bluuebunny/crossref_metadata_2025 huggingface dataset:
Large eddy simulation of stratified flow past prolate spheroids with varying aspect ratios
Authors: Gao Gang , Wang Yangjun , Liu Kefeng , Cao Liushuai , Wan Decheng
Published: February 2025

This study employs large eddy simulation and the Boussinesq approximation to investigate the characteristics of wakes generated by prolate spheroid with different aspect ratios (length-to-diameter ratios, L/D = 1.0, 1.5, 2.0, 3.0) in a linear stratified flow, with the Reynolds number (Re) of 3700 and the Froude number (Fr) of 3. The research primarily focuses on the effects of different aspect ratios on defect velocity, wake length scales, root mean square values of velocity components, power spectra, wake energy, and turbulent kinetic energy (TKE). The findings show that the defect velocity along the wake centerline follows the relationships: u ∼ (x/D)−0.08 (L/D = 1.0), as the aspect ratio increases, the exponent gradually decreases, indicating a shorter mean lifespan of the wake. After the starting position of the accelerated collapse stage, the half-width, half-height, the ratio of half-height to half-width, and the influence area of the wake oscillate periodically. With the aspect ratio increases, the half-width, half-height, the ratio of half-height to half-width, and the influence area of the wake are gradually becoming smaller, and the Reynolds stress gradually decreases in magnitude and becomes concentrated near the centerline of the wake. The turbulent kinetic energy for different aspect ratios follows the relationship TKE ∼ (x/D)−1.19. The mean kinetic energy, turbulent kinetic energy, and turbulent potential energy (TPE) of the wake all decrease with increasing aspect ratio. Both the energy of wake and transport, advection, and buoyancy terms in turbulent kinetic energy budget exhibit periodic oscillations, with the oscillation wavelength corresponding to half a buoyancy period (π·Fr). All terms in turbulent kinetic energy budget decrease with the aspect ratio increases.
Critical fragility in sociotechnical systems
Authors: Moran José , Pijpers Frank P. , Weitzel Utz , Bouchaud Jean-Philippe , Panja Debabrata
Published: February 2025

Sociotechnical systems, where technological and human elements interact in a goal-oriented manner, provide important functional support to our societies. Here, we draw attention to the underappreciated concept of timeliness—i.e., system elements being available at the right place at the right time—that has been ubiquitously and integrally adopted as a quality standard in the modus operandi of sociotechnical systems. We point out that a variety of incentives, often reinforced by competitive pressures, prompt system operators to myopically optimize for efficiencies, running the risk of inadvertently taking timeliness to the limit of its operational performance, correspondingly making the system critically fragile to perturbations by pushing the entire system toward the proverbial “edge of a cliff.” Invoking a stylized model for operational delays, we identify the limiting operational performance of timeliness, as a true critical point, where the smallest of perturbations can lead to a systemic collapse. Specifically for firm-to-firm production networks, we suggest that the proximity to critical fragility is an important ingredient for understanding the fundamental “excess volatility puzzle” in economics. Further, in generality for optimizing sociotechnical systems, we propose that critical fragility is a crucial aspect in managing the trade-off between efficiency and robustness.
Computational biology predicts metabolic engineering targets for increased production of 103 valuable chemicals in yeast
Authors: Domenzain Iván , Lu Yao , Wang Haoyu , Shi Junling , Lu Hongzhong , Nielsen Jens
Published: February 2025

Development of efficient cell factories that can compete with traditional chemical production processes is complex and generally driven by case-specific strategies, based on the product and microbial host of interest. Despite major advancements in the field of metabolic modeling in recent years, prediction of genetic modifications for increased production remains challenging. Here, we present a computational pipeline that leverages the concept of protein limitations in metabolism for prediction of optimal combinations of gene engineering targets for enhanced chemical bioproduction. We used our pipeline for prediction of engineering targets for 103 different chemicals using
Saccharomyces cerevisiae
as a host. Furthermore, we identified sets of gene targets predicted for groups of multiple chemicals, suggesting the possibility of rational model-driven design of platform strains for diversified chemical production.
Bipartite binding of the intrinsically disordered scaffold protein JIP1 to the kinase JNK1
Authors: Orand Thibault , Delaforge Elise , Lee Alexandra , Kragelj Jaka , Tengo Maud , Tengo Laura , Blackledge Martin , Boeri Erba Elisabetta , Davis Roger J. , Palencia Andrés , Jensen Malene Ringkjøbing
Published: February 2025

Scaffold proteins are key players in many signaling pathways where they ensure spatial and temporal control of molecular interactions by simultaneous tethering of multiple signaling components. The protein JIP1 acts as a scaffold within the c-Jun N-terminal kinase (JNK) signaling pathway by assembling three kinases, MLK3, MKK7, and JNK, into a macromolecular complex that enables their specific activation. The recruitment of these kinases depends on the 450-amino acid intrinsically disordered tail of JIP1, however, the structural details of this tail and the molecular mechanisms by which it binds kinases have remained elusive. Here, we provide an atomic resolution structural description of the JIP1 tail, and we study its interaction with the kinase JNK1. Using NMR spectroscopy, we show that JNK1 not only engages with the well-known docking site motif (D-motif) of JIP1, but also interacts with a noncanonical F-motif. We determine the crystal structure of the JIP1–JNK1 complex at 2.35 Å resolution revealing a bipartite binding mode of JIP1. Our work provides insights into the sequence determinants of F-motifs suggesting that these motifs may be more prevalent in JNK substrates than previously recognized. More broadly, our study highlights the power of NMR spectroscopy in uncovering kinase interaction motifs within disordered scaffold proteins, and it paves the way for atomic-resolution interaction studies of JIP1 with its multitude of interaction partners.
Negative Radiation Pressure Scheme for Simultaneous Suppression of Arduous Back-Action Evasion and Shot Noise in Gravitational Wave Detectors
Authors: Agasti Souvik , Nesladek Milos , shukla abhishek
Published: February 2025

