bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of apicobasal ridges on dental load-bearing capacity in aquatic-feeding predatory amniotes
Authors: MacKenzie Ailie S. , Brock Glenn A. , McCurry Matthew R.
Published: April 2024

Apicobasal ridges are longitudinal ridges of enamel that are particularly common in several clades of aquatic-feeding predatory amniotes, including Plesiosauria, Ichthyosauria, Mosasauridae, Crocodylia, and Spinosauridae, as well as some early members of Cetacea. Although the repeated evolution of these dental ridges in unrelated clades suggests an adaptive benefit, their primary function in feeding is debated. Hypothesized functions range from increasing tooth strength to improving prey puncture or removal efficiency, but these have never been quantitatively tested. This study utilizes finite element analysis (FEA) to assess the impact of apicobasal ridges upon tooth crown strength in aquatic-feeding amniotes. Drawing on morphometric data from fossilized tooth crowns, a set of digital models was constructed to calculate the performance of smooth and ridged tooth variants under simulated bite force loadings. The similarities in overall stress distribution patterns across models of the same tooth shape, regardless of the presence or morphology of ridges, indicate that apicobasal ridges have little impact on stress reduction within the tooth crown. Ultimately, these findings suggest that apicobasal ridges have a minimal role in improving crown strength and form a framework for future research into the remaining hypotheses.
Reducing Prejudice toward Refugees: Evidence That Social Networks Influence Attitude Change in Uganda
Authors: LARSON JENNIFER M. , LEWIS JANET I.
Published: April 2024

Interventions aimed at reducing prejudice toward refugees have shown promise in industrialized countries. However, the vast majority of refugees are in developing countries. Moreover, while these interventions focus on individual attitude change, attitudes often do not shift in isolation; people are embedded in rich social networks. We conducted a field experiment in northwestern Uganda (host to over a million refugees) and find that perspective-taking warmed individual attitudes there in the short term. We also find that the treatment effect spills over from treated households to control ones along social ties, that spillovers can be positive or negative depending on the source, and that peoples’ attitudes change based on informal conversations with others in the network after the treatment. The findings show the importance of understanding the social process that can reinforce or unravel individual-level attitude change toward refugees; it appears essential to designing interventions with a lasting effect on attitudes.
In the Eye of the Storm: Hurricanes, Climate Migration, and Climate Attitudes
Authors: ARIAS SABRINA B. , BLAIR CHRISTOPHER W.
Published: April 2024

Climate disasters raise the salience of climate change’s negative consequences, including climate-induced migration. Policy action to address climate displacement is especially contentious in the United States, where weak support for tackling climate change intersects with high opposition to migration. Do climate disasters foster receptivity toward climate migrants and broader willingness to combat climate change? To study this question, we leverage the occurrence of Hurricane Ian during fielding of a preregistered survey in autumn 2022. Hurricane exposure increased concern about and support for policies to address climate migration. Hurricane exposure also increased support for climate action and belief in anthropogenic climate change. Effects of hurricane exposure cross-cut partisanship, education, age, and other important correlates of climate attitudes but decay within 6 months. Together, these results suggest that climate disasters may briefly increase favorability toward climate migrants and climate policy action but are unlikely to durably mobilize support even in severely impacted areas.
How Misuse of Emergency Powers Dismantled the Rule of Law in Hungary
Authors: Mészáros Gábor
Published: April 2024

The Hungarian government has been utilising emergencies to expand its political power instead of upholding constitutionalism and the rule of law. This strategy has given the government almost unlimited power to enact emergency decrees, even when the state and the population are not in immediate danger. The ninth amendment to the Fundamental Law of Hungary has raised concerns about the government's use of emergency powers, granting the executive branch even more authority during exceptional times by allowing the government to prolong the ‘state of exception’ indefinitely and maintain pandemic-related emergency measures to respond to potential consequences of the war in Ukraine. As a result, the executive body has been able to exert significant political control without proper parliamentary oversight.
The Hegemonic Ashkenaziness of Hebrew Theatre
Authors: Shem-Tov Naphtaly
Published: April 2024

This article argues that Hebrew theatre is defined by a hegemonic Ashkenaziness that has been present from its beginning and which continues today. It identifies four main components of this hegemony, each of which is examined in turn. The first two components, Hebrew culture and Eurocentrism, are analyzed in relation to the repertoire of plays presented at such theatres as Habima, Ohel, and Cameri. This repertoire combines Yiddish plays and translations of European plays, while also reproducing Orientalist attitudes towards Mizrahi culture. The third component, privileged citizenship, centres on the privileges afforded to Ashkenazi artists and actors in the theatre when compared to Mizrahi actors, especially in terms of casting decisions. Finally, hegemonic Ashkenaziness is defined by membership of the middle class, which, in the theatre, leads to productions being targeted at an Ashkenazi audience and its cultural capital.
Do epiphytes affect the fitness of their phorophytes? The case of Tillandsia recurvata on Bursera copallifera
Authors: Vergara-Torres Carmen Agglael , Valencia-Díaz Susana , García-Franco José Guadalupe , Flores-Palacios Alejandro
Published: April 2024

