are advected over the poles of highly anisotropic latitude‐longitude grids with very large Courant numbers and on quasi‐uniform hexagonal and cubed‐sphere meshes with the same algorithm. Buoyant flow simulations with strong local updrafts also benefit from adaptively implicit advection. Stably stratified compressible flow simulations require a stable combination of implicit treatment of gravity and acoustic waves as well as advection in order to achieve long time‐steps.
Crustal Architecture and Magmatism of the Campos Rifted Margin: Along‐Strike Variability and Segmentation
Authors: Alvarez P. , Stanton N. , Péron‐Pinvidic G. , Magnavita L. , Borghi L.
Published: December 2024

We investigate the crustal architecture and structural domains of the Campos rifted margin in southeastern Brazil, focusing on rifting evolution and segmentation. Based on 2‐D and 3‐D seismic reflection interpretation and potential field modeling, our results reveal an along‐strike variability, in terms of margin architecture and magmatism, that segments the basin into three main sectors from south to north. Through the analysis of seismic reflection profiles, we interpret this lateral variability as a product of lower‐ to upper‐plate alternations and different magmatic inputs. We propose the Southern Campos margin to represent a lower‐plate tectonic setting, where the distal domain is characterized by the formation of the here named Gávea Supradetachment Basin associated with the development of a metamorphic core‐complex. The Central Campos margin is characterized by a massive residual block, representing an upper‐plate setting, with exhumation of different crustal levels in the distal domain. Our analysis suggests that the Central Campos sustained a high magmatic input throughout the rift evolution, supporting the interpretation of Seaward Dipping Reflectors and a magmatic crust in a transitional domain. The Northern Campos margin also represents an upper‐plate setting, but characterized by a progressively delaminated crust. Finally, we compare the Brazilian margin architecture with the conjugate Angola margin, discuss the role of transfer zones in the segmentation and propose along‐strike variations in the volume of magmatism.
Correlation of Crustal Kinematic Characteristics and the Uplift of the Southeastern Tibetan Plateau During the Paleogene
Authors: Tong Yabo , Pei Junling , Yang Zhenyu , Li Jianfeng , Hou Lifu , Sun Xinxin , Zhang Zijian
Published: December 2024

The mechanism of the uplift of the southeastern Tibetan Plateau during the Cenozoic is much debated. To address this problem, we conducted a paleomagnetic study of the Eocene sedimentary strata in the Relu Basin, in the southeastern Tibetan Plateau. Two primary magnetic components of Ds = 24.0°, Is = 26.8°, k = 156.8, α95 = 3.5° acquired during ∼48.0–43.0 Ma and Ds = 172.2°, Is = −38.0°, k = 38.6, α95 = 9.8° during ∼43.0–35.0 Ma were isolated. The results combined with previous Paleocene and Eocene paleomagnetic and paleo‐altimetry data sets from the southeastern Tibetan Plateau, revealed a spatio‐temporal correlation between crustal movement and the uplift process of the southeastern Tibetan Plateau. The results showed that the final collision between India and Asia at ∼53.0–47.0 Ma immediately triggered the latitudinal crustal convergence and rotational deformation within the southeastern Tibetan Plateau. Since ∼47.0 Ma the southeastern Tibetan Plateau underwent a coherent crustal rotational pattern, and by at least ∼43.0 Ma, it finished the substantial latitudinal crustal convergence. The crustal movement transformations coincided with the major uplift of the southeastern Tibetan Plateau during ∼47.0–35.0 Ma and the eruption of extensive mafic magmatic rocks across the southeastern Tibetan Plateau and its margin during ∼43.0–33.0 Ma. These spatio‐temporal relationships suggest that the integral uplift of the southeastern Tibetan Plateau was mainly associated with the asthenospheric mantle upwelling and convection resulting from the tearing of the mantle lithosphere of the India Plate beneath the southeastern Tibetan Plateau.
Widespread Increasing Control of Water Supply on Evapotranspiration
Authors: Zhang Yu , Liu Xiaomang , Wang Kaiwen , Zhang Dan , Liu Weihang
Published: December 2024