Aiming at applications for gravitational wave (GW) detection, in particular at the reduction of quantum back action noise, we propose a novel scheme how to obtain back action evading measurements performed on an opto-mechanical cavity, by introducing a negative radiation pressure coupling between the cavity field and the end mirror. The scheme consists of introducing a double cavity with end mirrors interlocked by a pivot and moving in opposite directions. The measurement is performed by sending a two-mode squeezed vacuum to both cavities and detecting the output through the heterodyne detection. Compared to the previously proposed hybrid negative mass spin-optomechanical system in [1], we see that our scheme is capable to suppress back action noise by nearly two orders of magnitude more in the lower frequency region. Overall, the setup has been able to squeeze the output noise below the standard quantum limit, with more efficiency. The scheme has also proven to be beneficial for reducing thermal noise by a significant amount. We confirm our result by a numerical analysis and compared it with the previous proposals [1].
On the nonlinear Poincaré flow
Authors: Crovisier Sylvain , Yang Dawei
Published: February 2025

We develop a tool in order to analyse the dynamics of differentiable flows with singularities. It provides an abstract model for the local dynamics that can be used in order to control the size of invariant manifolds. This work is the first part of the results announced in Crovisier and Yang (2017 arXiv:1702.05994).
Asymmetric Hexagonal Silicon Nanowires with Partial Cylindrical Hole Defects for Improved Energy Harvesting Efficiency
Authors: Khaled Awad , Hameed Mohamed Farhat O. , AREED NIHAL F. F. , Obayya Salah
Published: February 2025

Recently, nanostructured silicon nanowires (SiNWs) have provided an attractive solution for realizing an efficient light-trapping compared to conventional thin film solar cell (SC). However, the photoconversion efficiency of the SiNWs is still lower than the expectation from such emerging photovoltaic devices. In this paper, the idea of symmetry breaking into the silicon NWs SC is introduced by integrating a cylindrical nanohole (CNH) into a solid hexagonal nanowire (HNW). The asymmetric design allows a significantly improved optical absorption due to the intensified nanofocusing effect in the active material. Additionally, the proposed structure substantially enhances the sunlight absorption by increasing the number of excited modes through the HNW. Further, the high surface reflections are reduced, and the light confinement is increased due to the decrease in the surface filling ratio. The volume and the position of the CNH are tuned to break the structure symmetry and boost the effective absorption in almost the entire spectrum band and hence the electrical power conversion efficiency. The proposed NW is numerically analyzed by the Lumerical software package based on the 3D finite-difference-time-domain (3D FDTD) and 3D finite-element methods (3D FEM). The optical ultimate efficiency (η), absorption, short circuit current density (JSC), fill factor (FF), open circuit voltage (VOC), and the NW power conversion efficiency (PCE) are investigated. The asymmetric HNW design provides a JSC of 33.17 (35.88) mA/cm2, and PCE of 16.03 (17.40) % with an enhancement of 14.18 % (17.98 %) and 17.26 % (21.25 %) for transverse electric (TE) and transverse magnetic (TM) incidents, respectively compared to the solid HNW counterpart.
Asymmetries from a charged memory-burdened PBH
Authors: Barman Basabendu , Loho Kousik , Zapata Óscar
Published: February 2025

We explore a purely gravitational origin of observed baryon asymmetry and dark matter (DM) abundance from asymmetric Hawking radiation of light primordial black holes (PBH) in presence of a non-zero chemical potential, originating from the space-time curvature. Considering the PBHs are described by a Reissner-Nordström metric, and are produced in a radiation dominated Universe, we show, it is possible to simultaneously explain the matter-antimatter asymmetry along with right DM abundance satisfying bounds from big bang nucleosynthesis, cosmic microwave background and gravitational wave energy density due to PBH density fluctuation. We also obtain the parameter space beyond the semiclassical approximation, taking into account the quantum effects on charged PBH dynamics due to memory burden.
Testing gravitational waveforms in full General Relativity
Authors: D'Ambrosio Fabio , Gozzini Francesco , Heisenberg Lavinia , Inchauspé Henri , Maibach David , Zosso Jann
Published: February 2025

We perform a comprehensive analysis of state-of-the-art waveform models, focusing on their predictions concerning kick velocity and inferred gravitational wave memory. Recent advancements in gravitational wave instrumentation have established new benchmarks for the precision of future measurements. To fully exploit the potential of upcoming gravitational wave surveys, it is crucial to concurrently enhance both semi-analytical and numerical waveform models used for analyzing interferometer data. In this work, we establish a pathway towards achieving this goal by developing and implementing a pipeline to assess the accuracy of waveform models using energy-momentum balance laws derived in full, non-linear General Relativity. The numerical accuracy assessment is performed for precessing as well as non-precessing simulations for models belonging to the EOB, Phenom, and Surrogate families. Our analysis reveals statistically significant deviations, which we trace back to inaccuracies in modeling subdominant modes and inherent systematic errors in the chosen models. We corroborate our findings through analytical considerations regarding the mixing of harmonic modes in the computed kick velocities and inferred memories. The methodology developed and validated in this article provides a foundational approach for future waveform assessments and a selection guide for waveform models in practical applications.
The haloes that reionized the Universe
Authors: Joshi Nachiket , Sharma Mahavir
Published: February 2025