The studies about the negative effect of epiphytes on their phorophytes show contradictory results and are based on limited variables (e.g., shoot survival). On branches of Bursera copallifera, we experimented with the transplantation/removal of Tillandsia recurvata and artificial tussocks, measuring shoot survival, growth, generation of new shoots, and production of inflorescences and fruits. Most single traits did not differ between treatments. The generation of new shoots was lower in the treatments where T. recurvata was present and increased in the branches where it was removed. The lowest shoot survival was in the treatments where T. recurvata was present or was removed. Removing T. recurvata increased plant relative fitness, and it was 43% lower in branches with T. recurvata. Tillandsia recurvata is a structural parasite of B. copallifera. A negative effect of epiphytes on their phorophytes appears counterintuitive since it would not be evolutionarily stable for an epiphyte to shorten the lifespan of its support. Tillandsia recurvata populations are concentrated on B. copallifera branches between 2-4 cm in diameter, while smaller branches are mostly empty, so it is possible that the negative effect of T. recurvata occurs in the smallest branches, explaining why T. recurvata populations are biased to larger branches.
Revisiting the Origins of Felony Disenfranchisement in the United States
Authors: Schroedel Jean , Rogers Melissa , Dietrich Joseph , Garcia Blake
Published: April 2024

We trace the origin of felony disenfranchisement from the colonial period through Reconstruction. On the eve of the Civil War, three-quarters of states had criminal disenfranchisement statutes. These laws were based on “legal moralism” principles, which limited the franchise to those in good standing with the community. Efforts at disenfranchisement grew as access to the ballot increased and criminal justice reforms replaced capital and corporal punishment for imprisonment. We highlight important transformations in felony disenfranchisement during Reconstruction, specifically in new state constitutions and the Thirteenth and Fourteenth Amendments. All but one Southern state included felon disenfranchisement in their new constitutions that the Republican-controlled Congress ratified for readmission to the United States. Radical Republicans in Congress and state legislatures were in most cases advocates of felony disenfranchisement to exclude former Confederates from political participation.
AI-Inclusivity in Healthcare: Motivating an Institutional Epistemic Trust Perspective
Authors: Maheshwari Kritika , Jedan Christoph , Christiaans Imke , van Gijn Mariëlle , Maeckelberghe Els , Plantinga Mirjam
Published: April 2024

This paper motivates institutional epistemic trust as an important ethical consideration informing the responsible development and implementation of artificial intelligence (AI) technologies (or AI-inclusivity) in healthcare. Drawing on recent literature on epistemic trust and public trust in science, we start by examining the conditions under which we can have institutional epistemic trust in AI-inclusive healthcare systems and their members as providers of medical information and advice. In particular, we discuss that institutional epistemic trust in AI-inclusive healthcare depends, in part, on the reliability of AI-inclusive medical practices and programs, its knowledge and understanding among different stakeholders involved, its effect on epistemic and communicative duties and burdens on medical professionals and, finally, its interaction and alignment with the public’s ethical values and interests as well as background sociopolitical conditions against which AI-inclusive healthcare systems are embedded. To assess the applicability of these conditions, we explore a recent proposal for AI-inclusivity within the Dutch Newborn Screening Program. In doing so, we illustrate the importance, scope, and potential challenges of fostering and maintaining institutional epistemic trust in a context where generating, assessing, and providing reliable and timely screening results for genetic risk is of high priority. Finally, to motivate the general relevance of our discussion and case study, we end with suggestions for strategies, interventions, and measures for AI-inclusivity in healthcare more widely.
Identifying Relevant Topics for Inclusion in an Ethics Curriculum for Anesthesiology Trainees: A Survey of Practitioners in the Field
Authors: Pence Madeline J. , Pla Raymond A. , Heinz Eric , Douglas Rundell , Shaykhinurov Eduard , Jacobs Breanne
Published: April 2024

Anesthesiology training programs are tasked with equipping trainees with the skills to become medically and ethically competent in the practice of anesthesia and to be prepared to obtain board certification, yet there is currently no standardized ethics curriculum within anesthesia training programs in the United States. To bridge this gap, and to provide a validated ethics curriculum to meet the aforementioned needs, in July 2021, a survey was sent to anesthesia scholars in the field of biomedical ethics to identify key areas that should be included in such an ethics curriculum. The responses were rated on a Likert scale and ranked. This paper identifies the top ten topics identified as high priority for inclusion in an anesthesiology training program and consequently deemed most relevant to meet the educational needs of graduates of an anesthesiology residency: (1) capacity to consent; (2) capacity to refuse elective versus lifesaving treatment; (3) application of surrogate decisionmaking; (4) approach to do not resuscitate (DNR) status in the operating room; (5) patient autonomy and advance directives; (6) navigating patient beliefs that may impair care; (7) “futility” in end-of-life care: when to withdraw life support; (8) disclosure of medical errors; (9) clinical criteria for “brain death” and consequences of this definition; and (10) the impaired anesthesiologist.
Does the Porter hypothesis hold in China? evidence from the “2+26” regional air pollution treatment policy
Authors: Luo Weijie , Xiang Di , Zhang Xiaoming
Published: April 2024