Evapotranspiration (ET), a crucial component of water consumption in the hydrological process, is directly controlled by soil moisture (SM) and vapor pressure deficit (VPD) from the perspectives of water supply and demand. However, SM and VPD are strongly coupled through multiple physical processes, confounding their effects on ET. Here, we decouple the interaction between SM and VPD and then analyze the spatiotemporal pattern of their individual effects on ET based on multiple observation‐based data sets. The results show that ET is limited by SM rather than VPD in approximately 63% of global land areas (60°S–60°N), defined as water supply‐limited regions. From 1982 to 2014, the effect of SM on ET enhances significantly in 43% of the water supply‐limited regions. The trends can be attributed to changes in SM and VPD themselves as well as to changes in vegetation conditions. Using the findings from the observation‐based data sets as the benchmark, we show that Earth System Models (ESMs) can overall reproduce the spatial pattern of SM and VPD effects on ET but fail to capture their temporal trends. Our results highlight that the water supply and demand control on ET varies with changing environments, which should be explicitly considered when analyzing the terrestrial water cycle and land‐atmosphere interaction.
Supra- and sub-threshold intracellular-like recording of 2D and 3D neuronal networks using nanopillar electrode arrays
Authors: Shukla Shivani , Schwartz Joshua L. , Walsh Callum , Wong Wen Mai , Patel Vrund , Hsieh Yu-Peng , Onwuasoanya Chichi , Chen Shaoming , Offenhäusser Andreas , Cauwenberghs Gert , Santoro Francesca , Muotri Alysson R. , Yeo Gene W. , Chalasani Sreekanth H. , Jahed Zeinab
Published: December 2024

The brain integrates activity across networks of interconnected neurons to generate behavioral outputs. Several physiological and imaging-based approaches have been previously used to monitor responses of individual neurons. While these techniques can identify cellular responses greater than the neuron’s action potential threshold, less is known about the events that are smaller than this threshold or are localized to subcellular compartments. Here we use NEAs to obtain temporary intracellular access to neurons allowing us to record information-rich data that indicates action potentials, and sub-threshold electrical activity. We demonstrate these recordings from primary hippocampal neurons, induced pluripotent stem cell-derived (iPSC) neurons, and iPSC-derived brain organoids. Moreover, our results show that our arrays can record activity from subcellular compartments of the neuron. We suggest that these data might enable us to correlate activity changes in individual neurons with network behavior, a key goal of systems neuroscience.
CXCR1+ neutrophil infiltration orchestrates response to third-generation EGFR-TKI in EGFR mutant non-small-cell lung cancer
Authors: Wang Haowei , Xiong Anwen , Chen Xiaoxia , Guo Junhong , Tang Zhuoran , Wu Chunyan , Ren Shengxiang , Zhou Caicun , Chen Jian , Hou Likun , Jiang Tao
Published: December 2024