We study the reionization of the Universe due to haloes that host galaxies undergoing bursts of star formation. By comparing the recent results from the James Webb Space Telescope (JWST) with the cosmological hydrodynamical simulation eagle at z ≥ 6, we find that bursty galaxies have specific star formation rate, sSFR > 10-2 Myr-1, and magnitude, M
UV ≤ -17. Most of them reside in haloes of mass ∼ 109 M⊙ and some in more massive haloes. We then construct the models of escape fraction and find that a skewed Gaussian function with a flat tail towards the high mass end best describes the mean dependence of escape fraction on halo mass, considering the haloes hosting bursty galaxies as the primary drivers of reionization. We implement the models of escape fraction in the code 21cmfast to study the progress of reionization and derive the evolution of the mean ionized fraction that agrees well with observations. We also calculate the brightness temperature, spin temperature, and kinetic temperature and further study the spatial fluctuations in these quantities to gain insights into the progress of reionization. We compute the 21 cm power spectrum and predict a peak in power at 180 MHz corresponding to redshift, z ≈ 6.8, that is testable by the upcoming Square Kilometre Array (SKA). Our findings suggest that the Universe was reionized by the haloes of ≳ 109 M⊙.
Fast Determination of Oxygen in FeSiAl magnetic alloy by Inert Gas Fusion Method
Authors: Liu Pan , Chen Qianqian , Wang Shuo , Zhang Lijuan , Zhang Yi , Zhang Jianhao , Zhang Xinyao
Published: February 2025

A fast method that combines inert gas fusion with infrared absorption spectrometry for determination of total oxygen in FeSiAl magnetic alloy has been established. The whole analyzing process was introduced, especially the selection of sample weight, analytical power, fluxes and calibration. The blank test, precision test and spiked recovery test were conducted to verify the suitability and accuracy of the proposed method. Limit of quantifications were in the range of 0.010% to 0.012%, while relative standard deviations were less 9.5%. The recovery rates of oxygen in potassium hydrogen phthalate were between 90% and 107%. The inert gas fusion-infrared method of testing a sample needs 4 min. It has shown that the new method is accurate and efficient.
The Effect of Calibration with Different Matrix Reference Materials on the Accuracy of Oxygen Determination by Inert Gas Fusion-Infrared Absorptiometry
Authors: Li Ying , Sang Zhe , Zhao Zhihe , Zhu Lihui , Shi Xiaolu , Lu Huanming , Yingli Sun , Ke Peiling , Zhang Gongjun
Published: February 2025

The inert gas fusion-infrared absorptiometry is an effective means of determination of oxygen. The results need to be calibrated with reference materials (RMs), which is required to have the similar composition as the samples. However, due to the limited types of RMs on the market, currently, calibration with different matrix is widely used in the determination of oxygen of various materials. In this study, oxygen content was measured in 17 types of materials, including steels, metal oxides, non-metallic compounds, organic compounds, and oxygen-containing salts. The accuracy of oxygen determination was analyzed, and it was concluded that steel and iron oxide are effective RMs for low and high oxygen determination, respectively. It provides the experimental basis for the application of calibration with different matrix RMs to the determination of oxygen by inert gas fusion-infrared absorptiometry.
Investigation of pulse electromagnetic on Grain Refinement in 5356 Aluminum Alloy Casting
Authors: Xi Huangzhen , Bai Liang , Zhang Xinlong , Bao Xinyu , Liu Jingshun , Li Ze , Ma Yonglin
Published: February 2025

In the production of aluminum castings, grain refiners are extensively used to achieve the desired grain refinement. However, the high cost associated with these materials significantly increases the overall expenses of the casting process. As a result, one of the primary goals in foundry operations is to implement more cost-effective methods of grain refinement. This study focuses on the innovative use of low-energy pulsed electromagnetic energy as an alternative approach for grain refinement during the casting of 5356 aluminum alloy. The research conclusively demonstrates the effectiveness of applying electromagnetic energy directly to the molten metal to refine the grain structure. Experimental investigations were carried out in an industrial casting environment, where the influence of electromagnetic energy on the solidification behavior of the 5356 aluminum alloy was systematically analyzed. The findings revealed a significant improvement in grain refinement, with a 16% reduction in grain size observed in the low cooling region of the cast material. Moreover, the application of electromagnetic energy was shown to promote the precipitation of the silicon (Si) phase, further enhancing the microstructural properties of the alloy. These results highlight the potential of using low-energy pulsed electromagnetic technology as a practical and cost-effective solution for grain refinement in aluminum foundry operations. The insights gained from this research may contribute to the development of more efficient casting techniques, ultimately reducing production costs while maintaining or improving the quality of the final product.
State of art on enhancing the corrosion rate of biodegradable iron alloys
Authors: Wang Anguo , Zhao Menghe , Ji Jiasheng , Sun Yaochuan , Liu Weihao
Published: February 2025

