bluuebunny/crossref_metadata_2025 huggingface dataset:
Solitonic solutions for the reduced Maxwell-Bloch equations via the Darboux transformation and artificial neural network in nonlinear wave dynamics
Authors: Riaz H W A , Farooq Aamir
Published: November 2024

In this article, we explore nonlinear wave dynamics by presenting solitonic solutions for the reduced Maxwell-Bloch equations, a model relevant to both nonlinear optics and Bose–Einstein condensates. First, we write the Lax pair for the system and apply a Darboux transformation to obtain and analyze the soliton solutions. Then, we introduce a novel approach by integrating the Darboux transformation, a powerful analytical tool, with the Levenberg-Marquardt artificial neural network, a reliable numerical method. This combination enables the identification and validation of soliton solutions, supported by detailed graphical and tabular analyses. The Levenberg-Marquardt artificial neural network effectively demonstrates the uniqueness and convergence of the solutions, with the accuracy of the results validated through comprehensive graphical representations.
Area-delay efficient BCD adder in quantum dot cellular automata
Authors: S R Ramesh , T Jagadeep , Vamsi Krishna Maddala , Abhishek Sista Venkata Datta Sai , Vegunta Suraj Sai
Published: November 2024

Quantum-dot Cellular Automata (QCA) technology presents a promising avenue for the realization of ultralow-power and high-speed digital circuits owing to its inherent quantum properties and nanoscale dimensions. In this study, a novel design and analysis of a binary-coded decimal (BCD) adder implemented using QCA technology is proposed. The BCD adder is a fundamental component of digital arithmetic circuits and is widely applied in various computational systems, including calculators, processors, and digital signal processors. Leveraging the unique features of QCA, such as the absence of current flow and the potential for highly compact layouts, we present a detailed design methodology for the BCD adder circuit, including the implementation of basic QCA gates and construction of the BCD addition logic. Performance metrics, such as area, delay, and power consumption, were evaluated through extensive simulations using QCA Designer, QCA design, and a simulation tool. The Ripple Carry Adder (RCA) is one of the major blocks in the BCD circuit and a prominent factor in determining the area and delay of the circuit. Therefore, an efficient full adder was used to design an RCA with less area and delay. Clocking in a QCA impacts the polarization state of a QCA cell, and this scheme is utilized efficiently to achieve novelty. The proposed design occupies 15.625% less area, and the cell count is reduced by 11.55% compared with the existing state-of-the-art design. Power dissipation reports were obtained using the QCA Pro tool, which briefly describes the average leakage and average dissipation energy of the total circuit, and a spectrum to depict the energy dissipation of each cell in the circuit. The results demonstrate the feasibility and efficiency of the proposed BCD adder design in QCA technology, demonstrating its potential for realizing energy-efficient and high-performance digital arithmetic circuits. This work contributes to the growing body of research on QCA-based digital circuit design and lays the groundwork for the further exploration of QCA technology in practical computing applications.
Relay Observation Scheduling of Global Distributed Telescope Array Based on Integer Programming
Authors: Ju Junhan , Yu Ce , Hu Yi , Zhang Yajie , Sun Chao , Wei Jizeng
Published: November 2024

Certain transients require regular observations over several days at intervals of hours or shorter, which cannot be accomplished by telescopes at a single site. The deployment of globally distributed telescopes at geographic locations of different longitudes enables the periodic monitoring of transients through relay observation. However, the simultaneous relay observation of numerous targets requires a telescope array of multiple telescopes that can be efficiently coordinated, and an automated scheduler for the array. This paper proposes IPROS, an integer programming model relay observation scheduler for a telescope array, that accounts for the entire process of relay observation and is consistent with the practical scenarios. We introduce the integer programming mathematical model for the relay observation scheduling problem with the telescope array, upon which the scheduler is based. Additionally, we propose an algorithm to provide a comprehensive formulation of the optimization objective of minimizing cadence deviation in the model. Experimental results demonstrate that the relay observation scheduler based on the integer programming model can effectively address the telescope array relay observation problem. It shows superiority over a scheduler with non-specific consideration of relay observation in the modeling and a scheduler based on greedy thought.
Neural networks for reconstruction and uncertainty quantification of fast-ion phase-space distributions using FILD and INPA measurements
Authors: Schmidt B. S. , Rueda-Rueda J. , Galdon-Quíroga J. , García-Muñoz M. , Schneider P. A. , Salewski M. ,   the ASDEX Upgrade Team
Published: November 2024

This study introduces the use of a deep convolutional neural network for reconstructing fast-ion velocity distributions from fast-ion loss detectors and imaging neutral particle analyzers (INPAs), automatically integrating uncertainty quantification through Monte Carlo dropout. The network-based reconstructions reveal pitch-angle splitting in high-energy features of lost fast-ion velocity distributions at ASDEX Upgrade during active neutral beam injection, a previously observed phenomenon now confirmed through neural networks. Moreover, contrary to common theories attributing these high-energy features to edge localized mode (ELM)-driven acceleration, we provide experimental evidence that they also occur in type-I ELM-quiescent phases. Additionally, we demonstrate improved reconstructions from INPA measurements, both synthetic and from an ASDEX Upgrade commissioning discharge, with the reconstructions closely matching TRANSP simulations. These findings suggest that neural networks can provide robust reconstructions with well-defined uncertainties, improving the reliability of interpretations of fast-ion behavior in magnetically confined plasmas.
Interlacing eigenvectors of large Gaussian matrices
Authors: Attal Elie , Allez Romain
Published: November 2024

