bluuebunny/crossref_metadata_2025 huggingface dataset:
Storage Assignment Using Nested Metropolis Sampling and Approximations of Order Batching Travel Costs
Authors: Oxenstierna Johan , Malec Jacek , Krueger Volker
Published: April 2024

The Storage Location Assignment Problem (SLAP) is of central importance in warehouse operations. An important research challenge lies in generalizing the SLAP such that it is not tied to certain order-picking methodologies, constraints, or warehouse layouts. We propose the OBP-based SLAP, where the quality of a location assignment is obtained by optimizing an Order Batching Problem (OBP). For the optimization of the OBP-based SLAP, we propose a nested Metropolis algorithm. The algorithm includes an OBP-optimizer to obtain the cost of an assignment, as well as a filter which approximates OBP costs using a model based on the Quadratic Assignment Problem (QAP). In experiments, we tune two key parameters in the QAP model, and test whether its predictive quality warrants its use within the SLAP optimizer. Results show that the QAP model’s per-sample accuracy is only marginally better than a random baseline, but that it delivers predictions much faster than the OBP optimizer, implying that it can be used as an effective filter. We then run the SLAP optimizer with and without using the QAP model on industrial data. We observe a cost improvement of around 23% over 1 h with the QAP model, and 17% without it. We share results for public instances on the TSPLIB format.
Towards Data- and Compute-Efficient Fake-News Detection: An Approach Combining Active Learning and Pre-Trained Language Models
Authors: Folino Francesco , Folino Gianluigi , Guarascio Massimo , Pontieri Luigi , Zicari Paolo
Published: April 2024

In today’s digital era, dominated by social media platforms such asTwitter,Facebook, andInstagram, the swift dissemination of misinformation represents a significant concern, impacting public sentiment and influencing pivotal global events. Promptly detecting such deceptive content with the help of Machine Learning models is crucial, yet it comes with the challenge of dealing with labelled examples for training these models. Impressive performance results were recently achieved by high-capacity pre-trained transformer-based models (e.g., BERT). Still, such models are too data- and compute-demanding for many critical application contexts where memory, time, and energy consumption must be limited. Here, we propose an innovative semi-supervised method for efficient and effective fake news detection using a content-oriented classifier based on a small-sized BERT embedder. After fine-tuning this model on the sole few labelled data available, an iterative Active Learning (AL) process is carried out, which benefits from limited experts’ feedback to acquire more labelled data for improving the model. The proposed method ensures good detection performances using a few training samples, reasonably small human intervention, and compute/memory costs.
Absence of Metformin in Fetal Circulation Following Maternal Administration in Late Gestation Pregnant Sheep
Authors: Rozance Paul J. , Brown Laura D. , Wesolowski Stephanie R.
Published: April 2024

In human pregnancy, metformin administered to the mother crosses the placenta resulting in metformin exposure to the fetus. However, the effects of metformin exposure on the fetus are poorly understood and difficult to study in humans. Pregnant sheep are a powerful large animal model for studying fetal physiology. The objective of this study was to determine if maternally administered metformin at human dose-equivalent concentrations crosses the ovine placenta and equilibrates in the fetal circulation. To test this, metformin was administered to the pregnant ewe via continuous intravenous infusion or supplementation in the drinking water. Both administration routes increased maternal metformin concentrations to human dose-equivalent concentrations of ~ 10 µM, yet metformin was negligible in the fetus even after 3–4 days of maternal administration. In cotyledon and caruncle tissue, expression levels of the major metformin uptake transporter organic cation transporter 1 (OCT1) were < 1% of expression levels in the fetal liver, a tissue with abundant expression. Expression of other putative uptake transporters OCT2 and OCT3, and efflux transporters multidrug and toxin extrusion (MATE)1 and MATE2were more abundant. These results demonstrate that the ovine placenta is impermeable to maternal metformin administration. This is likely due to anatomical differences and increased interhaemal distance between the maternal and umbilical circulations in the ovine versus human placenta limiting placental metformin transport.
Youth Work, Youth Studies, and Co-design: Sustaining a Dynamic Nexus to Progress Youth Participation
Authors: Lohmeyer Ben Arnold , McGregor Joel Robert , Wood Bronwyn Elizabeth
Published: April 2024

Youth work practitioners and youth researchers both share a keen interest in the lives, experiences, and well-being of young people; however, the skills and expertise held by practitioners and researchers have not always been mutually valued leading to tensions and a research-practice gap. The rise of co-design methods that prioritise relational skills and ethics appears to mark a moment for closing or reducing this gap. Rather than accepting this convergence at face value, in this paper, we examine some of the key tensions around (1) relational ethics and decision-making, (2) holding multiple roles and expertise, and (3) structures that constrain or sustain participation to argue for sustaining a dynamic research-practice nexus. Drawing on our experience and practitioner-researchers, we argue that rather than simply overlooking the practical and ethical tensions between practice and research, sustaining a dynamic nexus comprising of continuing dialogue and collaboration can foster and progress co-design methods in pursuit of the aims of youth participation.
The contribution of qualitative methods to economic research in an era of polycrisis
Authors: Porak Laura , Reinke Rouven
Published: April 2024