Biodegradable implants help avoid the adverse residual effects and the need for secondary surgeries associated with permanent implants. Recently, biodegradable metals (BMs), which are designed to gradually corrode within the body, have gained significant research interest as promising materials to meet this need. Iron (Fe) alloys are promising metals for the fabrication biodegradable implants, which possess excellent mechanical properties. However, their corrosion rates can be too slow in physiological environments for specific applications, such as cardiovascular and osteogenic devices. Therefore, techniques on enhancing the corrosion rate of Fe alloys are worth to study. Various methods have been explored to enhance their degradation, including alloying, processing and surface treatments. The paper reviewed biodegradable Fe alloys and their corrosion mechanism, the methods on enhancing corrosion rate, based on the development of metallic implant materials.
Radiographic restoration technique based on a simple scatter-and-noise degradation model to enhance image visibility in cone-beam computed tomography systems using an offset detector
Authors: Park Jiwon , Jeon Duhee , Han Seohee , Kim Woosung , Park Sungmin , Cho Hyosung
Published: February 2025

This study presents a novel radiographic restoration technique based on a simple
scatter-and-noise degradation model to enhance image visibility in cone-beam computed tomography
(CBCT) systems using an offset detector. This method aims to address the challenges of scatter and
noise in CBCT images. It involves three main steps: estimating the scattering intensity and
transmission function from the acquired projections, restoring projections by removing scatter and
noise using the estimated quantities, and reconstructing the image using the standard
filtered-backprojection algorithm. To verify the efficacy of the proposed method, we conducted an
experiment on a commercially available test phantom using a tabletop setup of the micro-CT
configuration, demonstrating significant improvements in key image quality metrics such as
contrast-to-noise ratio (CNR), noise power spectrum (NPS), and modulation transfer function
(MTF). The CNR value of the restored CBCT image was approximately 2.1, representing a 5.3-fold
improvement over the original image; the NPS value evaluated at a spatial frequency of 3 lp/mm was
approximately 4.2 × 105, 55.3 times smaller than that for the descattered image;
and the spatial resolution evaluated at an MTF value of 0.1 was approximately 1.1 lp/mm, 8.4 times
greater than that of the original. Accordingly, our experimental results demonstrate that the
proposed method significantly enhances the visibility and quality of CBCT images. The method is
entirely software-based, making it practical for implementation without requiring additional
hardware or higher radiation doses.
Silicon Photonics Circuits for the optical readout of CERN detectors
Authors: Scarcella C. , Alfiero D. , Cristiano A. , Detraz S. , Muthuganesan H. , Olanterä L. , Quintana I. , Sigaud C. , Soós C. , Troska J.
Published: February 2025

The increasing luminosity in CERN experiments, enabled by future upgrades, demands optical links with enhanced bandwidth and radiation tolerance. Silicon Photonics (SiPh) has emerged as the optoelectronic technology meeting these requirements and is being considered for the next generation of optical readout systems for CERN detectors. This paper presents the measurement results from photonic circuits integrated into a test chip designed at CERN, along with the progress on the system aspects of SiPh radiation-tolerant optical links.
Design of γ-γ fast timing setup VENTURE-2.0 with CeBr3 detectors
Authors: Pal A. , Bahre P. , Jha M.K. , Basak S. , Kumar D. , Alam S.S. , Roy S. , Régis J.M. , Bhattacharjee T. , Bhattacharjee T.
Published: February 2025

The design of the γ-γ fast timing array
VENTURE-2.0 is presented as an upgradation of the VENTURE array
existing at Variable Energy Cyclotron Centre (VECC), Kolkata. The
development will give rise to the possibility of exotic nuclear
structure studies in terms of shapes, spin and isospin using
γ-γ fast timing spectroscopy. The new array is aimed
at measuring nuclear level lifetimes from few nanoseconds down to
about few picoseconds in nuclei produced with low cross
section. Nine different sizes of CeBr3 detectors with crystal
dimension (diameter (ϕ) × thickness (t))
varying between 1 in and 2 in were considered as the possible
components of the array. The Monte Carlo and electronic circuit
simulations have been performed to estimate full-energy peak (FEP)
detection efficiency and time resolution for these nine different
sizes of detectors. The simulation was experimentally verified using
available 1 in× 1 in CeBr3 crystals
coupled to R9779 PMTs. The design of VENTURE-2.0 has been finalized
to result in the best time precision of the setup that can be
achieved through optimising the detection efficiency, time
resolution and number of detectors in the setup. It is observed that
detectors having higher surface area (ϕ 2 in.) but lower
thickness (t 1 in.) is the most appropriate one for the
development of VENTURE-2.0.
Towards the high-stability simulation and optimization method of magnet supports for fourth-generation synchrotron light sources
Authors: Cao Xiang , Zhang Tianhao , Guo Zhengpeng , Ma Wei , Zou Liping , Lu Liang , Yang Zhen
Published: February 2025