We consider the eigenvectors of the principal minor of dimension n < N of the Dyson Brownian motion in

R

N

and investigate their asymptotic overlaps with the eigenvectors of the full matrix in the limit of large dimension. We explicitly compute the limiting rescaled mean squared overlaps in the large

n

,
N

limit with

n

/

N

tending to a fixed ratio q, for any initial symmetric matrix A. This is accomplished using a Burgers-type evolution equation for a specific resolvent. In the Gaussian orthogonal ensemble case, our formula simplifies, and we identify an eigenvector analogue of the well-known interlacing of eigenvalues. We investigate in particular the case where A has isolated eigenvalues. Our method is based on analysing the eigenvector flow under the Dyson Brownian motion.
Synthesis and characterization of space-time light sheets: a tutorial
Authors: Romer Miguel A , Hall Layton A , Abouraddy Ayman F
Published: November 2024

Space-time wave packets (STWPs) are a new class of pulsed optical beams with many unique and intriguing attributes, including propagation invariance and tunable group velocity in linear optical media. STWPs are a form of spatiotemporally structured light, so their synthesis poses challenges that are not shared by conventional monochromatic structured light fields. We present here a detailed description of the synthesis of STWPs that are localized along one transverse dimension and uniform along the other; i.e. space-time light sheets. We also describe the main characterization schemes needed for benchmarking the unique properties of space-time light sheets.
DPSNN: spiking neural network for low-latency streaming speech enhancement
Authors: Sun Tao , Bohté Sander
Published: November 2024

Speech enhancement improves communication in noisy environments, affecting areas such as automatic speech recognition (ASR), hearing aids, and telecommunications. With these domains typically being power-constrained and event-based, and often requiring low latency, neuromorphic algorithms–particularly spiking neural networks (SNNs)–hold significant potential. However, current effective SNN solutions require a long temporal window to calculate Short Time Fourier Transforms (STFTs) and thus impose substantial latency, typically around 32 ms, which is too long for applications such as hearing aids. Inspired by the Dual-Path Recurrent Neural Network (DPRNN) in deep neural networks (DNNs), we develop a two-phase time-domain streaming SNN fframework for speech enhancement, named Dual-Path Spiking Neural Network (DPSNN). DPSNNs achieve low latency by replacing the STFT and inverse STFT (iSTFT) in traditional frequency-domain models with a learned convolutional encoder and decoder. In the DPSNN, the first phase uses Spiking Convolutional Neural Networks (SCNNs) to capture temporal contextual information, while the second phase uses Spiking Recurrent Neural Networks (SRNNs) to focus on frequency-related features. In addition, threshold-based activation suppression, along with L
1 regularization loss, is applied to specific non-spiking layers in DPSNNs to further improve their energy efficiency. Evaluating on the Voice Cloning Toolkit (VCTK) Corpus and Intel N-DNS Challenge dataset, our approach demonstrates excellent performance in speech objective metrics, along with the very low latency (approximately 5 ms) required for applications like hearing aids.
Constructing Victimhood: Innocence, Guilt, and Definitional Dilemmas
Authors: Lawther Cheryl
Published: November 2024

Chapter 2 critically unpacks the complexity of victimhood post-conflict. Drawing from Christie (1986a), the first part of the chapter examines the construction of ‘ideal’ and ‘innocent’ victims. This conceptualisation of victimhood is then set against the increasing recognition of the ‘complex political victim’. These international debates are brought to bear on the Northern Ireland context in the second half of the chapter. Under the heading of ‘Victimhood as a “repertoire of contention”’, the chapter explores the construction and politicisation of victimhood in Northern Ireland. Conceptualising victimhood as a ‘definitional dilemma’ and competing interpretations of victimhood as ‘victimhood as innocence’ and ‘victimhood as resistance’, it is argued that defining victims as ‘innocent’ or ‘guilty’, ‘deserving’ or ‘undeserving’ may be less about victims’ needs and circumstances and more about making a statement on the ‘justifiability’ of the harms inflicted and the causes and consequences of the conflict within which their victimisation occurred.
Victimhood and Heroes and Hierarchies
Authors: Lawther Cheryl
Published: November 2024