This study analyzed the impact of environmental regulation, specifically the “2+26” regional strategy for air quality improvement, on corporate research and development (R&D) investment in China. We developed a theoretical model based on the argument that R&D investment rises with regulation intensity. Using 2010–2019 data from China's listed companies located in the Beijing-Tianjin-Hebei region and its surrounding areas, we treated the $2+26$ policy as a quasi-natural experiment and adopted a difference-in-differences approach to explore its effect on firm R&D input. A positive association was observed between firm R&D intensity and the $2+26$ strategy's implementation in major polluting industries. Our results provide in-depth insights into the $2+26$ strategy's economic consequences, which are potentially of interest to both scholars and policymakers.
More than the worksite cafeteria: the workplace food environment of small and medium-sized enterprises in the Netherlands
Authors: Geboers Lisanne , de Vet Emely , Rongen Frédérique C , Poelman Maartje P
Published: April 2024

Objective:

To characterise the food environment of Dutch small and medium-sized enterprises (SMEs), encompassing physical, sociocultural, economic and policy features and to explore variations within SMEs according to company characteristics (number of employees, location of work and presence of worksite cafeteria).

Design:

Online cross-sectional survey study of a representative Dutch SME sample by a panel agency.

Setting:

Dutch SMEs.

Participants:

Three hundred and fifteen employees of Dutch SMEs responsible for food and drink in their company.

Results:

Most SMEs did not have a worksite cafeteria, no provision of fruits or vegetables, and did not offer discounts on food or drinks. The food environment of these SMEs varied significantly based on company characteristics. For example, SMEs with a worksite cafeteria were significantly more likely to have fruits (OR = 8·76, 95 % CI (4·50, 17·06)), vegetables (OR = 10·29, 95 % CI (5·49, 19·31)) and company food policies (OR = 5·04, 95 % CI (2·08, 12·20)) than SMEs without. Additionally, SMEs with ≥ 50 employees were more likely to have fruits (OR = 2·39, 95 % CI (1·42, 4·03)), vegetables (OR = 1·89, 95 % CI (1·04, 3·46)) and company food policies (OR = 2·82, 95 % CI (1·09, 7·29) than SMEs with < 50 employees. Moreover, having a worksite cafeteria (B = 0·23, 95 % CI (0·08, 0·38)) and employees working mostly on-site (B = 0·14, 95 % CI (0·01, 0·28)) were associated with stronger social norms of healthy and sustainable eating at work compared to SMEs without a worksite cafeteria and working mostly off-site.

Conclusions:

In SMEs, an overall comprehensive picture of the food environment points to its limited active encouragement of healthy food choices, particularly so in small SMEs without a worksite cafeteria. Company characteristics strongly influence SME food environments and should be considered when developing interventions improving SME workplace food environments.
“When you have to shoot, shoot!” Rethinking the right to life of combatants during armed conflicts
Authors: Rosenzweig Ido
Published: April 2024

Does targeting combatants really provide a military advantage during an armed conflict? The limitations on the use of force against civilians and means and methods of warfare are well developed under contemporary international humanitarian law (IHL), but the issue of targetability of adversary combatants remains underdeveloped. This paper builds on contemporary developments in international human rights law and moral just war theory to offer a revised lex ferenda look at the basic principles of IHL through the internalization of the value of the lives of combatants. It is argued that such a reading of IHL would allow for a rejection of the automatic necessity of targeting combatants, and hence give due consideration to the value of life of combatants (both adversary combatants and own combatants) in the evaluation of the use of force during armed conflicts, including through reduced military advantage, force protection, and adjusted proportionality analysis.
Bocconia frutescens L. induces neurological defects in rat offspring
Authors: Bolado-García V.E. , Corona-Morales A.A. , Núñez-Murrieta M.A. , Martínez A.J. , Gheno-Heredia Y.A. , Sánchez-Medina A. , Santiago-Roque I.
Published: April 2024

Nearly 80% of the world’s population trusts traditional medicine and plant-based drug compounds to improve health, and more than 50% of women who participated in a study have used herbal remedies during pregnancy. Bocconia frutescens L. is a plant native to tropical America, where infusion of its leaves has been widely used for the treatment of several gastrointestinal disorders. We have already shown that orogastric consumption of B. frutescens L. during the organogenesis period at concentrations equivalent to human consumption produces teratogenic effects in rats, but effects on progeny development have not yet been studied. In this study, we aimed to investigate the possible association between the consumption of B. frutescens L. at a dose equivalent to that consumed by humans and the neurological development of rat progeny. Pregnant Wistar rats were administered lyophilized B. frutescens L. extract at 300 mg/kg/day or vehicle via the orogastric route during the organogenesis period (gestation days 7–13). The physical development and sensory and motor maturation of their offspring during lactation were analyzed with a battery of reflex and physical tests. B. frutescens L. produced a significant delay in physical development and sensorimotor maturation, compared to the control group. Proton nuclear magnetic resonance spectroscopy analysis showed signals for both flavonoids and alkaloids in the B. frutescens L. extract. We conclude that the delay in physical and neurological development could be interpreted as alterations in the maturation of some neuronal circuitries induced by B. frutescens L.
Glyphosate-resistant and susceptible downy brome (Bromus tectorum) management with soil-applied residual herbicides
Authors: Geddes Charles M. , Pittman Mattea M.
Published: April 2024

