bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimization of gene editing off-target effects by tissue restriction of expression
Authors: Kim Nam-Gyun , Aubert Martine , Haick Anoria K. , Massa Paola A. , Loprieno Michelle A. , Walter Marius , Kim Hyeong Geon , Nunley B. Ethan , Xie Hong , Stensland Laurence , Klouser Lindsay M. , Pérez-Osorio Ailyn C. , Stone Daniel , Roychoudhury Pavitra , Jerome Keith R.
Published: January 2025

Therapeuticin vivogene editing with highly specific nucleases has the potential to revolutionize treatment for a wide range of human diseases, including genetic disorders and latent viral infections like herpes simplex virus (HSV). However, challenges regarding specificity, efficiency, delivery, and safety must be addressed before its clinical application. A key concern is the risk of off-target effects, which can cause unintended and potentially harmful genetic changes. We previously developed a curativein vivogene editing approach to eliminate latent HSV using HSV-specific meganuclease delivered by an AAV vector. In this study, we investigate off-target effects of meganuclease by identifying potential off-target sites through GUIDE-tag analysis and assessing genetic alterations using amplicon deep sequencing in tissues from meganuclease treated mice. Our results show that meganuclease expression driven by a ubiquitous promoter leads to high off-target gene editing in the mouse liver, a non-relevant target tissue. However, restricting the meganuclease expression with a neuron-specific promoter and/or a liver-specific miRNA target sequence efficiently reduces off-target effects in both liver and trigeminal ganglia. These findings suggest that incorporation of regulatory DNA elements for tissue-specific expression in viral vectors can reduce off-target effects and improve the safety of therapeuticin vivogene editing.
Perinatal circadian desynchronization disrupts sleep and prefrontal cortex function in adult offspring
Authors: Roberts Brandon L. , Wang Jiexin , Chargui Haifa , Cupertino Nathan C. , Sorensen Walker , Karatsoreos Ilia N.
Published: January 2025

Sleep and circadian (daily) rhythms impact nearly all aspects of physiology and are critical for optimal organismal function. Disruption of the clock can lead to significant metabolic disorders, neuropsychiatric illness, and cognitive dysfunction. Our lab has previously shown that environmental circadian desynchronization (ECD) in adults alters the anatomical structure and neurophysiological function of prefrontal cortex (PFC) neurons, PFC mediated behaviors, as well as sleep quality. As the PFC undergoes significant development in utero and early life, and maternal disturbances during this period can have significant long-term ramifications, we hypothesized that disrupting the circadian environment of dams during the perinatal period would alter sleep and PFC function in adult offspring. Using a mouse model of ECD we investigated how perinatal ECD (pECD) modulates sleep quality in adult offspring. We also determined how pECD impacts PFC neural function in adult offspring usingex vivopatch-clamp electrophysiology, exploring how pECD alters synaptic function and action potential dynamics. We found that male pECD mice trended toward increased total sleep during the inactive (light) period with shorter sleep bouts during the active (dark) period. pECD did not change sleep behavior in female mice. Independent of time of day, pECD altered post-synaptic dynamics of excitatory neurotransmitter release onto plPFC pyramidal neurons. There was also a loss of time-of-day effects on cell endogenous properties in male pECD mice. Thus, pECD clearly alters sleep behavior and PFC function in male mice. However, female mice appear protected against the effects of pECD in these measures. Together, these experiments form the foundation for future studies to understand the lifelong neurobehavioral impact of pECD.
Protective mechanisms against Alzheimer’s Disease in APOE3-Christchurch homozygous astrocytes
Authors: Tian Xinran , Rivera Erica Keane , Nikitina Arina A. , Hwang Inyoung , Smith Jennifer A. , Cho Youngsuh J. , Sala-Jarque Julia , DuBose Austin , Andriola Clare , Gollan-Myers Toby , Kosik Kenneth S.
Published: January 2025

The APOE3-Christchurch (APOE3-Ch) variant has been linked to reduced Alzheimer’s Disease (AD) risk, but its protective mechanisms remain unclear. This study explores the neuroprotective phenotype of APOE3-Ch astrocytes, focusing on lipid metabolism and tau processing. APOE3-Ch astrocytes demonstrate enhanced tau oligomer uptake via HSPG- and LRP1-mediated pathways, facilitated by elevated HSPG expression, and achieve superior tau degradation through lysosomal pathways and proteasomal pathways, in contrast to wild-type astrocytes, which primarily use proteasomal mechanisms. Transcriptomic analysis reveals upregulation of genes involved in endocytosis and cell projection assembly, explaining enhanced tau uptake and clearance in APOE3-Ch astrocytes. Lipidomic profiling identifies reduced levels of pathological lipids such as ceramides and gamma-linolenic acid (GLA), potentially mitigating neuroinflammation. These findings provide insight into the protective mechanisms of APOE3-Ch astrocytes and underscore their potential as therapeutic targets for tauopathy and neurodegeneration in AD.