Hierarchies of victimhood are often predicated on distinctions between what Madlingozi (2007) has termed ‘good’ victims and ‘bad’ victims and the question of who can or should be considered a ‘victim’. Chapter 3 argues that the creation of hierarchies of victimhood frequently runs deeper than the demarcation of ‘good’ and ‘bad’ victims. Drawing on the themes of celebration and censure, this chapter offers a new lens through which to understand the construction of hierarchies of victimhood in transitional justice. Structured by three overlapping themes—hierarchies of ‘good’ and ‘bad’ victims; hierarchies and heroes for the cause; and hierarchies and ‘the silence of social opprobrium’—this chapter argues that in the transitional politics of praise and denunciation, the ‘net’ of social control is often tightly calibrated to highlight and celebrate the actions of those victims considered ‘heroes’ within each community and simultaneously exclude—or censure—less comfortable variants of victimhood (Cohen 1985).
Doing Victimhood: Agency, Activism, and the Mobilisation of Empathy
Authors: Lawther Cheryl
Published: November 2024

Chapter 5 interrogates the intersection between agency and the role of victims’ groups in the construction and politicisation of victimhood in transitional justice. It argues that where victims’ groups compete for empathy on the basis of opposing conceptualisations of victimhood, the practices undertaken and results gained may be profoundly disempowering, ‘trap’ victims in a victim identity, and reinforce polarised understandings of innocence and guilt. Organised into five parts, the chapter begins by tracing the evolution of victims’ groups in Northern Ireland. Using a case study approach, it then analyses how the direct use of individual and collective experiences of harm and the choice to explicitly foreground those experiences in campaigning efforts can be an expression of agency and a form of empowerment. The third, fourth, and fifth parts of the chapter take a more critical turn, interrogating the claim that a ‘victims industry’ exists in Northern Ireland; examining how victims’ groups mobilise empathy through contested ‘repertoires of victimhood’ (de Waardt 2016); and exploring how the intersection between competing mobilisation strategies and the political currency of victimhood can provide a fertile ground for the politicisation of victims’ groups and a trajectory of action that puts victims and survivors at risk of capture and exploitation by victim group leaders. In doing so, this chapter disrupts easy and uncritical assumptions that victim participation promotes enhanced agency and empowerment to bring into view crucial questions concerning politics, power relations, and the positionality of victim group leaders.
Conclusion
Authors: Lawther Cheryl
Published: November 2024

Chapter 8 concludes the book. It returns to the themes that have been covered and notes the way that they intersect and overlap. Drawing together the findings of the previous chapters, it reflects on the local and global significance of this work. The chapter then ends with a call to move beyond innocence and guilt so as to embrace narrative complexity when seeking to understand the construction, reproduction, and politicisation of victimhood. Doing so is vital to both interrogating what we ‘see’ and ‘hear’ as experiences of victimhood and coming to a more rounded and truly ‘victim-centred’ conceptualisation of harm.
Socialism and International Law: Legacies of Innovation, Contradiction, and Failure
Authors: Grosescu Raluca , Richardson-Little Ned
Published: November 2024

From Eastern Europe to Africa, Asia, and Latin America, socialist states and experts fundamentally shaped progressive ideas of international law: from anti-imperialism, to self-determination, to anti-racism and health as a human right. This introductory chapter argues for closer scrutiny of the role of global socialism in international law making and its role in contesting Eurocentric and liberal-focused approaches. It also invites for a nuanced analysis of the divisions that existed between socialisms from different world regions and across the North–South divide and which were crucial in undermining the creation of a unified global socialist vision of international law. Eastern European states often found it more productive to collaborate with the West while socialist states in the Global South had more in common with other postcolonial states regardless of ideology. Such scrutiny challenges two main meta-narratives of international law history: a Eurocentric canon of liberal progress and an anticolonial and anti-imperial account focusing solely on Third World contestations of the Western international order.
A Socialist Legal Universalism? Cold War Struggles Over International Law
Authors: Gehrig Sebastian
Published: November 2024

Recent scholarship on the history of international law has challenged the idea that state socialist countries stifled the development of international law until the end of the Cold War. This chapter traces the evolution of state socialist approaches to international law emanating from the Soviet Union since the October Revolution and their reception, adoption, and rejection across the socialist world. Against the often-siloed scholarship on domestic and international law, it argues that state socialist approaches to international law were intrinsically linked to the larger issue of what role law ought to play in the building of socialism and, later, in the maintenance of ‘developed socialism’. This deeper ideological issue of party-state doctrine invariably reflected on the thinking of state socialist legal experts about international law and their concepts of international order and the law governing it in a world changed by decolonization and the Cold War.
Soviet Lawyers and Concepts of Aggression in International Law
Authors: Penn Michelle
Published: November 2024

This chapter explores the different ways that Soviet lawyers articulated the concepts of aggression and crimes against peace to both domestic and international audiences. Focusing on the writings of Aron Trainin and Pyotr Romashkin, I argue that although Soviet approaches to the concepts of aggression and crimes against peace varied in their specifics according to both political concerns and evolving ideas in international law, there was a remarkable consistency to Soviet definitions of aggression between the 1930s and 1960s. This constancy was likely in part due to Soviet propaganda about the inherent peacefulness of socialist states, which made the concept of aggression more foundational to Soviet understandings of international law than other crimes. While the Soviet definitions of genocide and crimes against humanity changed with the international developments of the postwar period, aggression remained the criminal offence underlying essentially all international atrocities throughout the mid-twentieth century in Soviet international law.
Health as a Human Right and Eastern European Anticolonialism
Authors: Iacob Bogdan C
Published: November 2024