Downy brome is a cleistogamous facultative winter-annual grass weed that invades cropland, pastureland, and ruderal areas in western North America. Glyphosate-resistant downy brome, the first known glyphosate-resistant grass weed in Canada, was confirmed in a glyphosate-resistant canola field in southern Alberta in 2021. A controlled-environment study was conducted to determine the impact of preemergence soil-applied residual herbicides on glyphosate-resistant and susceptible downy brome in two field soils. Flumioxazin/pyroxasulfone (70/89 g ai ha−1), carfentrazone/pyroxasulfone (18/150 g ai ha−1), sulfentrazone/pyroxasulfone (100/100 or 150/150 g ai ha−1), and saflufenacil/pyroxasulfone (36/120 g ai ha−1) resulted in excellent (≥90%) visible control and downy brome biomass reduction 8 wk after treatment (WAT). The low rate of carfentrazone/pyroxasulfone (12/100 g ai ha−1) resulted in good (≥80%) visible control and biomass reduction 8 WAT, while the low and medium rates of saflufenacil/pyroxasulfone (18/60 or 25/84 g ai ha−1) resulted in ≥80% biomass reduction but suppression only (66% to 75%) based on visible control. Flumioxazin alone (105 g ai ha−1) resulted in good visible control (81%) 8 WAT in a sandy loam soil, but poor (13%) control in a clay loam soil. Soil type affected plant growth as evidenced by reduced growth in the untreated sandy loam soil compared to clay loam soil. The glyphosate-resistant population emerged and grew more vigorously than the glyphosate-susceptible population resulting in greater plant densities in the untreated control and some less-effective herbicide treatments. These results suggest that mixtures of a protoporphyrinogen oxidase-inhibiting herbicide with the very-long-chain fatty acid elongase inhibitor pyroxasulfone applied preemergence at ≥89 g ai ha−1 could be effective components of an herbicide layering strategy targeting glyphosate-resistant and glyphosate-susceptible downy brome.
A Refined Supply‐Demand Framework to Quantify Variability in Ecosystem Services Related to Surface Water in Support of Sustainable Development Goals
Authors: Li Feng , Xin Qinchuan , Fu Zheng , Sun Ying , Xiong Yujiu
Published: April 2024

As water‐related ecosystem services (WRES) encounter unprecedented threats with climate change and human activities, it is important to understand the impact of variations in the supply and demand for WRES on Sustainable Development Goals (SDGs). Previous studies commonly overlooked water quality and water‐use sectors when using comprehensive supply‐demand index (SDIcom), defined as the difference between water supply and demand, leading to challenges in applying WRES estimation to SDGs assessment. We constructed a refined supply‐demand framework for WRES, categorizing the water supply by water quality and the water demand by sectors. It allows the calculation of refined supply‐demand index (SDIref), addressing the limitations of SDIcom. Our findings demonstrate that SDIref could be effectively employed to assess SDGs and rectify the overestimation of SDIcom in the case study in Xinjiang. The supply‐demand relationship of water resources indicates surpluses in domestic and industrial water use and deficits in agricultural and ecological water use, with the latter worsening. SDIref is projected to be higher in the scenario with SSP2‐4.5 and high growth rate of irrigation efficiency. Our study suggested informed decisions based on SDG‐specific targets to either maintain or enhance SDG progress scores. The proposed refined supply‐demand framework of WRES established a quantitative link between WRES and human well‐being, providing applicable insights for other ecosystem service assessments in other regions.
Impact of Soil Moisture Dynamics and Precipitation Pattern on UK Urban Pluvial Flood Hazards Under Climate Change
Authors: Rong Youtong , Bates Paul , Neal Jeffrey , Archer Leanne , Hatchard Simbi , Kendon Elizabeth
Published: April 2024

The diversity of flood‐generating mechanisms superimposed on catchment physiographic features with non‐stationary meteorological drivers makes future flood hazard assessment a grand challenge. To date, many studies have examined patterns in rainfall and streamflow, but far fewer have investigated trends in the other drivers of flooding. The complex transfer function between precipitation and flooding makes it potentially misleading to simply look at the change in rainfall to express the hazard. Furthermore, there are very few studies that have directly used output from km‐scale climate models in flood modeling. Coarse resolution climate data sets may not credibly resolve local climate and weather extremes. Changes in rainfall distribution and antecedent moisture over extended time periods due to climate change have so far been ignored when assessing urban pluvial flood risk. In this paper, an urban flood hazard assessment framework using the latest 2.2 km resolution UK Climate Projections Local is proposed. Global warming induced changes in pluvial flood risks under RCP8.5 are projected, focusing on the impact of changing precipitation patterns and soil moisture dynamics on flood generation. Results indicate a strong increase in the frequency of occurrence of extreme floods, and the resultant future (2060–2080) annual flood volume is expected to increase up to 52.6% relative to 1980–2000 over a major UK urban region, and these patterns are likely to hold more generally elsewhere in the UK. Shifts to a later occurrence of extreme flooding is identified under global warming. Previous studies that have neglected soil moisture dynamics are unlikely to give accurate flood estimates.
Comparisons of Underwater Light From Atmospheric and Mechanically Stimulated Bioluminescence Sources in High Arctic Polar Night
Authors: Shulman Igor , Cohen Jonathan H. , Anderson Stephanie , Penta Bradley , Moline Mark A.
Published: April 2024