Teaser

APOE3-Christchurch astrocytes enhance tau clearance and mitigate neurotoxic lipid accumulation, unveiling protective mechanisms against Alzheimer’s.
GETgene-AI: A Framework for Prioritizing Actionable Cancer Drug Targets
Authors: Gu Adrian , Chen Jake Y
Published: January 2025

Identifying actionable drug targets is a critical challenge in cancer research, where high-dimensional genomic data and the complexity of tumor biology often hinder effective prioritization. To address this, we developedGETgene-AI, a novel computational framework that integrates network-based prioritization, machine learning, and automated literature analysis to identify and rank potential therapeutic targets. Central to GETgene-AI is theG.E.T. strategy, which combines three data streams: mutational frequency (G List), differential expression (E List), and known drug targets (T List). These components are iteratively refined and ranked using theBiological Entity Expansion and Ranking Engine (BEERE), leveraging protein-protein interaction networks, functional annotations, and experimental evidence. Additionally, GETgene-AI incorporates GPT-4o, an advanced large language model, to automate literature-based ranking, reducing manual curation and increasing efficiency.

In this study, we applied GETgene-AI to pancreatic cancer as a case study. The framework successfully identified high-priority targets such asPIK3CAandPRKCA, validated through experimental evidence and clinical relevance. Benchmarking against GEO2R and STRING demonstrated GETgene-AI’s superior performance, achieving higher precision, recall, and efficiency in prioritizing actionable targets. Moreover, the framework mitigated false positives by deprioritizing genes lacking functional or clinical significance.

While demonstrated on pancreatic cancer, the modular design of GETgene-AI enables scalability across diverse cancers and diseases. By integrating multi-omics datasets with advanced computational and AI-driven approaches, GETgene-AI provides a versatile and robust platform for accelerating cancer drug discovery. This framework bridges computational innovations with translational research to improve patient outcomes.
Identification of Specialized tRNA Expression in Early Human Brain Development
Authors: Bagi Alex L. , Lowe Todd M. , Salama Sofie R.
Published: January 2025

Transfer RNAs (tRNAs) are traditionally known for their role in protein translation, yet recent discoveries highlight their broader functions in gene regulation, particularly through tRNA-derived small RNAs (tDRs). Studies have shown the singular importance of one unique ArgUCU tRNA isodecoder in mouse neural development, yet potential function(s) of tDRs derived from this and all other tRNAs remain largely unexplored in early human brain development. In this study, we employed cerebral cortical organoid models and AlkB-facilitated RNA methylation sequencing (ARM-seq) to profile tDRs across distinct stages of early human cerebral cortex development. Our analysis reveals dynamic expression patterns of diverse tDR groups derived from a wide range of isodecoders, with several distinct groups showing neural-specific expression. Computational analyses of these tDRs shows biased sequence motifs in over-represented tRNAs that are enriched with particular RNA modifications, giving initial clues to traits that change within the pool of tDRs during neural development. This expanded catalog of tDRs provides a framework for future studies on tRNA function in brain development and offers a deeper understanding of the complexity of tDR dynamics in neural differentiation.
Large Animal Epilepsy Model Platform: Kainic Acid Porcine Model of Mesial Temporal Lobe Epilepsy
Authors: Mivalt Filip , Maltais Daniela , Kim Inyong , Kim Jiwon , Began Patrik , Duque Lopez Andrea , Krakorova Veronika , Winter Bailey , Gregg Nick , Montonye Dan , Gow Christopher , Miller Kai , Van Gompel Jamie , Leyde Kent , Kremen Vaclav , Chang Su-youne , Worrell Gregory A.
Published: January 2025

Objective

Translational animal models are essential for advancing neuromodulation therapies for drug-resistant epilepsy. Large animal epilepsy models that accommodate implantable neuromodulation devices designed for humans are needed to advance electrical brain stimulation and sensing applicaitons. We establish a kainic acid (KA) porcine model of mesial temporal lobe epilepsy (mTLE) for pre-clinical research and development of novel stimulating therapies.