The chapter explores the contributions of state socialist regimes to the codification of health as a human right. Their representatives’ interventions are ascertained at the intersection between the drafting of international law (the Universal Declaration of Human Rights and the International Covenant for Economic, Social and Cultural Rights) and activities at the World Health Organization. Eastern European experts connected health as a human right to self-determination, anti-racism, and ideas about state-managed, national medical services with the widest possible access for a country’s population. The chapter underlines the multipolar geography of these debates: Latin American and postcolonial states had an essential role in the codification of the right; the West too was not a monolith, just as state socialism was not. Eastern European experts and their allies consolidated health as a human right by making it interdependent with other rights—a legacy for the post-Cold War years.
Protecting Culture Through International Law in the Postwar World
Authors: Bekus Nelly
Published: November 2024

This chapter explores the contribution of Eastern European socialist states to the formation of the international protection of culture in the context of armed conflicts after the Second World War. Drawing on archival materials from international institutions and national governments, the chapter scrutinizes three acts of international lawmaking: the Nuremberg Trials, the 1948 Genocide Convention, and the 1954 Hague Convention for the Protection of Cultural Property in the Event of Armed Conflict. The chapter argues that the experience of Nazi occupation was deployed by various Eastern Europe states to reinforce the ideological battle against racism and Western colonialism, while countries from the same region, formerly aligned with the Axis, used socialist ideas to reinvent their international status. The development of a new regime of protection of culture reiterated major strains of conflicting interests in a Cold War order, but it also facilitated common initiatives between the East, the West, and the Third World.
Socialist Internationalism and Decolonizing Moralities in the UN Anti-Trafficking Regime, 1947–54
Authors: Dolinsek Sonja , Hetherington Philippa
Published: November 2024

In the late 1940s, state socialist governments proclaimed that commercial sex did not exist under socialism. At the same time, they were enthusiastic participants in the drafting of a new UN Convention for the Suppression of the Traffic in Persons and the Exploitation of the Prostitution of Others. This chapter explores state socialist involvement in the global moral reform drive accompanying the 1949 Convention. It traces the ideological coherence between Socialist Bloc and ‘Western’ delegations on the desirability of prostitution’s abolition. Conversely, it highlights splits on issues of jurisdiction, manifesting in the Soviet call for the eradication of the draft Convention’s ‘colonial clause’, which allowed states to adhere to or withdraw from international instruments on behalf of ‘non-self-governing territories’. It is argued that critiques of the colonial clause discursively stitched together global moral reform and opposition to imperialism, according socialist and newly decolonized delegations an ideological win in the early Cold War.
Terrorists, Revolutionaries, and Migrants: Cold War Conflicts and Convergences over International Air Hijacking Law
Authors: Richardson-Little Ned
Published: November 2024

State socialist Eastern Europe played a significant role in decolonizing aviation law but also in cementing the hijacking of civilian aircraft as a serious international crime that required prosecution or extradition. Motivated by fears of mass illicit emigration, Eastern Bloc states took an extremely hard line against hijacking—even when committed by ideological allies. As a result, alliances in the negotiations of international conventions against hijacking were ever shifting. The Eastern Bloc at times allied with the Global South against the West to make international law less colonial and more universally accessible, and at others allied with their Western capitalist rivals to try to eliminate the possibility of hijackers claiming asylum. The particular concerns of the Eastern Bloc about illicit emigration created a rift with Global South states, especially socialist states, which prioritized protecting national liberation movements that engaged in hijacking from prosecution as terrorists.
Christology and the Logic of Grace in Fifth-Century Gaul
Authors: Fairbairn Donald
Published: November 2024

Scholarly treatments of the ‘Semi-Pelagian Controversy’ give very little attention to the connection between Christology and grace in the thought of the fifth-century Gallic writers, but in fact, John Cassian, Vincent of Lérins, Prosper of Aquitaine, and Faustus of Riez all wrote against Nestorianism as well as writing on grace. The southern Gallic writers saw Nestorius as claiming that Christ was a man united to the Word by virtue of his merits. In contrast, these writers insisted, like Augustine, that we must understand Christ as the Word himself who has come down to live as a man for our salvation, and thus the Christology of both Augustine and the Gallic writers was Cyrillian/Chalcedonian, not ‘Antiochene’. But in spite of this similar Christology, the Gallic writers reasoned from Christology to grace differently than Augustine. Beginning with the inability of fallen humanity to accomplish salvation, Augustine reasoned from the Fall to predestination, and then to the particular aspects of grace in the lives of the elect, with little attention to more general effects of the Incarnation for all human beings. In contrast, the Gallic writers reasoned from the Fall to the Incarnation, and on the basis of this reasoning they emphasized the universal effects of the Incarnation on all, as well as the particular effects on individual Christians. The Gallic writers should not be called ‘Semi-Pelagian’, because they, like Augustine, stressed the priority of divine grace in salvation. But they secured this priority through their treatment of the Incarnation, not through a particular understanding of predestination.
Introduction
Authors: Fairbairn Donald
Published: November 2024