At high latitudes, polar night is a prolonged period of seasonal darkness with the sun remaining below the horizon throughout the diel cycle for up to 177 days at the North Pole. Along with diffuse atmospheric light from the sun and the moon, bioluminescence is an in‐water light source that can facilitate ecological interactions in an otherwise dim‐light environment. At high latitudes during polar night, bioluminescence rather than sunlight represents a significant portion of the photons available in the pelagic. We investigated depths of transition zones (called the bioluminescence transition depth) in the pelagic light field during polar night, defining the transition of a light field dominated by atmospheric irradiance, to one dominated by bioluminescent point sources. We derived relationships between values of the transition depth, bioluminescence potential, surface irradiance due to atmospheric light and the diffuse attenuation coefficient. We conducted studies for two Svalbard, Norway fjords, as well as for offshore areas located in the shelf‐break, shelf‐slope and in the Arctic basin. Based on our results for two polar nights, the transition from underwater light dominated by atmospheric sources to that dominated by bioluminescence occurs between 10 and 40 m in two Svalbard fjords, and between 18 and 60 m for offshore areas. These transition depths may be of particular importance to understanding how bioluminescence structures planktonic communities both in polar regions and at lower latitudes.
Baroclinic Rossby Waves With Phase Lag Cause Seasonal Upward‐Propagating Signals in the Mid‐Depth Equatorial Pacific Ocean
Authors: Luo Zhengpu , Yang Dezhou , Xu Lingjing , Li Yuxuan , Zhang Hang , Wang Jianing , Yin Baoshu
Published: April 2024

Based on OFES outputs verified by mooring observations, the seasonal characteristics in the middepth (1,000–3,000 m) equatorial Pacific Ocean are investigated in detail. The seasonal upward‐propagating signals, consisting of one positive and one negative anomaly, are identified at the equator. The harmonic analyses indicate that the seasonal variations in the middepth equatorial Pacific Ocean originate from the downward‐propagating energy dominated by the first meridional modes of Rossby waves. The superposition of first and second baroclinic modes of Rossby waves could reproduce the seasonal variations. Furthermore, a series of superposition experiments show that the phase lag between the two modes needs to be in the range of 0 to π to cause upward phase propagation. It implies that the baroclinic modes in the seasonal variations may not be generated simultaneously so that the Rossby waves with specific phase lag can cause upward‐propagating signals in the middepth equatorial Pacific Ocean. This new finding will enhance the understanding of seasonal variations in the middepth equatorial Pacific Ocean.
Structural Evolution of the Northern Agrio Fold and Trust Belt (∼37°30′S), Neuquén Basin, Argentina, Derived From Low‐Temperature Multi‐Thermochronometry
Authors: Sánchez N. P. , Coutand I. , Turienzo M. M. , Lebinson F. O. , Araujo V. S. , Bordese S. , Arzadún G. , Dimieri L. V.
Published: April 2024

The Agrio Fold and Thrust Belt (FTB), situated in the Southern Central Andes at 37–39°S, underwent two phases of contractional deformation: Late Cretaceous‐Eocene and middle‐late Miocene. Despite advances in understanding its tectonic history, many questions persist regarding the timing and activity of specific structures during these deformation phases. By combining low‐temperature multi‐thermochronometry, inverse thermal models and field structural data, we present a new thermal‐structural history for the northern Agrio FTB. Our findings unveil an initial cooling event between approximately 85–75 Ma and 55–50 Ma, involving cooling rates of 1.1–2°C/Ma and vertical displacement rates from 0.07 to 0.12 km/Ma. This slow event, confined to the inner zone, is associated with the growth of the basement‐cored Manzano anticline. Additionally, still in the inner zone of the Agrio FTB, a second and faster cooling event from ∼15–10 Ma to 0 Ma, marked by a cooling rate of 7°C/Ma and a vertical displacement rate ranging from 0.11 to 0.17 km/Ma, results from in‐sequence thick‐skinned thrusting at depth. In the outer zone of the FTB, only the younger cooling event from 15–10 Ma to 0 Ma is evident, with a cooling rate of 8.8°C/Ma and a vertical displacement rate ranging from ∼0.14 to 0.26 km/Ma, attributed to displacement along the basement‐involved Las Yeseras thrust. Furthermore, Apatite Fission Track (AFT) ages of detrital grains in the Tralalhué conglomerates support the maximum depositional age for these synorogenic strata to be between 14.1 and 9.2 Ma.
The genomic profiling of high-risk smoldering myeloma patients treated with an intensive strategy unveils potential markers of resistance and progression
Authors: Medina-Herrera A. , Vazquez I. , Cuenca I. , Rosa-Rosa J. M. , Ariceta B. , Jimenez C. , Fernandez-Mercado M. , Larrayoz M. J. , Gutierrez N. C. , Fernandez-Guijarro M. , Gonzalez-Calle V. , Rodriguez-Otero P. , Oriol A. , Rosiñol L. , Alegre A. , Escalante F. , De La Rubia J. , Teruel A. I. , De Arriba F. , Hernandez M. T. , Lopez-Jimenez J. , Ocio E. M. , Puig N. , Paiva B. , Lahuerta J. J. , Bladé J. , San Miguel J. F. , Mateos M. V. , Martinez-Lopez J. , Calasanz M. J. , Garcia-Sanz R. ,   GEM/PETHEMA (Grupo Español de Mieloma/Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group, Gonzalez-Calle V. , De La Rubia J. , De Arriba F. , Rios R. , Sureda A. , Blanchard M. J. , Martinez-Martinez R. , Moraleda J. M. , Bargay J. , Gironella M. , Palomera L. , Gonzalez-Montes Y. , Martí J. M. , Krsnik I. , Arguiñano J. M. , Gonzalez M. E. , Gonzalez A. P. , Casado L. F.
Published: April 2024

Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.
Identification of a set of genes potentially responsible for resistance to ferroptosis in lung adenocarcinoma cancer stem cells
Authors: Ascenzi Francesca , Esposito Antonella , Bruschini Sara , Salvati Valentina , De Vitis Claudia , De Arcangelis Valeria , Ricci Giulia , Catizione Angiolina , di Martino Simona , Buglioni Simonetta , Bassi Massimiliano , Venuta Federico , De Nicola Francesca , Massacci Alice , Grassucci Isabella , Pallocca Matteo , Ricci Alberto , Fanciulli Maurizio , Ciliberto Gennaro , Mancini Rita
Published: April 2024

Scientific literature supports the evidence that cancer stem cells (CSCs) retain inside low reactive oxygen species (ROS) levels and are, therefore, less susceptible to cell death, including ferroptosis, a type of cell death dependent on iron-driven lipid peroxidation. A collection of lung adenocarcinoma (LUAD) primary cell lines derived from malignant pleural effusions (MPEs) of patients was used to obtain 3D spheroids enriched for stem‐like properties. We observed that the ferroptosis inducer RSL3 triggered lipid peroxidation and cell death in LUAD cells when grown in 2D conditions; however, when grown in 3D conditions, all cell lines underwent a phenotypic switch, exhibiting substantial resistance to RSL3 and, therefore, protection against ferroptotic cell death. Interestingly, this phenomenon was reversed by disrupting 3D cells and growing them back in adherence, supporting the idea of CSCs plasticity, which holds that cancer cells have the dynamic ability to transition between a CSC state and a non-CSC state. Molecular analyses showed that ferroptosis resistance in 3D spheroids correlated with an increased expression of antioxidant genes and high levels of proteins involved in iron storage and export, indicating protection against oxidative stress and low availability of iron for the initiation of ferroptosis. Moreover, transcriptomic analyses highlighted a novel subset of genes commonly modulated in 3D spheroids and potentially capable of driving ferroptosis protection in LUAD-CSCs, thus allowing to better understand the mechanisms of CSC-mediated drug resistance in tumors.
Arsenic trioxide augments immunogenic cell death and induces cGAS-STING-IFN pathway activation in hepatocellular carcinoma
Authors: Li Xin , Pan Yu-Fei , Chen Yi-Bin , Wan Qian-Qian , Lin Yun-Kai , Shang Tai-Yu , Xu Meng-You , Jiang Tian-Yi , Pei Meng-Miao , Tan Ye-Xiong , Dong Li-Wei , Wan Xu-Ying
Published: April 2024

The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8+ T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study.
Mature neurons from iPSCs unveil neurodegeneration-related pathways in mucopolysaccharidosis type II: GSK-3β inhibition for therapeutic potential
Authors: Chen Tzu-Yu , Lin Shuan-Pei , Huang De-Fong , Huang Hsien-Sung , Tsai Feng-Chiao , Lee Li-Jen , Lin Hsiang-Yu , Huang Hsiang-Po
Published: April 2024

Mucopolysaccharidosis (MPS) type II is caused by a deficiency of iduronate-2-sulfatase and is characterized by the accumulation of glycosaminoglycans (GAGs). Without effective therapy, the severe form of MPS II causes progressive neurodegeneration and death. This study generated multiple clones of induced pluripotent stem cells (iPSCs) and their isogenic controls (ISO) from four patients with MPS II neurodegeneration. MPS II-iPSCs were successfully differentiated into cortical neurons with characteristic biochemical and cellular phenotypes, including axonal beadings positive for phosphorylated tau, and unique electrophysiological abnormalities, which were mostly rescued in ISO-iPSC-derived neurons. RNA sequencing analysis uncovered dysregulation in three major signaling pathways, including Wnt/β-catenin, p38 MAP kinase, and calcium pathways, in mature MPS II neurons. Further mechanistic characterization indicated that the dysregulation in calcium signaling led to an elevated intracellular calcium level, which might be linked to compromised survival of neurons. Based on these dysregulated pathways, several related chemicals and drugs were tested using this mature MPS II neuron-based platform and a small-molecule glycogen synthase kinase-3β inhibitor was found to significantly rescue neuronal survival, neurite morphology, and electrophysiological abnormalities in MPS II neurons. Our results underscore that the MPS II-iPSC-based platform significantly contributes to unraveling the mechanisms underlying the degeneration and death of MPS II neurons and assessing potential drug candidates. Furthermore, the study revealed that targeting the specific dysregulation of signaling pathways downstream of GAG accumulation in MPS II neurons with a well-characterized drug could potentially ameliorate neuronal degeneration.
Nucleoside Phosphorylases make N7-xanthosine
Authors: Westarp Sarah , Brandt Felix , Neumair Lena , Betz Christina , Dagane Amin , Kemper Sebastian , Jacob Christoph R. , Neubauer Peter , Kurreck Anke , Kaspar Felix
Published: April 2024