Methods

We developed a platform integrating MRI-guided stereotactic electrode and chemotoxin delivery with intraoperative and long-term electrophysiology monitoring. Six domestic pigs underwent MRI-guided stereotactic implantation of bilateral hippocampal (HPC) and anterior nucleus of the thalamus (ANT) electrodes, followed by KA infusion into the right HPC. Local field potential (LFP) monitoring was conducted intraoperatively with a bedside workstation and chronically with an implantable neural sensing and recording (INSR) device designed for human use. Cresyl violet staining, commonly used to visualize neurons, was used to assess the neuropathophysiological effect of the KA infusion.

Results

KA infusion led to the emergence of interictal epileptiform discharges (IEDs), acute status epilepticus (SE), and spontaneous seizure activity. Acute IEDs and electrographic SE was observed in all cases, with two pigs euthanized due to uncontrolled seizures. Of the surviving four pigs, spontaneous IEDs were detected in all, and spontaneous seizures within 2 weeks were observed in three. Seizures in freely behaving animals varied from subclinical events to focal and generalized tonic-clonic seizures. Single pulse evoked response potentials (SPEP) measured in two pigs demonstrated functional connectivity between ANT and HPC circuits. Neuronal disorganization and loss, both major components of mTLE neuropathology were observed.

Significance

The KA-induced porcine mTLE model supports the feasibility of testing human neuromodulation devices and provides a translational platform for studying therapeutic electrical sensing and stimulation. In particular, the model should be useful for advancing automated seizure diaries, closed-loop and adaptive therapies targeting Papez circuit nodes.
The Binary Cellular Biology of Human Growth: II. Calculating the Size of the Human Fetus from the Size of its Parts
Authors: Gu Zifan , Gupta Rashi , Cantonwine David E , McElrath Thomas F , Tiemeier Henning , Michaelson James Selib
Published: January 2025

Assessing and understanding theSizeof the human fetus provides essential information for the management of the health of the newborn and its mother, a quality that is commonly measured byFetal Ultrasound. Many equations for making such calculations have been considered, none of which have been entirely satisfactory. As we have shown in the previous paper in this series, a consideration of the formation of the body, in units of numbers of cells,N, an approach we callBinary Cellular Analysis, provides new quantitative tools for estimating theSizeandAgeof the fetus. These tools include a new mathematical basis for creating useful expressions,Binary Cellular Estimated Fetal Weight Equations, for calculating humanFetal WeightfromUltrasound Measurements. As we show here, the most promising of these expressions, theAbdominal Circumference Binary Cellular Estimated Fetal Weight Equation, performs better than other currently usedFetal Weight Equations, while also yielding up new methods for improving ultrasound size assessment. Web-based calculators (https://kidzgrowth.com) make these mathematical manipulations available for obstetric care.
Electronic-decay-process spectra including nuclear degrees of freedom
Authors: Riegel Alexander V. , Fasshauer Elke
Published: January 2025

In the field of chemistry, where nuclear motion has traditionally been a focal point, we now explore the ultrarapid electronic motion spanning attoseconds to femtoseconds, demonstrating that it is equally integral and relevant to the discipline. The advent of ultrashort attosecond pulse technology has revolutionized our ability to directly observe electronic rearrangements in atoms and molecules, offering a time-resolved insight into these swift processes. Prominent examples include Auger-Meitner decay and interparticle Coulombic decay. However, the real challenge lies in interpreting these observations, where theoretical models are indispensable. Building upon the analytical framework introduced by Fasshauer and Madsen [], which analyzed the spectra of electrons emitted during electronic decay processes from a purely electronic perspective, we extend this theoretical base to include nuclear dynamics, utilizing the Born-Oppenheimer approximation to deepen our understanding of the intricate interaction between electronic and nuclear motion in these processes. We illustrate the impact of incorporating nuclear degrees of freedom in several theoretical cases characterized by different numbers of vibrational bound states in both the electronic resonance and the electronic final state. This approach not only clarifies complex spectral features and unusual peak shapes but also demonstrates a method for extracting the energy differences between multiple vibrational resonance states through their distinctive interference patterns.