This article argues that the considerable socio-economic and political challenges posed by the polycrisis can be better understood through the application of qualitative methods in economic research as quantitative methods fall short in this context. We argue that the integration of qualitative methods into economic research is crucial for two main reasons: first, from a philosophical point of view, a more comprehensive perspective on economic phenomena increases the epistemic quality of economic knowledge, and second, for political reasons, more pluralism in economics increases the democratic quality of capitalistic societies. We provide a review of the literature of the use of qualitative methods in economics and its philosophical underpinnings. Using specific examples of the application of qualitative methods in economic policy research, we show how valuable such perspectives are in facilitating a deeper understanding of the polycrisis. We address concerns against qualitative research in the economic discipline and how our analysis serves to mitigate some of these concerns in the context of the polycrisis. We conclude with a discussion on the potential role of qualitative methods in economic research.
Performance of GFRP-RC precast cap beam to column connections with epoxy-anchored reinforcement: a numerical study
Authors: El-Naqeeb Mohamed H. , Hassanli Reza , Zhuge Yan , Ma Xing , Bazli Milad , Manalo Allan
Published: April 2024

In this study, a detailed finite element investigation was conducted to evaluate the performance of glass fibre-reinforced polymer (GFRP) RC precast cap beam to column connections connected with epoxy-anchored reinforcement (epoxy duct connection). The developed model was initially validated against three experimental results with different anchored GFRP reinforcement considering the effect of reinforcement slippage. Different interaction models for slippage simulation were evaluated and discussed. The validated model was then utilized to investigate the effect of anchored length, bar diameters, anchored reinforcement amount, and the geometry of the connection. The results indicate that an optimum anchored length, equal to 25 times the bar's diameter, should be provided. It was also found that the precast beam-to-column element connection should be designed for a moment capacity at least 25% higher than that of the column section. Moreover, a minimum beam width, depth and beam overhanging length of 1.75, 1.6 and 0.25 times the column width respectively were recommended to be considered in design. The results from this study can provide direct guidelines for the design of precast GFRP-RC cap beam to the column connection with epoxy anchored reinforcement, especially in applications where precast elements need to be erected quickly, a novel method that can accelerate the construction of jetties and bridges.
Convergence Research and Training in Computational Bioengineering: A Case Study on AI/ML-Driven Biofilm–Material Interaction Discovery
Authors: Zylla Jessica L. S. , Bomgni Alain B. , Sani Rajesh K. , Subramaniam Mahadevan , Lushbough Carol , Winter Robb , Gadhamshetty Venkataramana R. , Chundi Parvathi , Gnimpieba Etienne Z.
Published: April 2024

Historically, research disciplines have successfully operated independently. However, the emergence of transdisciplinary research has led to convergence methodologies, resulting in groundbreaking discoveries. Despite the benefits, graduate programs face challenges in implementing transdisciplinary research and preparing students for real-world collaboration across diverse disciplines and experience levels. We propose a convergence training framework integrating project-based learning, training modules, and collaborative teaming to address this. This approach, tested in a multi-institutional workshop, proved effective in bridging expertise gaps and fostering successful convergence learning experiences in computational biointerface (material–biology interface) research. Here, biointerface research focuses on control of biomolecular interactions with technologically relevant material surfaces, which is a critical component of biotechnology and engineering applications. Positive outcomes, including conference presentations and published models, endorse the framework's application in graduate curricula, particularly for students engaging in transdisciplinary collaboration.
Some Challenges for Moreau's Theory of Wrongful Discrimination
Authors: Gilabert Pablo
Published: April 2024

At the heart of Sophia Moreau's theory of wrongful discrimination is the moral duty to treat others as equals. This article raises some challenges regarding the contours of this duty and suggests some ways to make the theory stronger. In particular, it suggests that we incorporate a cosmopolitan view of the duty's scope, that we illuminate the features at the basis of individuals’ equal moral status to determine its grounds, and that we identify some considerations about important interests to articulate its contents. The relation between Moreau's theory and human rights discourse is also briefly examined, and more engagement with the latter is recommended.
Pluralist Theories of Wrongful Discrimination
Authors: Smith Dale
Published: April 2024

In Faces of Inequality, Sophia Moreau offers a pluralist theory of discrimination, according to which discriminatory conduct involves one or more of (at least) three types of wrong. She claims, further, that each of these wrongs represents a failure to treat some people as the equal of others. I argue that this further claim is mistaken. I also suggest that there may be no need for a pluralist theory of discrimination to identify a property that is shared by the different types of wrong recognised by the theory (beyond the fact that each is present in cases of wrongful discrimination).
Discrimination, Pluralism, and Social Subordination: On Moreau's Faces of Inequality
Authors: Sangiovanni Andrea
Published: April 2024