Although third-generation Epidermal growth factor receptor—tyrosine kinase inhibitors (EGFR-TKI) is standard of care for patients with EGFR-mutant Non-small cell lung cancer (NSCLC), little is known about the predictors of response or resistance. Here, we integrated single-cell RNA (scRNA) sequencing, bulk RNA sequencing, multiplexed immunofluorescence and flow cytometry data from pretreatment and post-resistant tumor samples of EGFR-mutant NSCLC patients received third-generation EGFR-TKIs. We show that resistant samples had a markedly enriched CXCR1+ neutrophils infiltration (P < 0.01) than pretreatment samples, which were distinguished from other subtypes of neutrophils and displayed immunosupressive characteristics. Spatial analysis showed that increased CXCR1+ neutrophils predominantly infiltrated into the tumor core in resistant samples and the average distance of neutrophils to tumor cells markedly reduced from 33 to 19 μm. Deep analysis of scRNA and bulk RNA sequencing data revealed the increased interactions between CXCR1+ neutrophils and tumor cells and activated TNF-α/NF-κB signaling pathway in tumor cells of resistant samples. In vitro and in vivo experiments validated that CXCR1+ neutrophils resulted in resistance to third-generation EGFR-TKI via activating TNF-α/NF-κB signaling pathway in tumor cells. Importantly, patients with low pretreatment CXCR1+ neutrophil infiltration abundance had a dramatically longer progression-free survival (11.8 vs. 7.5 months; P = 0.019) and overall survival (33.0 vs. 23.5 months; P = 0.029) than those with high infiltration abundance. Collectively, these findings suggest that CXCR1+ neutrophils infiltration was associated with the efficacy of third-generation EGFR-TKI in patients with EGFR-mutant NSCLC.
Neutrophil diversity and function in health and disease
Authors: Zhang Fengyuan , Xia Yidan , Su Jiayang , Quan Fushi , Zhou Hengzong , Li Qirong , Feng Qiang , Lin Chao , Wang Dongxu , Jiang Ziping
Published: December 2024

Neutrophils, the most abundant type of granulocyte, are widely recognized as one of the pivotal contributors to the acute inflammatory response. Initially, neutrophils were considered the mobile infantry of the innate immune system, tasked with the immediate response to invading pathogens. However, recent studies have demonstrated that neutrophils are versatile cells, capable of regulating various biological processes and impacting both human health and disease. Cytokines and other active mediators regulate the functional activity of neutrophils by activating multiple receptors on these cells, thereby initiating downstream signal transduction pathways. Dysfunctions in neutrophils and disruptions in neutrophil homeostasis have been implicated in the pathogenesis of numerous diseases, including cancer and inflammatory disorders, often due to aberrant intracellular signaling. This review provides a comprehensive synthesis of neutrophil biological functions, integrating recent advancements in this field. Moreover, it examines the biological roles of receptors on neutrophils and downstream signaling pathways involved in the regulation of neutrophil activity. The pathophysiology of neutrophils in numerous human diseases and emerging therapeutic approaches targeting them are also elaborated. This review also addresses the current limitations within the field of neutrophil research, highlighting critical gaps in knowledge that warrant further investigation. In summary, this review seeks to establish a comprehensive and multidimensional model of neutrophil regulation, providing new perspectives for potential clinical applications and further research.
Prefrontal electrophysiological biomarkers and mechanism-based drug effects in a rat model of alcohol addiction
Authors: Habelt Bettina , Afanasenkau Dzmitry , Schwarz Cindy , Domanegg Kevin , Kuchar Martin , Werner Carsten , Minev Ivan R. , Spanagel Rainer , Meinhardt Marcus W. , Bernhardt Nadine
Published: December 2024

Patients with alcohol use disorder (AUD) who seek treatment show highly variable outcomes. A precision medicine approach with biomarkers responsive to new treatments is warranted to overcome this limitation. Promising biomarkers relate to prefrontal control mechanisms that are severely disturbed in AUD. This results in reduced inhibitory control of compulsive behavior and, eventually, relapse. We reasoned here that prefrontal dysfunction, which underlies vulnerability to relapse, is evidenced by altered neuroelectric signatures and should be restored by pharmacological interventions that specifically target prefrontal dysfunction. To test this, we applied our recently developed biocompatible neuroprosthesis to measure prefrontal neural function in a well-established rat model of alcohol addiction and relapse. We monitored neural oscillations and event-related potentials in awake alcohol-dependent rats during abstinence and following treatment with psilocybin or LY379268, agonists of the serotonin 2A receptor (5-HT2AR), and the metabotropic glutamate receptor 2 (mGluR2), that are known to reduce prefrontal dysfunction and relapse. Electrophysiological impairments in alcohol-dependent rats are reduced amplitudes of P1N1 and N1P2 components and attenuated event-related oscillatory activity. Psilocybin and LY379268 were able to restore these impairments. Furthermore, alcohol-dependent animals displayed a dominance in higher beta frequencies indicative of a state of hyperarousal that is prone to relapse, which particularly psilocybin was able to counteract. In summary, we provide prefrontal markers indicative of relapse and treatment response, especially for psychedelic drugs.
Student confidence in clinical competence during dental education
Authors: Brundin Malin , Sjöström Mats
Published: December 2024