Published by the American Physical Society
2025
Information limits and Thouless-Anderson-Palmer equations for spiked matrix models with structured noise
Authors: Barbier Jean , Camilli Francesco , Xu Yizhou , Mondelli Marco
Published: January 2025

We consider a prototypical problem of Bayesian inference for a structured spiked model: a low-rank signal is corrupted by additive noise. While both information-theoretic and algorithmic limits are well understood when the noise is a Gaussian Wigner matrix, the more realistic case of structured noise still remains challenging. To capture the structure while maintaining mathematical tractability, a line of work has focused on rotationally invariant noise. However, existing studies either provide suboptimal algorithms or are limited to a special class of noise ensembles. In this paper, using tools from statistical physics (replica method) and random matrix theory (generalized spherical integrals) we establish the characterization of the information-theoretic limits for a noise matrix drawn from a general trace ensemble. Remarkably, our analysis unveils the asymptotic equivalence between the rotationally invariant model and a surrogate Gaussian one. Finally, we show how to saturate the predicted statistical limits using an efficient algorithm inspired by the theory of adaptive Thouless-Anderson-Palmer (TAP) equations.

Published by the American Physical Society
2025
Specification of a smart-analysis system of sound events for smart environments
Authors: Santiago Gabriela , Aguilar Jose
Published: January 2025

Purpose

In this work, we proposed a smart-analysis system of sound events for smart/intelligent environments based on an autonomic cycle of data analysis tasks.

Design/methodology/approach

We propose an autonomic cycle of data analysis tasks. An autonomic cycle of data analysis tasks is a set of data analysis tasks that supervise and control a process anonymously, which are based on knowledge models (of prediction, recognition, etc.), interacting with each other to reach a common goal. Each task has a different function in the cycle: observation of the process, or its analysis, or decision-making.

Findings

This work presents the autonomic cycle. With its components, this autonomic cycle detects sound information using a taxonomic model of the sound events to analyze them and give a recommendation about the context. The taxonomic model is a hierarchical pattern that considers different aspects to recognize the sound events. This work defines the architecture of this autonomic cycle, specifies its machine-learning-based analysis tasks and evaluates its capabilities of reasoning, adaptation and communication in case studies.

Research limitations/implications

It is important to work in the future on the improvement of the accuracy of the system by implementing neural networks or more sophisticated techniques. To take the implemented autonomic cycle to a higher level, it could use parallel function management. The automation also needs improvement. In addition to that, future works are going to be directed not only to sound events but also to include emotion recognition and its relation with sound events happening simultaneously.

Originality/value

The main contributions of this paper are as follows: the detailed description of the intelligent sound analysis (ISA) autonomic cycle for the smart sound analysis of sound events (SAS-SE) in an intelligent environment (IE); the specification of the machine-learning-based analysis tasks of ISA for the smart sound analysis and the development of a case study that settles the use of the system in different IEs.
Linking paternalistic leadership and service behaviours through perceived support from supervisor and organisation: empirical evidence from the Pakistani healthcare sector
Authors: Hussain Muzammil , Luu Trong Tuan , Marjoribanks Timothy
Published: January 2025

Purpose

Drawing upon social exchange theory, this study aims to assess whether paternalistic leadership style (authoritarianism, benevolence and morality) influences employee in-role service behaviour and extra-role service behaviour, particularly patient-oriented organisational citizenship behaviour via a dual mediation mechanism, i.e. perceived supervisor support and perceived organisational support.

Design/methodology/approach

The data were gathered from doctors and nurses working in Pakistan’s public, private and semi-government hospitals. We used SPSS and AMOS 27 to run structural equation modelling.

Findings

Results revealed that authoritarianism was negatively associated with in-role service behaviour and patient-oriented organisational citizenship behaviour through perceived supervisor support and perceived organisational support. In contrast, benevolent and moral behaviours of leaders were positively associated with in-role service behaviour via perceived supervisor support and perceived organisational support. However, perceived supervisor support did not mediate the relations between paternalistic leadership dimensions and patient-oriented organisational citizenship behaviour.

Originality/value

Our research advances the paternalistic leadership literature concerning paternalistic leadership and employees’ service behaviours through dual mediation mechanisms and in a relatively understudied sector and national context.
Developing a probabilistic model for evaluating the organisational safety climate factors in offsite manufacturing
Authors: Vithanage Sadith Chinthaka , Sing Michael C.P. , Davis Peter Rex , Newaz Tanvi
Published: January 2025

Purpose

Offsite manufacturing (OSM) is a modern construction technique that offers several advantages over traditional construction, including using less material to produce a similar product, lowering costs, increasing quality and enhancing environmental sustainability of the final product in several ways. However, there is evidence of increased safety related incidents at an OSM facility due to the varying nature of its organisational safety climate. Therefore, this study aims to ascertain the relationships between organisational safety climate factors and safety performance in an OSM context, with a view to developing better safety outcomes.