Fourth-generation synchrotron light sources pursue
ultra-high brightness and high spatial coherence, aiming to reduce
beam emittance to the diffraction-limit, which imposes stricter
requirements on the stability of the storage ring mechanical
system. Mechanical support serves as the foundation for all physical
components, ensuring their corresponding physical performance. This
study utilizes Design of Experiments method to simulate and analyze
the effects of different boundary conditions and component
structures on the eigenfrequency of Magnet-Girder
Assemblies. Through analyzing boundary conditions and performing
topology optimization, the design process of girder structures is
elaborated with the eigenfrequency as the optimization target,
ultimately achieving the 1st eigenfrequency of
61.298 Hz. This paper summarizes the principles influencing the
eigenfrequency of Magnet-Girder Assemblies with six-point support,
providing reference for future girder design and development.
Assessing rain-on-snow event dynamics over Alaska using 30-year satellite microwave observations
Authors: Du Jinyang , Kirchner Peter B , Pan Caleb G. , Watts Jennifer D , Kimball John S
Published: February 2025

Rain-on-snow (ROS) events are characterized by liquid precipitation or condensation onto snow surfaces that can lead to snowmelt and the formation of ice layers. ROS events can directly alter the physical structure and thermal properties of the snowpack, leading to rapid melting and runoff-induced flooding, reduced snow insulation, and permafrost degradation. However, tracking ROS events and regional trends remain uncertain due to limited ground measurements and lack of long-term satellite ROS observations representing vast and remote boreal-Arctic landscapes. We quantified ROS dynamics over Alaska by developing a daily 6-km resolution ROS record using an established Gradient Ratio Polarization (GRP) approach and 30-year (1988-2017) satellite observations from the Special Sensor Microwave Imager/Image Sounder (SSMI/S) sensors. The data record captured well-documented ROS events and showed high consistency (R 0.94) with alternative ROS predictions from the Advanced Microwave Scanning Radiometer-EOS/2 (AMSR) sensors. Analysis showed an overall increasing ROS frequency with significant trends mainly identified during early winter. Notable rises in ROS frequency were also detected in mid-to-high elevation ranges (>400 m ASL), while this increase diminished at higher elevations (>1000 m ASL). Our analysis further confirmed that the warming climate plays a fundamental role in driving these ROS events, with significantly positive correlations between ROS frequency and air temperature. However, the significant correlations did not extend to the Eastern and Western Gulf climate zones of southern Alaska, where the ROS retrievals were likely affected by coastal ocean contamination of SSMI/S observations.
Tunable Anisotropy in Wide-Bandgap 2D Crystal CaNb2O6 Utilizing Nanomechanical Resonators
Authors: Liang Yachun , Wang Luming , Wu Jiaqi , Wu Song , Zhu Jiankai , Qin Jiaze , Fan Xiulian , Zhang Zejuan , Xu Bo , Jiao Chenyin , Pei Shenghai , Zhou Yu , Xia Juan , Wang Zenghui
Published: February 2025

As an ultrathin wide-bandgap (WBG) material, CaNb2O6 exhibits excellent optical and electrical properties. Particularly, its highly asymmetric crystal structure further provides new opportunities for designing novel nanodevices with directional functionality. However, due to the significant challenges in applying conventional techniques to nanoscale samples, the in-plane anisotropy of CaNb2O6 has still remained yet to be explored. Here, we leverage the resonant nanoelectromechanical systems (NEMS) platform, and successfully quantify both the mechanical and thermal anisotropies in such an ultrathin WBG crystal. Specifically, by measuring the dynamic response in both spectral and spatial domains, we determine the anisotropic Young’s modulus of CaNb2O6 as EY(a) = 70.42 GPa and EY(b) = 116.2 GPa. By further expanding this technique to cryogenic temperatures, we unveil the anisotropy in thermal expansion coefficients as α(a) = 13.5 ppm/K, α(b) = 2.9 ppm/K. Interestingly, through thermal strain engineering we successfully modulate the mode sequence and achieve crossing of (1×2) - (2×1) modes with perfect degeneracy. Our study provides guidelines for future CaNb2O6 nanodevices with additional degrees of freedom and new device functions.
Introduction to Pilgrimage in Buddhism
Authors: Hartmann Catherine
Published: February 2025

This chapter provides a broad introduction to pilgrimage in Buddhist traditions, with a specific focus on the history of pilgrimage practices in Tibet. It draws on a wide range of sources, including Theravada, Mahayana, and Vajrayana scriptures and commentaries, as well as contemporary ethnography. For readers unfamiliar with Buddhism or Tibet, it provides an accessible introduction to pilgrimage that will ground the rest of the book and situate Tibetan mountain pilgrimage in the landscape of Buddhist pilgrimage. For readers more familiar with Buddhist pilgrimage, it argues for seeing as a technique for making the Buddha’s presence feel real that runs throughout the history of Buddhist pilgrimage.
One Thing, Many Appearances
Authors: Hartmann Catherine
Published: February 2025

This chapter examines a centuries-long debate about the authenticity of Kailash, considered by most Tibetans to be the famed Mount Himavat or Mount Meru. Focusing mainly on two central texts in this debate—one by Sakya Paṇḍita (1182–1251) and one by Chödrak Yeshe (1453–1524)—this chapter shows that the main issue fueling debate is the gap between fantastic descriptions of the wonders of pilgrimage places and the mundane way those same places appear to ordinary perception. While Sakya Paṇḍita takes mundane ordinary perception as evidence that Kailash is not legitimate, Chödrak Yeshe articulates an account of how a single object can appear to different people in different ways. He separates the ordinary perception possessed by most humans from the extraordinary perception possessed by gods and masters and related in scripture. Ordinary pilgrims cannot see the extraordinary vision of Kailash and must instead imagine its presence at the pilgrimage site.
The Salvation of the Non-Philosopher
Authors: Laurens Hannah
Published: February 2025