The Introduction surveys scholarship on the ‘Semi-Pelagian Controversy’ in order to show that whereas older scholarship adopted a paradigm of degrees of emphasis on divine and human action in order to distinguish the Gallic writers from Augustine, newer scholarship has identified many different factors in the discussion. The survey also notes the relative lack of attention to Christology in the interpretation of that discussion and explains the way this study will build on the work of Fairbairn, Casiday, and Jaros that does give some attention to the relation between Christology and grace. The Introduction also includes a brief overview of the relation between grace and Christology in the thought of Theodore and Nestorius, as well as a survey of the Nestorian controversy itself, as background to the reflections of the Gallic writers on ‘Nestorianism’. Key terms such as ‘Nestorianism’, ‘Pelagianism’, ‘non-Augustinian’ (as opposed to ‘anti-Augustinian’ or ‘anti-Augustine’) are explained.
Leporius
Authors: Fairbairn Donald
Published: November 2024

This chapter looks in detail at Leporius’s Libellus emendationis in order to explore the connections between ‘Pelagian’ ideas and proto-‘Nestorian’ ones in the thought of the pre-correction Leporius. Before his correction, Leporius saw Christ as a man united to the Word, and there are also indications that he saw salvation as an upward ascent of humankind to God. In sharp contrast, under the correction of Augustine and others, the monk began to see Christ as the Word himself who had become human, and to see salvation in terms of the downward action of God to the human sphere. There is no indication of whether Leporius would have followed Augustine in linking the predestination of the man Christ to the predestination of Christians, but Leporian thought, along with that of Augustine, is a key component of the background to the Gallic writers on whom the study will concentrate.
Conclusion
Authors: Fairbairn Donald
Published: November 2024

This work has demonstrated that the Christology of the Gallic writers, like that of Augustine, was not ‘Antiochene’ but was anti-‘Nestorian’ and broadly Cyrillian/Chalcedonian. In spite of this broad agreement on Christology, however, the Gallic writers diverged significantly from Augustine on charitology. Nevertheless, this does not mean that Christology and grace are unrelated issues. Instead, the issues are connected, but the Gallic writers reasoned from the Fall to the Incarnation and then to grace, whereas Augustine reasoned from the Fall to predestination and then to the Incarnation. The connections described in this study imply that further work may need to be done on subsequent charitological developments in Gaul (especially the Second Council of Orange), and it may also be fruitful to explore the connections between the Gallic conception of Christology and grace outlined here and the understanding of the same issues in other regions of the patristic church. The ‘Gallic’ conception may not have been merely regional but may have been common to other parts of the church as well.
Comparative legal teaching in eighteenth-century Oxford: an analysis of Thomas Bever’s Appendix to his lectures
Authors: Korporowicz Łukasz Jan
Published: November 2024

In the 1760s and 1770s, Thomas Bever, a once-eminent but today nearly-forgotten English civilian, was delivering a course of lectures devoted to civil law at Oxford. The final part of those lectures, known as the Appendix, was of a different character from the earlier parts. In the Appendix Bever discussed the development of the law and constitution of 15 European countries. His description was an attempt to compare different systems and to abstract general legal concepts common to different countries. Along with other issues, Bever was specifically interested in abstracting the common roots of medieval feudalism. The analysis offered in this article is the result of archival investigation comparing two different versions of Bever’s lecture notes. The main objective of the article is to reconstruct Bever’s narrative, together with analysing his methodology and the intellectual framework of his work. This investigation reveals the intricacies of the legal education offered at Oxford in the second half of the eighteenth century.
CMTT-JTracker: a fully test-time adaptive framework serving automated cell lineage construction
Authors: Chen Liuyin , Fu Sanyuan , Zhang Zijun
Published: November 2024

Cell tracking is an essential function needed in automated cellular activity monitoring. In practice, processing methods striking a balance between computational efficiency and accuracy as well as demonstrating robust generalizability across diverse cell datasets are highly desired. This paper develops a central-metric fully test-time adaptive framework for cell tracking (CMTT-JTracker). Firstly, a CMTT mechanism is designed for the pre-segmentation of cell images, which enables extracting target information at different resolutions without additional training. Next, a multi-task learning network with the spatial attention scheme is developed to simultaneously realize detection and re-identification tasks based on features extracted by CMTT. Experimental results demonstrate that the CMTT-JTracker exhibits remarkable biological and tracking performance compared with benchmarking tracking methods. It achieves a multiple object tracking accuracy (MOTA) of $0.894$ on Fluo-N2DH-SIM+ and a MOTA of $0.850$ on PhC-C2DL-PSC. Experimental results further confirm that the CMTT applied solely as a segmentation unit outperforms the SOTA segmentation benchmarks on various datasets, particularly excelling in scenarios with dense cells. The Dice coefficients of the CMTT range from a high of $0.928$ to a low of $0.758$ across different datasets.
Three-dimensional tissue engineered skeletal muscle modelling facioscapulohumeral muscular dystrophy
Authors: Franken Marnix , van der Wal Erik , Zheng Dongxu , den Hamer Bianca , van der Vliet Patrick J , Lemmers Richard J L F , van den Heuvel Anita , Dorn Alexandra L , Duivenvoorden Cas G A , in’t Groen Stijn L M , Freund Christian , Eussen Bert , Tawil Rabi , van Engelen Baziel G M , Pijnappel Pim W W M P , van der Maarel Silvère M , de Greef Jessica C
Published: November 2024