Sophia Moreau's wide-ranging and nuanced book defends a pluralist view of wrongful discrimination. I argue three points. First, I argue that Moreau's account of deliberative freedom does not provide a distinct ground for objecting to discrimination. Second, I argue that there is not as wide a gap between her view and expressivism as she makes there out to be. Third, there is an intriguing gap in the argument that deserves further exploration: Moreau never provides us with an account of when and why social subordination is wrong.
Equality, Subordination, and Methodology in Discrimination Theory: A Reply to Critics
Authors: Moreau Sophia
Published: April 2024

In this Reply to Critics, I respond to essays by Professors Alysia Blackham, Jessica Eisen, Pablo Gilabert, Andrea Sangiovanni, Dale Smith, Iyiola Solanke, and Daniel Viehoff on the theory of wrongful discrimination developed in my book, Faces of Inequality. Among the topics I discuss are: the relationship between equality and discrimination, the role of social subordination in my theory of wrongful discrimination, and methodology in discrimination theory.
The survival of three large agricultural estates on the north Hampshire-south Berkshire border during the interwar period
Authors: Jones Gareth , Burchardt Jeremy , Tranter Richard
Published: April 2024

Historians credit the interwar period with the demise of the great agricultural estates but many survived, reduced in area and refocussed on new priorities. Three estates lying in close proximity in north Hampshire and south Berkshire had very divergent interests, but there were similarities, and significant differences, in the manner in which they survived the interwar period. One invested in a programme of renewal of houses and farm buildings, and another adopted a more commercial approach to managing its diverse interests and the third retrenched, cutting investment but maintaining the status quo as an agricultural and shooting estate. All three survived, relatively intact and financially stable, and remain in operation today. An examination of estate financial performance before and after the Great War provides the context to the strategies pursued by the owners and their Land Agents, and their place in the broader rural landscape of the 1920s and 1930s.
UK Asbestos Working Party Update 2020
Authors:   Institute and Faculty of Actuaries UK Asbestos Working Party
Published: April 2024

The Institute and Faculty of Actuaries UK Asbestos Working Party update 2020 sets out the methodology and assumptions used to estimate the potential cost of asbestos-related claims to the UK Employers’ Liability Insurance Market. The Working Party has estimated the UK EL Insurance Market cost for the following asbestos-related disease types: mesothelioma, lung cancer, asbestosis and pleural thickening, and pleural plaques. For each disease type the Working Party has constructed a range of scenarios to highlight the uncertainty of these estimates. The Working Party reminds practitioners that use the Working Party scenarios that they should always consider the experience and trends that have occurred since the scenarios were published, adjusting the scenarios to take into account new information.
Recovering Differential Forces From the GRACE‐D Accelerometer
Authors: Harvey Nate , Bertiger Willy , McCullough Christopher M. , Miller Mark , Save Himanshu , Yuan Dah‐Ning
Published: April 2024

The reduction of non‐gravitational accelerations through an onboard accelerometer is a vital part of accurately estimating gravity fields for Gravity Recovery and Climate Experiment (GRACE) Follow‐On (GRACE‐FO). Current accelerometer quality, specifically a defect on the GRACE‐D accelerometer, necessitates the use of extensive calibration techniques to optimally utilize the accelerometer measurements. This paper describes these techniques and correction algorithms as they are used for the official GRACE‐FO accelerometer products, which rest on the information present in the partially functional GRACE‐D accelerometer. First, transplanted data from GRACE‐C is used to remove common effects between the spacecraft. Then, GRACE‐D data is utilized to compute a correction to the transplanted data to account for solar radiation pressure (SRP) and albedo using a parity argument and to account for non‐common drag and thruster leaks in the attitude control system. The SRP and albedo term predominantly improves C3,0 while the drag and leaky thruster term improves the gravity field across the entire spectrum. Finally, some comments on alternative data usage, initial modifications to the algorithms to account for other spacecraft operational modes, and future outlook are provided.
Tracing Deep Carbon Cycling by Zinc Isotopes in a Peralkaline‐Carbonatite Suite
Authors: Wei Bowen , Zhang Zhaochong , Cheng Zhiguo , Xie Qiuhong , Santosh M. , Kong Weiliang , Liu Bingxiang , Reichow Marc K. , Li Yingjie
Published: April 2024