One of the central tenets of Spinoza’s Ethics is that freedom is attained through knowledge: first through the adequate ideas of reason, and once reason is perfected through those of scientia intuitiva. It is the philosopher who is said to achieve blessedness (beatitudo): a profound contentment of mind (acquiescentia animi) that in its love and union with God constitutes salvation (salus). But if knowledge is the means to this freedom, what about those who are not of a philosophical disposition but instead live by the rules and regulations of religion? This essay argues, against the view of most scholars, that in the Tractatus Theologico-Politicus Spinoza maintains that salvation is not the prerogative of philosophers but is available to religious believers as well: they too may become entirely blessed (omnino beatus). On the basis of their understanding of divine law believers follow precepts that lead to a habit of virtue. Although their habitus virtutis is not grounded in knowledge (and their love of God is practical rather than intellectual), it successfully quiets a restless mind. The believer’s acquiescentia may be of a lesser intensity than the philosopher’s; still, insofar as theirs is a life lived in union with God, their acquiescentia animi is true, hence their salvation genuine.
The Genesis of Relationism
Authors: De Risi Vincenzo
Published: February 2025

This essay provides a history of the development of Leibniz’s ideas about space. Contrary to standard readings, Leibniz did not defend a relational theory of space until 1688, when he read Newton’s Principia and realized that he had to respond to the theory of absolute space with a new, powerful, and rich alternative theory. The essay details Leibniz’s theories of space prior to the relational theory and their philosophical sources. It discusses Leibniz’s theory of space in relation to his theories of time, motion, and geometry. Finally, it shows the role of Newton in the genesis of Leibniz’s relational theory.
Why we need to consider frailty in the assisted dying debate
Authors: Hopkins Sarah A , Price Annabel , Etkind Simon N
Published: February 2025

Background

Assisted dying/assisted suicide (AD/AS) is legal or decriminalised in several countries and Bills to legalise it are currently being considered by the UK and Scottish Parliaments. Older adults living with frailty make up an increasing proportion of those who die, yet the possible implications of AD/AS for these individuals are relatively unexplored. Here, we discuss some of these issues.

Discussion

Frailty complicates AD/AS in relation to eligibility because of ambiguity over whether frailty constitutes a terminal illness, challenges in accurately predicting prognosis, and difficulty determining reversibility of suffering. Frailty also blurs the distinction between terminal illness and disability, in contrast to the clear-cut language of current proposed legislation where those with a terminal illness are eligible, but those with disability are not.

We discuss that decisions regarding AD/AS are often framed in terms of individual autonomy, whereas relational autonomy is the norm for many living with frailty, meaning that concerns regarding implicit coercion need careful consideration. Further, there is an established link between frailty and feeling a burden to others. There is an open question as to whether this, combined with persisting ageist attitudes in society, could influence decisions of people living with frailty about an assisted death.

Conclusion

The above issues make the place of frailty in proposed legislation on AD/AS uncertain. Further consideration is needed regarding eligibility, safeguards in the context of relational autonomy and for those who already feel a burden, and how to mitigate risks of further entrenching ableist and ageist attitudes.
Systematic review and meta-analysis of the epidemiology of man-made vitreous fibres and respiratory health outcomes
Authors: McElvenny Damien M , Iskandar Ireny , Daniels Sarah , Gittins Matthew , van Tongeren Martie
Published: February 2025

Objectives

The generic term man-made vitreous fibres (MMVFs) also known as man-made mineral fibres (MMMFs) denotes non-crystalline, fibrous inorganic material manufactured primarily from glass, rock, minerals, slag, glass, and processed inorganic oxides. The International Agency for Research on Cancer has classified rock (stone) wool, glass wool, and continuous glass filament as Group 3 (not classifiable for carcinogenicity). This study contains an updated systematic review and meta-analysis of respiratory health outcomes and MMMFs.

Methods

Cinahl, EMBASE, Medline, Web of Science, and OpenGrey were searched for epidemiological studies of occupational MMMF exposure and malignant and non-malignant respiratory diseases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were adopted for reporting. Meta-analyses were carried out separately for cohort and case–control studies.

Results

A total of 25 studies were identified for inclusion in the systematic review, with 19 of these (9 cohort; 10 case–control) providing risk estimates for the meta-analyses. Of the cohort studies, 3 were carried out in Sweden, 2 each in Canada and the United States, one in France, and one several European countries. The start of follow-up ranged from 1933 to 1975. The meta-RR for lung cancer from cohort studies (incidence or mortality) was 1.15 (95% CI: 1.01 to 1.32), for laryngeal cancer was 1.03 (95% CI: 0.78 to 1.37), and for non-malignant respiratory diseases (NMRD) mortality was 0.89 (95% CI: 0.66 to 1.22). Of the case-control studies, 9 examined lung cancer and one laryngeal cancer. Three of the lung cancer studies were carried out in France and one each in Germany, Russia, Canada, and China, with one in several European countries and one was a nested case–control study of several case cohorts from across the globe. The meta-OR for lung cancer from the case–control studies was 1.28 (95% CI: 1.10 to 1.50).