Facioscapulohumeral muscular dystrophy (FSHD) is caused by sporadic misexpression of the transcription factor double homeobox 4 (DUX4) in skeletal muscles. So far, monolayer cultures and animal models have been used to study the FSHD disease mechanism and for FSHD therapy development, but these models do not fully recapitulate the disease and there is a lack of knowledge on how DUX4 misexpression leads to skeletal muscle dysfunction.

To overcome these barriers, we have developed a three-dimensional tissue engineered skeletal muscle (3D-TESM) model by generating genetically matched myogenic progenitors (MPs) from human induced pluripotent stem cells of three mosaic FSHD patients.

3D-TESMs derived from genetically affected MPs recapitulate pathological features including DUX4 and DUX4 target gene expression, smaller myofiber diameters, and reduced absolute forces upon electrical stimulation. RNA sequencing data illustrates increased expression of DUX4 target genes in 3D-TESMs compared to two-dimensional (2D) myotubes, and cellular differentiation was improved by 3D culture conditions. Treatment of 3D-TESMs with three different small molecules identified in drug development screens in 2D muscle cultures showed no improvements, and sometimes even declines, in contractile force and sarcomere organization. These results suggest that these compounds either have a detrimental effect on the formation of 3D-TESMs, an effect that might have been overlooked or was challenging to detect in 2D cultures and in vivo models, and/or that further development of the 3D-TESM model is needed.

In conclusion, we have developed a 3D skeletal muscle model for FSHD that can be employed for preclinical research focusing on DUX4 expression and downstream pathways of FSHD in relation to contractile properties. In the future, we expect that this model can also be used for preclinical drug screening.
Bleeding risk using non-steroidal anti-inflammatory drugs with anticoagulants after venous thromboembolism: a nationwide Danish study
Authors: Petersen Søren Riis , Bonnesen Kasper , Grove Erik Lerkevang , Pedersen Lars , Schmidt Morten
Published: November 2024

Background and Aims

The bleeding risk of using non-steroidal anti-inflammatory drugs (NSAIDs) in patients treated with oral anticoagulants for venous thromboembolism (VTE) remains unclear.

Methods

A nationwide cohort study of 51 794 VTE patients initiating oral anticoagulants between 1 January 2012 and 31 December 2022 was conducted. Time-dependent multivariate cause-specific Cox regression was used to compute adjusted hazard ratios between NSAID use and hospital-diagnosed bleeding episodes.

Results

Event rates for any bleeding per 100 person-years were 3.5 [95% confidence interval (CI), 3.4–3.7] during periods without NSAID use and 6.3 (95% CI, 5.1–7.9) during periods with NSAID use (number needed to harm = 36 patients treated for 1 year). Compared with non-use, the adjusted hazard ratios for any bleeding associated with NSAID use were 2.09 (95% CI, 1.67–2.62) overall, 1.79 (95% CI, 1.36–2.36) for ibuprofen, 3.30 (95% CI, 1.82–5.97) for diclofenac, and 4.10 (95% CI, 2.13–7.91) for naproxen. Compared with non-use, the adjusted hazard ratios associated with NSAID use were 2.24 (95% CI, 1.61–3.11) for gastrointestinal bleeding, 3.22 (95% CI, 1.69–6.14) for intracranial bleeding, 1.36 (95% CI, .67–2.77) for thoracic and respiratory tract bleeding, 1.57 (95% CI, .98–2.51) for urinary tract bleeding, and 2.99 (95% CI, 1.45–6.18) for anaemia caused by bleeding. Results were consistent for anticoagulant and VTE subtypes.

Conclusions

Patients treated with oral anticoagulants for VTE had a more than two-fold increased bleeding rate when using NSAIDs. This increased bleeding rate was not restricted to the gastrointestinal tract.
Acentric chromosome congression and alignment on the metaphase plate via kinetochore-independent forces
Authors: Vicars Hannah , Mills Alison , Karg Travis , Sullivan William
Published: November 2024