Sedimentary carbonates are known to be carried into the deep mantle by subducted slabs, and studies on mantle‐derived magmas have attempted to trace the recycled carbonate in their mantle source. However, the final depth of storage of recycled carbonate and the role of recycled carbonate in the partial melting of mantle remain controversial. Peralkaline‐carbonatite suites are considered to have been derived from a carbonated mantle source and are windows to evaluate carbon in the mantle. In this study, we report the Zn isotopic compositions of a peralkaline‐carbonatite suite from the Tarim Large Igneous Province (Tarim LIP). The peralkaline‐carbonatite suite has heavier δ66Zn than normal mantle with δ66Zn of 0.34–0.40 ‰ for nephelinite, 0.35–0.47 ‰ for aillikite, 0.51–0.55 ‰ for nepheline syenite, 0.58–0.67 ‰ for calciocarbonatite and 0.38–0.56 ‰ for magnesiocarbonatite. The heavy Zn isotopic compositions of the peralkaline‐carbonatite suite in the Wajilitag complex suggest the incorporation of recycled carbonate‐bearing materials into the deep mantle. We infer that the calciocarbonatite was produced by the initial partial melting of subducted MgSiO3/MgO + C‐bearing carbonated eclogite, whereas the magnesiocarbonatite, aillikite, and nephelinite are considered as reacted melts between carbonated eclogite‐derived melts and peridotite. The heavy Zn isotopic compositions of the nepheline syenite are attributed to fractional crystallization from nephelinite magma in the magma reservoir. Our study highlights the incorporation of carbonated eclogite as an important agent of recycled carbon in the deep mantle and interactions between carbonated eclogite‐derived melts and peridotite lead to the complex lithological heterogeneities in the peralkaline‐carbonatite suite in Tarim LIP.
Statistical Analysis of Whistler Precursors Upstream of Foreshock Transient Shocks: MMS Observations
Authors: Wang Mengmeng , Liu Terry Z. , Zhang Hui , Liu Kaijun , Shi Quanqi , Guo Ruilong , Tian Anmin , Sun Weijie , Shen Xiao‐Chen , Wu Siyuan , Degeling Alexander W. , Wang Yan , Bai Shi‐Chen , Yao Zhonghua , Li Wenya , Zhang Shuai , Pitkänen Timo , Yao Shutao , Liu Ji , Cheng Kun , Ma Xiao , Liu Yuqi
Published: April 2024

Using the high‐time‐resolution data from the Magnetospheric Multiscale mission, precursor waves upstream of foreshock transient (FT) shocks are statistically investigated using the four‐spacecraft timing method. The wave frequencies and wave vectors determined in the plasma rest frame (PRF) are shown to follow the cold plasma dispersion relation for whistler waves. Combining with the feature of the right‐hand polarization in the PRF, the precursors are identified as whistler‐mode waves around the lower hybrid frequency. The occurrence of whistler precursors is independent of the Alfvén Mach number and the FT shock normal angle. More importantly, all the whistler precursors have group velocities pointing upstream in the shock frame, suggesting the dispersive radiation to be a possible generation mechanism. The study improves the understanding of not only the whistler precursors but also the overall FT shock dynamics.
Future Slower Reduction of Anthropogenic Aerosols Enhances Extratropical Ocean Surface Warming Trends
Authors: Gu Pingting , Gan Bolan , Cai Wenju , Wang Hai , Wu Lixin
Published: April 2024

Global surface temperature short‐term trends fluctuate between cooling and fast‐warming under the combined action of external forcing and internal variability, significantly influencing the detectability of near‐term climate change. A key driver of these variations is anthropogenic aerosols (AAs), which have undergone a non‐monotonic evolution with rapid reduction in recent decades. However, their reduction is projected to decelerate under a high carbon emission scenario, yet the impact on surface temperature trends remains unknown. Here, using initial‐perturbation large ensembles, we find that future slowdown in AA reduction over Europe and North America expedites the subpolar North Atlantic surface warming by intensifying the Atlantic meridional overturning circulation. Further, it accelerates the South Indian Ocean and Southern Ocean surface warming through positive low‐cloud feedback and oceanic dynamical adjustment, triggered by the poleward migration of westerlies under interhemispheric energy constraint. These AA‐driven warmings exacerbate greenhouse warming, significantly enhancing the detectability of local decadal warming trends.
Modeling Field Line Curvature Scattering Loss of 1–10 MeV Protons During Geomagnetic Storms
Authors: Lozinski Alexander R. , Horne Richard B. , Glauert Sarah A. , Kellerman Adam C. , Bortnik Jacob , Claudpierre Seth G. , Manweiler Jerry W. , Spence Harlan E.
Published: April 2024

The proton radiation belt contains high fluxes of adiabatically trapped protons varying in energy from ∼one to hundreds of megaelectron volts (MeV). At large radial distances, magnetospheric field lines become stretched on the nightside of Earth and exhibit a small radius of curvature RC near the equator. This leads protons to undergo field line curvature (FLC) scattering, whereby changes to the first adiabatic invariant accumulate as field strength becomes nonuniform across a gyroorbit. The outer boundary of the proton belt at a given energy corresponds to the range of magnetic L shell over which this transition to nonadiabatic motion takes place, and is sensitive to the occurrence of geomagnetic storms. In this work, we first find expressions for nightside equatorial RC and field strength Be as functions of Dst and L* to fit the TS04 field model. We then apply the Tu et al. (2014, https://doi.org/10.1002/2014ja019864) condition for nonadiabatic onset to solve the outer boundary L*, and refine our expression for RC to achieve agreement with Van Allen Probes observations of 1–50 MeV proton flux over the 2014–2018 era. Finally, we implement this nonadiabatic onset condition into the British Antarctic Survey proton belt model (BAS‐PRO) to solve the temporal evolution of proton fluxes at L ≤ 4. Compared with observations, BAS‐PRO reproduces storm losses due to FLC scattering, but there is a discrepancy in mid‐2017 that suggests a ∼5 MeV proton source not accounted for. Our work sheds light on outer zone proton belt variability at 1–10 MeV and demonstrates a useful tool for real‐time forecasting.
How to Quantify Heavy Mineral Fertility From Point‐Counting Data
Authors: Stutenbecker L. , Krieg D. , Djahansouzi A. , Glotzbach C. , Falkowski S. , Adolffs T. , Sindern S. , Hinderer M.
Published: April 2024