Conclusions

Our findings broadly agree with a previously published meta-analysis of respiratory system cancers, in that they were similar in terms of magnitude of relative risk. However, overall, our results suggest that exposure to MMMFs is associated with a small, but statistically significantly elevated risk for lung cancer, but not for laryngeal cancer or NMRDs. Given the heterogeneity between studies, and the possibility of residual confounding, further work is required to determine if this association is causal.
Efficacy and safety of roxadustat for treating anemia in patients with chronic kidney disease and heart failure: a retrospective cohort study
Authors: Liu Jiang , Meng Zhen , Feng Lina , Zhuo Li , Liang Yan , Yang Mengxi , Su Lina , Zheng Zhaoqi , Liu Bowei , Ren Jingyi
Published: February 2025

Background

Anemia is a common comorbidity in patients with chronic kidney disease (CKD) and heart failure (HF). Roxadustat has been approved for the treatment of anemia in patients with CKD. However, its efficacy and safety in treating anemia in patients with both CKD and HF remain unclear. We conducted a retrospective study with propensity score matching (PSM) to evaluate the efficacy and safety of roxadustat in this population.

Methods

This retrospective study enrolled patients diagnosed with HF comorbid with CKD and anemia. The patients were divided into two groups: the roxadustat and control groups. One-to-one PSM was used to balance baseline characteristics between the groups. The primary endpoint was the change in hemoglobin (Hb) at week 8. Secondary endpoints included Hb response, changes in hematocrit, ໿iron parameters, echocardiographic parameters, B-type natriuretic peptides, and lipid levels. Exploratory endpoints were mortality and rehospitalization rates over 30 days to 2 years. Safety endpoints included the incidence of hyperkalemia, liver damage, and thrombotic events.

Results

A total of 1 055 patients were screened. After PSM, 206 patients were included. Baseline characteristics were comparable between the matched cohorts. ໿At week 8, the roxadustat group experienced a greater increase in Hb than the control group, with a difference of 0.8 g/dL (95% confidence interval, 0.3 to 1.3, P = 0.003). The roxadustat group also demonstrated a higher Hb response (60.2% vs. 28.2%, P < 0.001), and a greater increase in hematocrit (4.7 ± 0.9% vs. 2.8 ± 0.6%, P = 0.008) than the control group. No significant differences were observed for other secondary endpoints. Thrombotic events were similar between the two groups, and there were no differences in the risks of mortality or rehospitalization.

Conclusions

Roxadustat was effective in correcting and maintaining Hb levels in patients with anemia, HF, and CKD. It did not increase thrombotic and other adverse events, mortality, or rehospitalization risks, making it a promising treatment option for anemia in this population.
Five Years of Post-Marketing Liver Safety Data from the Tolvaptan Risk Evaluation and Mitigation Strategy
Authors: Lohrmann Emanuel , Jaeger Thomas , Enekebe  , Zhang Zhen , Wilt Timothy , Riggen Michele , Stemhagen Annette , Nair Indu , Nunna Sasikiran , Fernandes Ancilla W , Gandhi Hema , Sergeyeva Olga , George Vinu
Published: February 2025

Background

Approval of tolvaptan in the United States for the treatment of autosomal dominant polycystic kidney disease (ADPKD) was contingent on implementation of a Risk Evaluation and Mitigation Strategy (REMS) that includes monitoring for drug-induced liver injury (DILI). Liver safety data from the REMS were published previously for the period from program start (May 2018) to February 2021. To further characterize the post-marketing liver safety of tolvaptan, we provide a REMS update.

Methods

We analyzed prospective pharmacovigilance data on ADPKD patients who initiated tolvaptan in the post-marketing setting. The data capture period was May 2018—February 2023.

Results

Among 10,879 tolvaptan-treated patients, exposure was >12 months for 45% and >18 months for 35%. Since the 3-year analysis, in which 60/6711 (0.9%) patients were reported with possible severe DILI, the frequency has remained consistent to 5 years (i.e., 82/10,879 [0.8%]). Incidence of possible severe DILI in the REMS at 5 years was 0.52 events per 100 patient-years. Confirmation of possible severe DILI events as serious and potentially fatal was made for 4/82 events, with no new cases confirmed since the 3-year reporting period. No fatalities or liver transplants attributable to tolvaptan-related DILI have been reported in the REMS.

Conclusions

Five years of data support adherence to the per-label tolvaptan liver function monitoring schedule to promptly detect and manage liver toxicity. Conclusions are limited by data availability at the time of analysis cutoff, with the possibility that additional cases of possible severe DILI and/or serious and potentially fatal events may be identified.
Novel Ultrasound-Guided Adrenal Venous Sampling in Iodine Contrast Intolerant Patients: Two Case Reports
Authors: Hishida Yoshiaki , Hashimoto Kazuki , Mochizuki Ryota , Yasuda Hiroki , Nagasaka Tomoyuki , Deguchi Yuki , Sugiura Yoshiya , Yokota Kenichi , Ohike Nobuyuki , Sone Masakatsu
Published: February 2025

Adrenal venous sampling (AVS) is an important procedure for determining primary aldosteronism (PA) subtypes. To guide the catheter to the adrenal veins and confirm cannulation, an iodinated contrast medium (ICM) is typically used. As an ultrasound-based device, the AcuNav intracardiac echocardiography (ICE) catheter allows for real-time visualisation of vessels, offering a safer and less invasive option for patients at risk of using ICM. This report introduces a novel AVS technique using the AcuNav ICE catheter in two patients with PA with contraindications to ICM. One patient had a documented ICM allergy, and the other had active bronchial asthma. The AcuNav ICE catheter successfully enabled cannulation of the adrenal veins in both cases without the need for ICM or alternative agents. This ultrasound-guided technique is novel for AVS and highlights the potential of this method for broader applications in the management of patients with PA with ICM intolerance.
Impact of Remission Status in Endogenous Cushing's Syndrome on Cancer Incidence
Authors: Rudman Yaron , Fleseriu Maria , Masri-Iraqi Hiba , Shochat Tzipora , Kushnir Shiri , Shimon Ilan , Akirov Amit
Published: February 2025

Objective

Endogenous Cushing's syndrome (CS) has been linked with an increased risk of cancer. We aimed to evaluate the association between cancer risk and disease remission post-surgery in adrenal CS and Cushing's disease (CD).