Modern, highly evolved nucleoside-processing enzymes are known to exhibit perfect regioselectivity over the glycosylation of purine nucleobases at N9. We herein report an exception to this paradigm. Wild-type nucleoside phosphorylases also furnish N7-xanthosine, a “non-native” ribosylation regioisomer of xanthosine. This unusual nucleoside possesses several atypical physicochemical properties such as redshifted absorption spectra, a high equilibrium constant of phosphorolysis and low acidity. Ultimately, the biosynthesis of this previously unknown natural product illustrates how even highly evolved, essential enzymes from primary metabolism are imperfect catalysts.
Allotrope-dependent activity-stability relationships of molybdenum sulfide hydrogen evolution electrocatalysts
Authors: Escalera-López Daniel , Iffelsberger Christian , Zlatar Matej , Novčić Katarina , Maselj Nik , Van Pham Chuyen , Jovanovič Primož , Hodnik Nejc , Thiele Simon , Pumera Martin , Cherevko Serhiy
Published: April 2024

Molybdenum disulfide (MoS2) is widely regarded as a competitive hydrogen evolution reaction (HER) catalyst to replace platinum in proton exchange membrane water electrolysers (PEMWEs). Despite the extensive knowledge of its HER activity, stability insights under HER operation are scarce. This is paramount to ensure long-term operation of Pt-free PEMWEs, and gain full understanding on the electrocatalytically-induced processes responsible for HER active site generation. The latter are highly dependent on the MoS2 allotropic phase, and still under debate. We rigorously assess these by simultaneously monitoring Mo and S dissolution products using a dedicated scanning flow cell coupled with downstream analytics (ICP-MS), besides an electrochemical mass spectrometry setup for volatile species analysis. We observe that MoS2 stability is allotrope-dependent: lamellar-like MoS2 is highly unstable under open circuit conditions, whereas cluster-like amorphous MoS3-x instability is induced by a severe S loss during the HER and undercoordinated Mo site generation. Guidelines to operate non-noble PEMWEs are therefore provided based on the stability number metrics, and an HER mechanism which accounts for Mo and S dissolution pathways is proposed.
Global census of the significance of giant mesopelagic protists to the marine carbon and silicon cycles
Authors: Laget Manon , Drago Laetitia , Panaïotis Thelma , Kiko Rainer , Stemmann Lars , Rogge Andreas , Llopis-Monferrer Natalia , Leynaert Aude , Irisson Jean-Olivier , Biard Tristan
Published: April 2024

Thriving in both epipelagic and mesopelagic layers, Rhizaria are biomineralizing protists, mixotrophs or flux-feeders, often reaching gigantic sizes. In situ imaging showed their contribution to oceanic carbon stock, but left their contribution to element cycling unquantified. Here, we compile a global dataset of 167,551 Underwater Vision Profiler 5 Rhizaria images, and apply machine learning models to predict their organic carbon and biogenic silica biomasses in the uppermost 1000 m. We estimate that Rhizaria represent up to 1.7% of mesozooplankton carbon biomass in the top 500 m. Rhizaria biomass, dominated by Phaeodaria, is more than twice as high in the mesopelagic than in the epipelagic layer. Globally, the carbon demand of mesopelagic, flux-feeding Phaeodaria reaches 0.46 Pg C y−1, representing 3.8 to 9.2% of gravitational carbon export. Furthermore, we show that Rhizaria are a unique source of biogenic silica production in the mesopelagic layer, where no other silicifiers are present. Our global census further highlights the importance of Rhizaria for ocean biogeochemistry.
Alternative splicing controls teneurin-3 compact dimer formation for neuronal recognition
Authors: Gogou Christos , Beugelink J. Wouter , Frias Cátia P. , Kresik Leanid , Jaroszynska Natalia , Drescher Uwe , Janssen Bert J. C. , Hindges Robert , Meijer Dimphna H.
Published: April 2024

Neuronal network formation is facilitated by recognition between synaptic cell adhesion molecules at the cell surface. Alternative splicing of cell adhesion molecules provides additional specificity in forming neuronal connections. For the teneurin family of cell adhesion molecules, alternative splicing of the EGF-repeats and NHL domain controls synaptic protein-protein interactions. Here we present cryo-EM structures of the compact dimeric ectodomain of two teneurin-3 isoforms that harbour the splice insert in the EGF-repeats. This dimer is stabilised by an EGF8-ABD contact between subunits. Cryo-EM reconstructions of all four splice variants, together with SAXS and negative stain EM, reveal compacted dimers for each, with variant-specific dimeric arrangements. This results in specific trans-cellular interactions, as tested in cell clustering and stripe assays. The compact conformations provide a structural basis for teneurin homo- and heterophilic interactions. Altogether, our findings demonstrate how alternative splicing results in rearrangements of the dimeric subunits, influencing neuronal recognition and likely circuit wiring.
New Late Pleistocene age for the Homo sapiens skeleton from Liujiang southern China
Authors: Ge Junyi , Xing Song , Grün Rainer , Deng Chenglong , Jiang Yuanjin , Jiang Tingyun , Yang Shixia , Zhao Keliang , Gao Xing , Yang Huili , Guo Zhengtang , Petraglia Michael D. , Shao Qingfeng
Published: April 2024