Heavy minerals (HM) are widely used in provenance studies, for example, for reconstructing source areas and quantifying sediment budgets. Source rock mineral fertility influences the composition and concentration of HM in sediments. The resulting bias is of particular interest when interpreting single‐grain data such as detrital age distributions. However, the quantification of fertility is complex and there are no robust data for most HM, which prevents the routine implementation of fertility in many studies. In this study, we test whether mineral fertility can be assessed by quantifying mineral concentrations in detrital samples through point counting and quantitative evaluation of minerals by scanning electron microscopy (QEMSCAN). The challenge is to transform the resulting area percentage into mass percentage, which is a prerequisite for comparing those data with grain size or geochemical data. We suggest overcoming this problem by recording grain‐size and shape metrics of minerals using image analysis, and applying several transformation steps. We test our method by (a) using a series of detrital grain mixtures of known density and mass, and (b) applying it to a natural sediment from the European Alps. Our results agree with existing methods developed for apatite and zircon, that is, the quantification of fertility through geochemistry (with P2O5 and Zr concentrations as proxies for apatite and zircon) and the separation of pure apatite and zircon concentrates using additional separation steps. The advantage of our method is its applicability to all HM (not only apatite and zircon) and the redundancy of additional separation steps, which might create bias.
Large Igneous Province Control on Ocean Anoxia and Eutrophication in the North Sea at the Paleocene–Eocene Thermal Maximum
Authors: Mariani Erica , Kender Sev , Hesselbo Stephen P. , Bogus Kara , Littler Kate , Riding James B. , Leng Melanie J. , Kemp Simon J. , Dybkjær Karen , Pedersen Gunver K. , Wagner Thomas , Dickson Alexander J.
Published: April 2024

The Paleocene–Eocene Thermal Maximum (PETM) was a global hyperthermal event ∼56 Ma characterized by massive input of carbon into the ocean–atmosphere system and global warming. A leading hypothesis for its trigger is the emplacement of the North Atlantic Igneous Province (NAIP), with extensive extrusion/intrusion of igneous material into nearby sedimentary basins, forcing local uplift and warming‐inducing carbon emissions. It remains unclear if oceanographic changes in the North Sea–Norwegian Sea–Arctic basins, such as anoxia and productivity, were causally linked to local NAIP uplift/activity, and at what time scales these perturbations occurred. To test mechanisms and time scales, we present geochemical proxies (XRF analysis, clay mineralogy, molybdenum isotopes, and pyrite framboid size distribution) in undisrupted marine sediment core E−8X located in the central North Sea. We find evidence for a rapid onset of anoxia/euxinia at the negative carbon isotope excursion from redox proxies, followed by a gradual drawdown of molybdenum/total organic carbon (Mo/TOC) during the PETM main phase indicative of tectonically‐restricted basin likely from NAIP uplift. A short‐lived increase in Mo, pyrite and TOC occurred during a precursor event associated with a sedimentary mercury pulse indicative of volcanic activity. We suggest thermal uplift and flood basalt volcanism tectonically restricted the North Sea and tipped it into an euxinic state via volcanic emission–oceanographic feedbacks inducing eutrophication. This fine temporal separation of tectonic versus climatic geochemical proxies, combined with pulsed NAIP volcanism, demonstrates that Large Igneous Province emplacements can, at least locally, result in ocean biogeochemical feedbacks operating on relatively short timescales.
Effects of a Vertical Cloud Condensation Nuclei Concentration Explosion in an Idealized Hailstorm Simulation
Authors: Ma Rongjun , Li Xiaofei
Published: April 2024

Determination of the key vertical level for cloud condensation nuclei concentration (CCNC) explosions has been a long‐term issue in CCN‐cloud interaction studies. An idealized hailstorm is simulated with 37 sensitivity runs, including an initial CCNC grouping vertically from the ground to the cloud top, increasing from 100 to 3,000 mg−1. The results reveal a key zone from 750 to 800 hPa near the median boundary layer, where an explosion of CCNC plays a dominant role in the nonmonotonic response of the hail precipitation rate. The explosion of CCNC in this zone could initially result in the condensation of more water vapor into the clouds, which could be transported to a greater vertical extent to significantly affect the riming collection efficiency. However, the dominant zone for the total precipitation rate is wider at heights of 700–800 hPa due to the lower sensitivity of the riming collection efficiency.
SRY-Box transcription factor 9 triggers YAP nuclear entry via direct interaction in tumors
Authors: Qian Hui , Ding Chen-Hong , Liu Fang , Chen Shi-Jie , Huang Chen-Kai , Xiao Meng-Chao , Hong Xia-Lu , Wang Ming-Chen , Yan Fang-Zhi , Ding Kai , Cui Ya-Lu , Zheng Bai-Nan , Ding Jin , Luo Cheng , Zhang Xin , Xie Wei-Fen
Published: April 2024