Chromosome congression and alignment on the metaphase plate involves lateral and microtubule plus-end interactions with the kinetochore. Here we take advantage of our ability to efficiently generate a GFP-marked acentric X chromosome fragment in Drosophila neuroblasts to identify forces acting on chromosome arms that drive congression and alignment. We find acentrics efficiently congress and align on the metaphase plate, often more rapidly than kinetochore-bearing chromosomes. Unlike intact chromosomes, the paired sister acentrics oscillate as they move to and reside on the metaphase plate in a plane distinct and significantly further from the main mass of intact chromosomes. Consequently, at anaphase onset, acentrics are oriented either parallel or perpendicular to the spindle. Parallel-oriented sisters separate by sliding while those oriented perpendicularly separate via unzipping. This oscillation, together with the fact that in the presence of spindles with disrupted interpolar microtubules acentrics are rapidly shunted away from the poles, indicates that distributed plus-end–directed forces are primarily responsible for acentric migration. This conclusion is supported by the observation that reduction of EB1 preferentially disrupts acentric alignment. Taken together, these studies suggest that plus-end forces mediated by the outer interpolar microtubules contribute significantly to acentric congression and alignment. Surprisingly, we observe disrupted telomere pairing and alignment of sister acentrics indicating that the kinetochore is required to ensure proper gene-to-gene alignment of sister chromatids. Finally, we demonstrate that like mammalian cells, the Drosophila congressed chromosomes on occasion exhibit a toroid configuration.
Collaborative dynamics and shared motivation: exploring tobacco control policy development in Zambia
Authors: Silumbwe Adam , Sebastian Miguel San , Zulu Joseph Mumba , Michelo Charles , Johansson Klara
Published: November 2024

In Zambia, efforts to produce a tobacco control policy have stalled for over a decade, and the country is not yet close to developing one. Limited studies have explored the dynamics in this policy process and how they affect the attainment of policy goals and outcomes. This study explored how collaborative dynamics within tobacco control policy development shaped shared motivation among stakeholders in Zambia. The study used a qualitative case study design that adopted a collaborative governance lens, comprising an in-depth exploration of the tobacco control policy working group meetings and their internal collaborative dynamics. The integrative framework for collaborative governance, which identifies mutual trust, mutual understanding, internal legitimacy and shared commitment as key elements of shared motivation, was adapted for this study. Data were collected from 27 key informants and analysed using thematic analysis. Several collaborative dynamics thwarted mutual trust among tobacco control stakeholders, including concerns about associated loyalties, fear of a ban on tobacco production, silo-mentality and lack of comprehensive dialogue. All stakeholders agreed that the limited sharing of information on tobacco control and the lack of reliable local evidence on the tobacco burden hindered mutual understanding. Diverse factors hampered internal legitimacy, including sector representatives’ lack of authority and the perceived lack of contextualization of the proposed policy content. Acknowledgement of the need for multisectoral action, lack of political will from other sectors and limited local allocation of funds to the process were some of the factors that shaped shared commitment. To accelerate the development of tobacco control policies in Zambia and elsewhere, policymakers must adopt strategies founded on shared motivation that deliberately create opportunities for open discourse and respectful interactions, promote a cultural shift towards collaborative information sharing and address unequal power relations to enable shaping of appropriate tobacco control actions in respective sectors.
Strengthening policy engagement when scaling up interventions targeting non-communicable diseases: insights from a qualitative study across 20 countries
Authors: Ramani-Chander Anusha , Thrift Amanda G , van Olmen Josefien , Wouters Edwin , Delobelle Peter , Vedanthan Rajesh , Miranda J Jaime , De Neve Jan-Walter , Esandi Maria Eugenia , Koot Jaap , Ojji Dike , Ortiz Zulma , R Sherwood Stephen , Teede Helena , Joshi Rohina
Published: November 2024

Policy engagement is an essential component of implementation research for scaling up interventions targeting non-communicable diseases (NCDs). It refers to the many ways that research team members, implementers and policymakers, who represent government decision-making, connect and interact to explore common interests. Well-conducted engagement activities foster co-production, local contextualization and assist in the successful translation of research evidence into policy and practice. We aimed to identify the challenges and facilitators to policy engagement during the early implementation phase of scale-up research studies. This qualitative study was focused on the research projects that were funded through the Global Alliance for Chronic Diseases in the 2019 round. Nineteen project teams opted to participate, with these studies implemented in 20 countries. Forty-three semi-structured stakeholder interviews, representing research, implementation and government were undertaken between August 2020 and July 2021. Transcripts were open-coded using thematic analysis to extract 63 codes which generated 15 themes reflecting both challenges and facilitators to undertaking policy engagement. Knowledge of the local government structures and trusting relationships provided the foundation for successful engagement and were strengthened by the research. Four cross-cutting concepts for engagement were identified and included: (1) the importance of understanding the policy landscape; (2) facilitating a network of suitable policy champions, (3) providing an environment for policy leaders to genuinely contribute to co-creation and (4) promoting two-way learning during researcher–policymaker engagement. We recommend undertaking formative policy analysis to gain a strategic understanding of the policy landscape and develop targeted engagement plans. Through engagement, researchers must facilitate cohesive vision and build a team of policy champions to advocate NCD research within their networks and spheres of influence. Ensuring equitable partnerships is essential for enabling local ownership and leadership. Further, engagement efforts must create a synergistic policymaker–researcher lens to promote the uptake of evidence into policy.
Intersectoral collaboration and health system resilience during COVID-19: learnings from Ahmedabad, India
Authors: Yasobant Sandul , Lekha K Shruti , Thacker Hardi , Solanki Bhavin , Bruchhausen Walter , Saxena Deepak
Published: November 2024