Introduction

Dental education blends theoretical and practical training to prepare students for independent patient care. This study examines the confidence levels of dental students at Umeå University, Sweden regarding independent performance of general dentistry tasks, and whether this confidence changes after clinical training.

Material and methods

Surveys were conducted before and after a summer clinical internship, with students rating their comfort levels on a scale from 0 to 10 for various procedures.

Results

Results from 64 initial surveys and 54 follow-up surveys showed no significant difference in confidence before and after the internship except for performing a tooth extraction (p = 0.010). However, confidence levels varied based on whether students had practiced specific tasks during the internship.

Discussion

Students felt least confident in managing acute dental trauma (mean 6.1–6.2) and treating cavities in young children (mean 6.2–6.7), while they were most confident in tasks like obtaining radiographic surveys (mean 8.5–8.6) and debriding periodontally compromised dentition (mean 8.2–8.3). Tooth extraction and dental fillings were the most practiced procedures during the internship.

Conclusions

The study concludes that the internship between the ninth and tenth semesters does not notably boost students’ confidence in specific dental procedures except for dental extractions. This result can possibly be explained due to the short duration of the training. Further exploration, including input from clinical supervisors, is suggested to optimise clinical training in dental education.
Real-world characteristics and outcomes of patients with high-risk and non-high-risk smoldering multiple myeloma using the Flatiron Health database
Authors: Rajkumar S. Vincent , Mateos María-Victoria , Schaeffer Marcy , Lin Xiwu , Bathija Sacheeta , Gupta-Werner Niodita , Lam Annette , Carson Robin , Dennis Robyn , Kaila Shuchita , Matt Kathryn , Duran Joana , Lonial Sagar
Published: December 2024

This study aimed to provide real-world evidence on progression risk in patients with high-risk smoldering multiple myeloma (SMM). This retrospective, observational study leveraged data from the Flatiron Health database. Eligible patients had SMM and relevant measures to apply Mayo 2018, International Myeloma Working Group (IMWG) 2020, and AQUILA trial risk criteria. Time to progression to active MM (TTP), progression or death (PFS), and death or progression on first-line MM therapy (PFS2) were evaluated using Kaplan–Meier methods and multivariate Cox regression models adjusted for age, Charlson Comorbidity Index, and time from SMM diagnosis to risk classification date. Across the three risk models (Mayo 2018, IMWG 2020, and AQUILA trial), high-risk patients with SMM had 3.0–4.0 times the risk of TTP, 2.1–3.5 times the risk of PFS, and 1.7–3.2 times the risk of PFS2 versus non-high-risk patients (p < 0.001 for all comparisons). Similar results were observed when patients with early treatment, early progression, and/or bone disease were excluded. This study demonstrates that high-risk patients with SMM have worse prognoses than non-high-risk patients, regardless of the criteria used, and highlights a need for early intervention testing.
Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy
Authors: Merz Maximilian , Dima Danai , Hashmi Hamza , Ahmed Nausheen , Stölzel Friedrich , Holderried Tobias A. W. , Fenk Roland , Müller Fabian , Tovar Natalia , Oliver-Cáldes Aina , Rathje Kristin , Davis James A. , Fandrei David , Vucinic Vladan , Kharboutli Soraya , Baermann Ben-Niklas , Ayuk Francis , Platzbecker Uwe , Albici Anca-Maria , Schub Nathalie , Schmitz Friederike , Shune Leyla , Khouri Jack , Anwer Faiz , Raza Shahzad , McGuirk Joseph , Mahmoudjafari Zahra , Green Kimberly , Khandanpour Cyrus , Teichert Marcel , Jeker Barbara , Hoffmann Michele , Kröger Nicolaus , von Tresckow Bastian , de Larrea Carlos Fernández , Pabst Thomas , Abdallah Al-Ola , Gagelmann Nico
Published: December 2024

Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P < 0.001). Duration of response, as well as median survival, was significantly improved with bispecific antibodies (P < 0.001, respectively). Bispecific antibodies seemed to overcome the poor prognosis associated with early relapse and EMD, and were independent predictors for improved survival in multivariable analysis. In summary, these results suggest bispecific antibodies as the standard of care for relapse after CAR T-cell therapy for RRMM.
Mitophagy in gynecological malignancies: roles, advances, and therapeutic potential
Authors: Wang Jiao , Wang Dandan
Published: December 2024

Mitophagy is a process in which impaired or dysfunctional mitochondria are selectively eliminated through the autophagy mechanism to maintain mitochondrial quality control and cellular homeostasis. Based on specific target signals, several mitophagy processes have been identified. Defects in mitophagy are associated with various pathological conditions, including neurodegenerative disorders, cardiovascular diseases, metabolic diseases, and cancer. Mitophagy has been shown to play a critical role in the pathogenesis of gynecological malignancies and the development of drug resistance. In this review, we have summarized and discussed the role and recent advances in understanding the therapeutic potential of mitophagy in the development of gynecological malignancies. Therefore, the valuable insights provided in this review may serve as a basis for further studies that contribute to the development of novel treatment strategies and improved patient outcomes.
Eccentricity pacing and rapid termination of the early Antarctic ice ages
Authors: van Peer Tim E. , Liebrand Diederik , Taylor Victoria E. , Brzelinski Swaantje , Wolf Iris , Bornemann André , Friedrich Oliver , Bohaty Steven M. , Xuan Chuang , Lippert Peter C. , Wilson Paul A.
Published: December 2024

Earth’s obliquity and eccentricity cycles are strongly imprinted on Earth’s climate and widely used to measure geological time. However, the record of these imprints on the oxygen isotope record in deep-sea benthic foraminifera (δ18Ob) shows contradictory signals that violate isotopic principles and cause controversy over climate-ice sheet interactions. Here, we present a δ18Ob record of high fidelity from International Ocean Drilling Program (IODP) Site U1406 in the northwest Atlantic Ocean. We compare our record to other records for the time interval between 28 and 20 million years ago, when Earth was warmer than today, and only Antarctic ice sheets existed. The imprint of eccentricity on δ18Ob is remarkably consistent globally whereas the obliquity signal is inconsistent between sites, indicating that eccentricity was the primary pacemaker of land ice volume. The larger eccentricity-paced early Antarctic ice ages were vulnerable to rapid termination. These findings imply that the self-stabilizing hysteresis effects of large land-based early Antarctic ice sheets were strong enough to maintain ice growth despite consecutive insolation-induced polar warming episodes. However, rapid ice age terminations indicate that resistance to melting was weaker than simulated by numerical models and regularly overpowered, sometimes abruptly.
Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer’s Disease
Authors: Baligács Nóra , Albertini Giulia , Borrie Sarah C. , Serneels Lutgarde , Pridans Clare , Balusu Sriram , De Strooper Bart
Published: December 2024