The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression. However, the precise molecular mechanisms governing the nuclear import of YAP are not fully understood. In this study, we have uncovered a crucial role of SOX9 in the activation of YAP. SOX9 promotes the nuclear translocation of YAP by direct interaction. Importantly, we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP. Additionally, we have discovered a novel asymmetrical dimethylation of YAP at Arg-124 (YAP-R124me2a) catalyzed by PRMT1. YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers. Furthermore, we disrupted the interaction between SOX9 and YAP using a competitive peptide, S-A1, which mimics an α-helix of SOX9 containing Asp-125. S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth. This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.
Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial
Authors: Wang Jinyuan , Zhang Jinlu , Yu Shicheng , Li Hongyan , Chen Shaohong , Luo Jingting , Wang Haibo , Guan Yuxia , Zhang Haihan , Yin Shiyi , Wang Huili , Li Heping , Liu Junle , Zhu Jingyuan , Yang Qiong , Sha Ying , Zhang Chuan , Yang Yuhang , Yang Xuan , Zhang Xifang , Zhao Xiuli , Wang Likun , Yang Liping , Wei Wenbin
Published: April 2024

Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2, which results in blindness in the working-age population, and there is currently no available treatment. Here, we report the results of the first-in-human clinical trial (NCT04722107) of gene therapy for Bietti crystalline corneoretinal dystrophy, including 12 participants who were followed up for 180–365 days. This open-label, single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein (rAAV2/8-hCYP4V2). Participants received a single unilateral subretinal injection of 7.5 × 1010 vector genomes of rAAV2/8-hCYP4V2. Overall, 73 treatment-emergent adverse events were reported, with the majority (98.6%) being of mild or moderate intensity and considered to be procedure- or corticosteroid-related; no treatment-related serious adverse events or local/systemic immune toxicities were observed. Compared with that measured at baseline, 77.8% of the treated eyes showed improvement in best-corrected visual acuity (BCVA) on day 180, with a mean ± standard deviation increase of 9.0 ± 10.8 letters in the 9 eyes analyzed (p = 0.021). By day 365, 80% of the treated eyes showed an increase in BCVA, with a mean increase of 11.0 ± 10.6 letters in the 5 eyes assessed (p = 0.125). Importantly, the patients’ improvement observed using multifocal electroretinogram, microperimetry, and Visual Function Questionnaire-25 further supported the beneficial effects of the treatment. We conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2 (named ZVS101e).
Effect of polymer concentration on molecular alignment behavior during scanning wave photopolymerization
Authors: Ishiyama Takuto , Kobayashi Yoshiaki , Nakamura Hirona , Aizawa Miho , Hisano Kyohei , Kubo Shoichi , Shishido Atsushi
Published: April 2024

Molecularly aligned liquid-crystalline (LC) polymer films hold great promise for next-generation high-performance photonics, electronics, robotics, and medical devices. Photoalignment methods capable of achieving precise molecular alignment in a noncontact manner have been actively studied. Recently, we proposed the concept of using spatiotemporal photopolymerization to induce molecular diffusion and the resulting alignment, termed scanning wave photopolymerization (SWaP). The spatial gradient of the polymer concentration is the dominant factor in inducing the molecular diffusion and alignment of LCs. However, the effect of polymer concentration on molecular alignment behavior remains unclear. In this study, we performed SWaP at different exposure energies to modulate the polymer concentration during polymerization. We found that a certain polymer concentration was required to initiate the alignment. Furthermore, the phase diagram of the polymer/monomer mixtures and real-time observations during SWaP revealed that phase emergence and unidirectional molecular alignment occurred simultaneously when the polymer concentration exceeded 50%. Since SWaP achieves molecular alignment coincident with photopolymerization, it has the potential to revolutionize material fabrication by consolidating the multiple-step processes required to create functional materials in a single step.
Giant piezoelectricity driven by Thouless pump in conjugated polymers
Authors: Villani Stefano Paolo , Campetella Marco , Barone Paolo , Mauri Francesco
Published: April 2024

Piezoelectricity of organic polymers has attracted increasing interest because of several advantages they exhibit over traditional inorganic ceramics. While most organic piezoelectrics rely on the presence of intrinsic local dipoles, a highly nonlocal electronic polarisation can be foreseen in conjugated polymers, characterised by delocalised and highly responsive π-electrons. These 1D systems represent a physical realisation of a Thouless pump, a mechanism of adiabatic charge transport of a topological nature which results, as shown in this work, in anomalously large dynamical effective charges, inversely proportional to the bandgap energy. A structural (ferroelectric) phase transition further contributes to an enhancement of the piezoelectric response reminiscent of that observed in piezoelectric perovskites close to morphotropic phase boundaries. First-principles density functional theory (DFT) calculations performed in two representative conjugated polymers using hybrid functionals, show that state-of-the-art organic piezoelectric are outperformed by piezoelectric conjugated polymers, mostly thanks to strongly anomalous effective charges of carbon, larger than 5e—ordinary values being of the order of 1e—and reaching the giant value of 30e for band gaps of the order of 1 eV.
A relational approach to characterizing householder perceptions of disruption in heat transitions
Authors: Thomas Gareth Hugh , Flower Jack , Gross Rob , Henwood Karen , Shirani Fiona , Speirs Jamie , Pidgeon Nick
Published: April 2024