Health system resilience refers to the capacity of a health system to effectively anticipate, assimilate, adjust to and recuperate from unforeseen disruptions and pressures. Evidence indicates that low- and middle-income countries (LMICs) have a double burden of dealing with the existing shortage of health resources in managing both non-emergency care and emergency care during epidemics. Intersectoral collaboration plays a pivotal role in managing crises such as pandemics. The World Health Organization has emphasized that effective intersectoral collaboration is vital for uninterrupted essential services during a pandemic. The study aimed to look at the collaborations entered into at various levels for managing the COVID-19 pandemic, taking as an example the municipal corporation in Ahmedabad, India. We undertook a qualitative study that involved conducting 52 in-depth interviews with officials from the health department, and other departments at the Ahmedabad Municipal Corporation (AMC), including firefighting, estate, engineering and education, as well as private stakeholders. Many diverse observations were documented in this study as collaboration varied across the sectors. A lack of hospital beds and shortage of essential drugs and oxygen posed challenges for healthcare providers and provided an opportunity to collaborate with private stakeholders. Mandatory COVID testing and mobile units such as the Sanjivani van and Vadil ghar seva were examples of some of the initiatives taken by the AMC to manage the pandemic that were instigated and implemented with support from various departments such as education, engineering, tax, estate, animal husbandry and firefighting. Proper communication between public and private entities will result in unfragmented efforts to combat emergencies. Thus, a resilient health system is necessary as well as systematic intersectoral collaboration to ensure the uninterrupted delivery of essential health services during health emergencies.
Leveraging the social networks of informal healthcare providers for universal health coverage: insights from the Indian Sundarbans
Authors: Brahmachari Rittika , Mishra Manasee , Gotsadze George , Mandal Sabyasachi
Published: November 2024

India’s healthcare landscape is characterized by a multitude of public and private healthcare providers, yet its health systems remain weak in many areas. Informal healthcare providers (IHPs) bridge this gap, particularly in rural India, and are deeply embedded within local communities. While their importance is widely recognized, there is a knowledge gap regarding the specifics of their social networks with actors in health systems. The aim of this study was to map the social networks of IHPs to elucidate the type and nature of their relationships, in order to explore opportunities for intersectoral collaboration to achieve universal health coverage (UHC). We have adopted the social network analysis (SNA) approach using qualitative ego-network methodology to evaluate the types and strengths of ties in the Indian Sundarbans. A total of 34 IHPs participated in the study. Qualitative data were analysed using NVivo10 and Kumu.io was used to visualize the social networks. Results show that the 34 IHPs had a total of 1362 ties with diverse actors, spanning the government, private sector and community. The majority of the ties were strong, with various motivating factors underpinning the relationships. Most of these ties were active and have continued for over a decade. The robust presence of IHPs in the Indian Sundarbans is attributable to the numerous, strong and often mutually beneficial ties. The findings suggest a need to reconsider the engagement of IHPs within formal health systems. Rather than isolation, a nuanced approach is required based on intersectoral collaboration capitalizing on these social ties with other actors to achieve UHC in impoverished and underserved regions globally.
FGF8 Protects Against Polymicrobial Sepsis by Enhancing the Host's Anti-infective Immunity
Authors: Chen Kai , Ruan Yanting , Ma Wenjing , Yu Xiaoyan , Hu Ying , Li Yue , Tang Hong , Zhang Xuemei , Yin Yibing , Chen Dapeng , Song Zhixin
Published: November 2024

Background

Sepsis is characterized by a life-threatening syndrome caused by an unbalanced host response to infection. Fibroblast growth factor 8 (FGF8) has been newly identified to play important roles in inflammation and innate immunity, but its role in host response to sepsis is undefined.

Methods

A cecal ligation and puncture (CLP)-induced mouse sepsis model was established to evaluate the immunomodulatory function of FGF8 during sepsis. The underlying molecular mechanisms were elucidated by cell models using relevant molecular biology experiments. The clinical value of FGF8 in the adjuvant diagnosis of sepsis was evaluated using clinical samples.

Results

FGF8 protein concentrations were elevated in CLP-induced septic mice compared to controls. In vivo, FGF8 blockade using anti-FGF8 antibody significantly increased mortality and bacterial burden and was paralleled by significantly aggravated tissue injury after CLP. Therapeutic administration of recombinant FGF8 (rFGF8) improved the bacterial clearance and mortality of septic mice in a FGFR1-dependent manner. In vitro, FGF8 directly enhanced bacterial phagocytosis and killing of macrophages by enhancing the phosphorylation of the ERK1/2 signaling pathway, which could be abrogated with the ERK1/2 pathway inhibitor U0126. Clinically, serum FGF8 levels in both adult and pediatric patients with sepsis in an intensive care unit were significantly higher than those in healthy controls.

Conclusions

These results present a previously unrecognized role of FGF8 in improving survival of sepsis by enhancing host immune defense. Therefore, targeting FGF8 may provide new strategies for the diagnosis and immunotherapy of sepsis.