The emergence of Homo sapiens in Eastern Asia is a topic of significant research interest. However, well-preserved human fossils in secure, dateable contexts in this region are extremely rare, and often the subject of intense debate owing to stratigraphic and geochronological problems. Tongtianyan cave, in Liujiang District of Liuzhou City, southern China is one of the most important fossils finds of H. sapiens, though its age has been debated, with chronometric dates ranging from the late Middle Pleistocene to the early Late Pleistocene. Here we provide new age estimates and revised provenience information for the Liujiang human fossils, which represent one of the most complete fossil skeletons of H. sapiens in China. U-series dating on the human fossils and radiocarbon and optically stimulated luminescence dating on the fossil-bearing sediments provided ages ranging from ~33,000 to 23,000 years ago (ka). The revised age estimates correspond with the dates of other human fossils in northern China, at Tianyuan Cave (~40.8–38.1 ka) and Zhoukoudian Upper Cave (39.0–36.3 ka), indicating the geographically widespread presence of H. sapiens across Eastern Asia in the Late Pleistocene, which is significant for better understanding human dispersals and adaptations in the region.
Distinguishing individual photobodies using Oligopaints reveals thermo-sensitive and -insensitive phytochrome B condensation at distinct subnuclear locations
Authors: Du Juan , Kim Keunhwa , Chen Meng
Published: April 2024

Photobodies (PBs) are membraneless subnuclear organelles that self-assemble via concentration-dependent liquid-liquid phase separation (LLPS) of the plant photoreceptor and thermosensor phytochrome B (PHYB). The current PHYB LLPS model posits that PHYB phase separates randomly in the nucleoplasm regardless of the cellular or nuclear context. Here, we established a robust Oligopaints method inArabidopsisto determine the positioning of individual PBs. We show surprisingly that even in PHYB overexpression lines – where PHYB condensation would be more likely to occur randomly – PBs positioned at twelve distinct subnuclear locations distinguishable by chromocenter and nucleolus landmarks, suggesting that PHYB condensation occurs nonrandomly at preferred seeding sites. Intriguingly, warm temperatures reduce PB number by inducing the disappearance of specific thermo-sensitive PBs, demonstrating that individual PBs possess different thermosensitivities. These results reveal a nonrandom PB nucleation model, which provides the framework for the biogenesis of spatially distinct individual PBs with diverse environmental sensitivities within a single plant nucleus.
Nonmagnetic framboid and associated iron nanoparticles with a space-weathered feature from asteroid Ryugu
Authors: Kimura Yuki , Kato Takeharu , Anada Satoshi , Yoshida Ryuji , Yamamoto Kazuo , Tanigaki Toshiaki , Akashi Tetsuya , Kasai Hiroto , Kurosawa Kosuke , Nakamura Tomoki , Noguchi Takaaki , Sato Masahiko , Matsumoto Toru , Morita Tomoyo , Kikuiri Mizuha , Amano Kana , Kagawa Eiichi , Yada Toru , Nishimura Masahiro , Nakato Aiko , Miyazaki Akiko , Yogata Kasumi , Abe Masanao , Okada Tatsuaki , Usui Tomohiro , Yoshikawa Makoto , Saiki Takanao , Tanaka Satoshi , Terui Fuyuto , Nakazawa Satoru , Yurimoto Hisayoshi , Okazaki Ryuji , Yabuta Hikaru , Naraoka Hiroshi , Sakamoto Kanako , Watanabe Sei-ichiro , Tsuda Yuichi , Tachibana Shogo
Published: April 2024

Extraterrestrial minerals on the surface of airless Solar System bodies undergo gradual alteration processes known as space weathering over long periods of time. The signatures of space weathering help us understand the phenomena occurring in the Solar System. However, meteorites rarely retain the signatures, making it impossible to study the space weathering processes precisely. Here, we examine samples retrieved from the asteroid Ryugu by the Hayabusa2 spacecraft and discover the presence of nonmagnetic framboids through electron holography measurements that can visualize magnetic flux. Magnetite particles, which normally provide a record of the nebular magnetic field, have lost their magnetic properties by reduction via a high-velocity (>5 km s–1) impact of a micrometeoroid with a diameter ranging from 2 to 20 μm after destruction of the parent body of Ryugu. Around these particles, thousands of metallic-iron nanoparticles with a vortex magnetic domain structure, which could have recorded a magnetic field in the impact event, are found. Through measuring the remanent magnetization of the iron nanoparticles, future studies are expected to elucidate the nature of the nebular/interplanetary magnetic fields after the termination of aqueous alteration in an asteroid.