Design

A nationwide retrospective matched-cohort study of patients with CS diagnosed between 2000-2023 in Israel, using Clalit Health Services’ database.

Methods

Patients with CS were matched 1:5 with controls by age, sex, socioeconomic status, and BMI. Remission status post-surgery was assessed within two years after the diagnosis of CS. The outcome measured was time to first diagnosis of malignancy, at least three years post-CS diagnosis, excluding those who died or developed cancer earlier. Malignancy risk, stratified by remission status, was evaluated using Cox proportional hazards with death as a competing event.

Results

The cohort comprised 388 cases and 1,862 controls [mean age at diagnosis, 47.4±16.8 years; 1,534 (68.2%) women].

Among patients with CD, those who did not achieve remission within 2 years post diagnosis (n=69) had a higher risk of malignancy compared to those who achieved remission (n=99) (HR 3.89, 95% CI 1.41-10.75). Cancer risk in patients with CD who achieved remission was similar to that of the controls (HR 0.58, 95% CI 0.23-1.47).

In patients with adrenal CS, the risk of cancer was comparable between those who did not achieve early remission (n=39) and those who did (n=113) (HR 1.68, 95% CI 0.83-3.40).

Conclusion

Though cancer risk is higher in both CD and adrenal CS, we have shown that achieving surgical remission within 2 years may attenuate cancer risk in patients with CD, but not in those with adrenal CS.
Reappraisal of statin primary prevention trials: implications for identification of the statin-eligible primary prevention patient
Authors: Mancini G B John , Ryomoto Arnold , Yeoh Eunice , Iatan Iulia , Brunham Liam R , Hegele Robert A
Published: February 2025

Background and Aims

Identification of patients eligible for primary prevention statin therapy is complex, often relying upon risk algorithms that diverge internationally. Our goal was to develop a simpler global definition of statin-eligible primary prevention patients.

Methods

Randomized clinical trials (RCTs) cited in North American and European dyslipidemia guidelines justifying primary prevention statins for cardiovascular risk reduction were critically reappraised according to eligibility criteria and characteristics of actual enrollees. Statin-eligibility based on meeting minimal enrolment criteria versus risks calculated using either the Framingham Risk Score, the Pooled Cohort Equation and the Systematic Coronary Risk Estimate 2 were contrasted.

Results

Patient scenarios meeting minimal RCT eligibility criteria seldom attained high enough 10 year risk of events according to the algorithms tested and thus would not be eligible for statin therapy. Overall, enrollees were 63.9 ± 8.9 years (mean ± SD) with low density lipoprotein-cholesterol (LDL-C) 3.53 ± 0.91 mmol/L. Enrollees in trials studying the lowest LDL-C levels were generally older and had additional risk factors.

Conclusions

Results of primary prevention RCTs justify treatment of more subjects and lower risk subjects than current risk algorithm-based guidelines. Based on a synthesis of RCT inclusion/exclusion criteria and the characteristics of enrollees, we propose that a statin-indicated primary prevention subject is one who is 40 to 70 years with a low density lipoprotein-cholesterol (LDL-C) ≥ 3.0 mmol/L or is 55 to 80 years with LDL-C ≥ 1.8 mmol/L and additional risk factors.
The homie insulator has sub-elements with different insulating and long-range pairing properties
Authors: Fujioka Miki , Ke Wenfan , Schedl Paul , Jaynes James B
Published: February 2025

Chromatin insulators are major determinants of chromosome architecture. Specific architectures induced by insulators profoundly influence nuclear processes, including how enhancers and promoters interact over long distances and between homologous chromosomes. Insulators can pair with copies of themselves in trans to facilitate homolog pairing. They can also pair with other insulators, sometimes with great specificity, inducing long-range chromosomal loops. Contrary to their canonical function of enhancer blocking, these loops can bring distant enhancers and promoters together to activate gene expression, while at the same time blocking other interactions in cis. The details of these effects depend on the choice of pairing partner, and on the orientation specificity of pairing, implicating the 3-dimensional architecture as a major functional determinant. Here we dissect the homie insulator from the Drosophila even skipped (eve) locus, to understand its substructure. We test pairing function based on homie-carrying transgenes interacting with endogenous eve. The assay is sensitive to both pairing strength and orientation. Using this assay, we found that a Su(Hw) binding site in homie is required for efficient long-range interaction, although some activity remains without it. This binding site also contributes to the canonical insulator activities of enhancer blocking and barrier function. Based on this and other results from our functional dissection, each of the canonical insulator activities, chromosomal loop formation, enhancer blocking, and barrier activity, are partially separable. Our results show the complexity inherent in insulator functions, which can be provided by an array of different proteins with both shared and distinct properties.