The role of microglia in the amyloid cascade of Alzheimer’s disease (AD) is debated due to conflicting findings. Using a genetic and a pharmacological approach we demonstrate that depletion of microglia before amyloid-β (Aβ) plaque deposition, leads to a reduction in plaque numbers and neuritic dystrophy, confirming their role in plaque initiation. Transplanting human microglia restores Aβ plaque formation. While microglia depletion reduces insoluble Aβ levels, soluble Aβ concentrations stay consistent, challenging the view that microglia clear Aβ. In later stages, microglial depletion decreases plaque compaction and increases neuritic dystrophy, suggesting a protective role. Human microglia with the TREM2R47H/R47H mutation exacerbate plaque pathology, emphasizing the importance of non-reactive microglia in the initiation of the amyloid cascade. Adaptive immune depletion (Rag2-/-) does not affect microglia’s impact on plaque formation. These findings clarify conflicting reports, identifying microglia as key drivers of amyloid pathology, and raise questions about optimal therapeutic strategies for AD.
Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome
Authors: Eom Tae-Yeon , Schmitt J. Eric , Li Yiran , Davenport Christopher M. , Steinberg Jeffrey , Bonnan Audrey , Alam Shahinur , Ryu Young Sang , Paul Leena , Hansen Baranda S. , Khairy Khaled , Pelletier Stephane , Pruett-Miller Shondra M. , Roalf David R. , Gur Raquel E. , Emanuel Beverly S. , McDonald-McGinn Donna M. , Smith Jesse N. , Li Cai , Christie Jason M. , Northcott Paul A. , Zakharenko Stanislav S.
Published: December 2024

Neurodevelopmental disorders are thought to arise from intrinsic brain abnormalities. Alternatively, they may arise from disrupted crosstalk among tissues. Here we show the local reduction of two vestibulo-cerebellar lobules, the paraflocculus and flocculus, in mouse models and humans with 22q11.2 deletion syndrome (22q11DS). In mice, this paraflocculus/flocculus dysplasia is associated with haploinsufficiency of the Tbx1 gene. Tbx1 haploinsufficiency also leads to impaired cerebellar synaptic plasticity and motor learning. However, neural cell compositions and neurogenesis are not altered in the dysplastic paraflocculus/flocculus. Interestingly, 22q11DS and Tbx1+/– mice have malformations of the subarcuate fossa, a part of the petrous temporal bone, which encapsulates the paraflocculus/flocculus. Single-nuclei RNA sequencing reveals that Tbx1 haploinsufficiency leads to precocious differentiation of chondrocytes to osteoblasts in the petrous temporal bone autonomous to paraflocculus/flocculus cell populations. These findings suggest a previously unrecognized pathogenic structure/function relation in 22q11DS in which local skeletal deformity and cerebellar dysplasia result in behavioral deficiencies.
SARS-CoV-2 N protein recruits G3BP to double membrane vesicles to promote translation of viral mRNAs
Authors: Long Siwen , Guzyk Mykhailo , Perez Vidakovics Laura , Han Xiao , Sun Renhua , Wang Megan , Panas Marc D. , Urgard Egon , Coquet Jonathan M. , Merits Andres , Achour Adnane , McInerney Gerald M.
Published: December 2024

Ras-GTPase-activating protein SH3-domain-binding proteins (G3BP) are critical for the formation of stress granules (SGs) through their RNA- and ribosome-binding properties. SARS-CoV-2 nucleocapsid (N) protein exhibits strong binding affinity for G3BP and inhibits infection-induced SG formation soon after infection. To study the impact of the G3BP-N interaction on viral replication and pathogenesis in detail, we generated a mutant SARS-CoV-2 (RATA) that specifically lacks the G3BP-binding motif in the N protein. RATA triggers a stronger and more persistent SG response in infected cells, showing reduced replication across various cell lines, and greatly reduced pathogenesis in K18-hACE2 transgenic mice. At early times of infection, G3BP and WT N protein strongly colocalise with dsRNA and with non-structural protein 3 (nsp3), a component of the pore complex in double membrane vesicles (DMVs) from which nascent viral RNA emerges. Furthermore, G3BP-N complexes promote highly localized translation of viral mRNAs in the immediate vicinity of the DMVs and thus contribute to efficient viral gene expression and replication. In contrast, G3BP is absent from the DMVs in cells infected with RATA and translation of viral mRNAs is less efficient. This work provides a fuller understanding of the multifunctional roles of G3BP in SARS-CoV-2 infection.