Heat decarbonization threatens substantial disruptions in temperate countries. However, the concept of disruption carries diverse meanings, potentially relating to cost, material space and everyday heating practices. Here, using interpretive risk theory, this article elucidates a relational understanding of how disruption is experienced and takes on meaning in everyday life. We deploy this framework to examine perceptions of four low-carbon heating technologies—heat pumps, hydrogen, hybrid heating and heat networks—alongside associated upgrades to distribution network infrastructure. Drawing on data from six, 1-day workshops representing a diversity of geographic and housing contexts across the United Kingdom, we address how existing relationships shape hopes, fears and expectations for heat decarbonization. Our findings help clarify the role of affective relationships, feelings of precarity, security and pressure in distinguishing material inconveniences from more fundamental disruptions to valued ways of life, and may be particularly relevant in other gas-dependent countries and regions.
Computational scoring and experimental evaluation of enzymes generated by neural networks
Authors: Johnson Sean R. , Fu Xiaozhi , Viknander Sandra , Goldin Clara , Monaco Sarah , Zelezniak Aleksej , Yang Kevin K.
Published: April 2024

In recent years, generative protein sequence models have been developed to sample novel sequences. However, predicting whether generated proteins will fold and function remains challenging. We evaluate a set of 20 diverse computational metrics to assess the quality of enzyme sequences produced by three contrasting generative models: ancestral sequence reconstruction, a generative adversarial network and a protein language model. Focusing on two enzyme families, we expressed and purified over 500 natural and generated sequences with 70–90% identity to the most similar natural sequences to benchmark computational metrics for predicting in vitro enzyme activity. Over three rounds of experiments, we developed a computational filter that improved the rate of experimental success by 50–150%. The proposed metrics and models will drive protein engineering research by serving as a benchmark for generative protein sequence models and helping to select active variants for experimental testing.
Chromosome-scale genome assembly of bread wheat’s wild relative Triticum timopheevii
Authors: Grewal Surbhi , Yang Cai-yun , Scholefield Duncan , Ashling Stephen , Ghosh Sreya , Swarbreck David , Collins Joanna , Yao Eric , Sen Taner Z. , Wilson Michael , Yant Levi , King Ian P. , King Julie
Published: April 2024

Wheat (Triticum aestivum) is one of the most important food crops with an urgent need for increase in its production to feed the growing world. Triticum timopheevii (2n = 4x = 28) is an allotetraploid wheat wild relative species containing the At and G genomes that has been exploited in many pre-breeding programmes for wheat improvement. In this study, we report the generation of a chromosome-scale reference genome assembly of T. timopheevii accession PI 94760 based on PacBio HiFi reads and chromosome conformation capture (Hi-C). The assembly comprised a total size of 9.35 Gb, featuring a contig N50 of 42.4 Mb and included the mitochondrial and plastid genome sequences. Genome annotation predicted 166,325 gene models including 70,365 genes with high confidence. DNA methylation analysis showed that the G genome had on average more methylated bases than the At genome. In summary, the T. timopheevii genome assembly provides a valuable resource for genome-informed discovery of agronomically important genes for food security.
Long-term outcomes of patients with embolic stroke of undetermined source according to subtype
Authors: Lee Il Hyung , Heo JoonNyung , Lee Hyungwoo , Jeong JaeWook , Kim Joonho , Han Minho , Yoo Joonsang , Kim Jinkwon , Baik Minyoul , Park Hyungjong , Jung Jae Wook , Kim Young Dae , Nam Hyo Suk
Published: April 2024

The prognosis of patients with embolic stroke of undetermined source (ESUS) may vary according to the underlying cause. Therefore, we aimed to divide ESUS into subtypes and assess the long-term outcomes. Consecutive patients with acute ischemic stroke who underwent a comprehensive workup, including transesophageal echocardiography and prolonged electrocardiography monitoring, were enrolled. We classified ESUS into minor cardioembolic (CE) ESUS, arteriogenic ESUS, two or more causes ESUS, and no cause ESUS. Arteriogenic ESUS was sub-classified into complex aortic plaque (CAP) ESUS and non-stenotic (< 50%) relevant artery plaque (NAP) ESUS. A total of 775 patients were enrolled. During 1286 ± 748 days follow-up, 116 major adverse cardiovascular events (MACE) occurred (4.2 events/100 patient-years). Among the ESUS subtypes, CAP ESUS was associated with the highest MACE frequency (9.7/100 patient-years, p = 0.021). Cox regression analyses showed that CAP ESUS was associated with MACE (hazard ratio 2.466, 95% confidence interval 1.305–4.660) and any stroke recurrence (hazard ratio 2.470, 95% confidence interval, 1.108–5.508). The prognosis of ESUS varies according to the subtype, with CAP ESUS having the worst prognosis. Categorizing ESUS into subtypes could improve patient care and refine clinical trials.
Hybrid cheetah particle swarm optimization based optimal hierarchical control of multiple microgrids
Authors: Mohamed Mohamed Ahmed Ebrahim , Mahmoud Ahmed Mohamed , Saied Ebtisam Mostafa Mohamed , Hadi Hossam Abdel
Published: April 2024

The emergence of microgrids arises from the growing integration of Renewable Energy Resources (RES) and Energy Storage Systems (ESSs) into Distribution Networks (DNs). Effective integration, coordination, and control of Multiple Microgrids (MMGs) whereas navigating the complexities of energy transition within this context poses a significant challenge. The dynamic operation of MMGs is a challenge faced by the traditional distributed hierarchical control techniques. The application of Artificial Intelligence (AI) techniques is a promising way to improve the control and dynamic operation of MMGs in future smart DNs. In this paper, an innovative hybrid optimization technique that originates from Cheetah Optimization (CHO) and Particle Swarm Optimization (PSO) techniques is proposed, known as HYCHOPSO. Extensive benchmark testing validates HYCHOPSO’s superiority over CHO and PSO in terms of convergence performance. The objective for this hybridization stems from the complementary strengths of CHO and PSO. CHO demonstrates rapid convergence in local search spaces, while PSO excels in global exploration. By combining these techniques, the aim is to leverage their respective advantages and enhance the algorithm's overall performance in addressing complex optimization problems. The contribution of this paper offering a unique approach to addressing optimization challenges in microgrid systems. Through a comprehensive comparative study, HYCHOPSO is evaluated against various metaheuristic optimization approaches, demonstrating superior performance, particularly in optimizing the design parameters of Proportional-Integral (PI) controllers for hierarchical control systems within microgrids. This contribution expands the repertoire of available optimization methodologies and offers practical solutions to critical challenges in microgrid optimization, enhancing the efficiency, reliability, and sustainability of microgrid operations. HYCHOPSO achieves its optimal score within fewer than 50 iterations, unlike CHO, GWO, PSO, Hybrid-GWO-PSO, and SSIA-PSO, which stabilize after around 200 iterations. Across various benchmark functions, HYCHOPSO consistently demonstrates the lowest mean values, attains scores closer to the optimal values of the benchmark functions, underscoring its robust convergence capabilities.the proposed HYCHOPSO algorithm, paired with a PI controller for distributed hierarchical control, minimizes errors and enhances system reliability during dynamic MMG operations. Using HYCHOPSO framework, an accurate power sharing, voltage/frequency stability, seamless grid-to-island transition, and smooth resynchronization are achieved. This enhances the real application's reliability, flexibility, scalability and robustness.
Phage-antibiotic combinations to control Pseudomonas aeruginosa–Candida two-species biofilms
Authors: Manohar Prasanth , Loh Belinda , Nachimuthu Ramesh , Leptihn Sebastian
Published: April 2024

Phage-antibiotic combinations to treat bacterial infections are gaining increased attention due to the synergistic effects often observed when applying both components together. Most studies however focus on a single pathogen, although in many clinical cases multiple species are present at the site of infection. The aim of this study was to investigate the anti-biofilm activity of phage-antibiotic/antifungal combinations on single- and dual-species biofilms formed by P. aeruginosa and the fungal pathogen Candida albicans. The Pseudomonas phage Motto in combination with ciprofloxacin had significant anti-biofilm activity. We then compared biofilms formed by P. aeruginosa alone with the dual-species biofilms formed by bacteria and C. albicans. Here, we found that the phage together with the antifungal fluconazole was active against 6-h-old dual-species biofilms but showed only negligible activity against 24-h-old biofilms. This study lays the first foundation for potential therapeutic approaches to treat co-infections caused by bacteria and fungi using phage-antibiotic combinations.
Medical equipment effectiveness evaluation model based on cone-constrained DEA and attention-based bi-LSTM
Authors: Huang Luying , Lv Wenqian , Huang Qingming , Zhang Haikang , Jin Siyuan , Chen Tong , Shen Bing
Published: April 2024

This study constructs a composite indicator system covering the core dimensions of medical equipment input and output. Based on this system, an innovative cone-constrained data envelopment analysis (DEA) model is designed. The model integrates the advantages of the analytic hierarchy process (AHP) with an improved criterion importance through intercriteria correlation (CRITIC) method to determine subjective and objective weights and employs game theory to obtain the final combined weights, which are further incorporated as constraints to form the cone-constrained DEA model. Finally, a bidirectional long short-term memory (Bi-LSTM) model with an attention mechanism is introduced for integration, aiming to provide a novel and practical model for evaluating the effectiveness of medical equipment. The proposed model has essential reference value for optimizing medical equipment management decision-making and investment strategies.