Design/methodology/approach

A Bayesian Network (BN) approach was adopted to uncover the probabilistic relationships among organisational safety climate factors. First, a literature review was conducted to develop a conceptual model, which was validated by industry experts. Second, a questionnaire survey with Australian OSM professionals was employed to quantify the BN model. Finally, a sensitivity analysis was performed to validate the BN model and identify critical factors.

Findings

Owing to the influence of organisational safety climate dimensions, there is a 79% probability that Australian OSM facilities obtain “high” safety performance. Despite this result, improvements in management safety response, the balance between safety and production, supervisor safety expectations, credibility in training and accessibility to safety rules and procedures are critical to maintaining and improving this current outcome.

Originality/value

This study develops a probabilistic model determining relationships between organisational safety climate factors and safety performance, particularly in an OSM context. The proposed model facilitates safety managers’ comprehension of safety climate issues and provides decision-making support when implementing safety management strategies.
Big-data AI analytics in value-chain innovation and international marketing strategy: insights from SMEs in cultural and creative industries
Authors: Zong Zupan , Anwar Muhammad Azfar , Khan Sana , Asmi Fahad , Hussain Nazim
Published: January 2025

Purpose

Despite great consensus on the positive impact of big-data-driven artificial intelligence (AI) analytics (BDAI) on a firm’s performance, it still appears to be a black box mechanism through which small and medium-sized enterprises (SMEs) strengthen their dynamic competencies to innovate and expand their global footprint. To fill this theoretical and empirical gap we examine the relationship between BDAI affordances, digital marketing capabilities (DMCs), value-chain innovation and international market goals.

Design/methodology/approach

The study incorporates the dynamic capability view an extension of the resource-based view and the knowledge-based view to empirically examine the primary data collected from marketing managers and executives of SMEs in cultural and creative industries utilizing Structural Equation Modeling (SEM) analysis.

Findings

The study highlights the significant role of BDAI affordances such as intelligent process recommendations, customer intelligence and market intelligence on DMCs, where DMCs significantly affect value-chain innovation and international market strategy both directly and indirectly.

Research limitations/implications

The study minimizes the gap in identifying the BDAI affordances to drive innovation and international market strategy in the context of SMEs in cultural and creative industries. Marketing managers can incorporate these findings to enhance their digital capabilities for competitive advantages in international markets.

Originality/value

The study proposes a holistic framework of BDAI affordances for the strategic use of digital resources and knowledge to transform digital capabilities into new forms of value to expand in the international market. These insights are robust and grounded in findings provided by marketing practitioners.
Sentiments and sustainability: stakeholder perceptions of sustainable fashion on social media
Authors: Blazkova Tereza , Pedersen Esben Rahbek Gjerdrum , Andersen Kirsti Reitan Reitan
Published: January 2025

Purpose

This study aims to deepen the understanding of what stakeholders talk about when it comes to sustainable fashion on social media and how. Sustainable fashion is a broad umbrella term, which can distract attention from the differences between the individual subtopics and the sentiments ascribed to them. However, little systematic research exists on how the stakeholder activity and dominant sentiments vary across different sustainable fashion topics.

Design/methodology/approach

This study is based on a social media analysis of 19,179 tweets authored by 1,819 distinct stakeholders on Twitter (now “X”) from 2007 to 2022. A large language model, a type of artificial intelligence (AI) that focuses on understanding and generating human language, is used to conduct a sentiment analysis of six stakeholder groups and 81 keywords linked to sustainable fashion. Two case examples are used to highlight the differences in stakeholder perceptions of sustainable fashion.

Findings

The social media analysis demonstrates how subcategories of sustainable fashion significantly differ in terms of stakeholder interest, activity and sentiments. For instance, tweets on circular economy and relevant subcategories (closed loop, recycling, upcycling, etc.) are popular, whereas issues linked to environmental, social and governance (ESG) and due diligence receive little attention on social media. While sentiments toward sustainable fashion are in general positive, discussions on topics such as labor rights issues are consistently associated with negative sentiments across most stakeholder groups.

Originality/value

This study contributes to the literature by demonstrating how stakeholders and sentiments vary across different topics linked to sustainable fashion on social media, which has become one of the main channels for communicating sustainability content. The findings thereby shed new light on dominant stakeholder positions regarding a wide variety of sustainable fashion topics.
Carrying the load: a moderated mediation study exploring the link between perceived organizational support and burnout amongst management consultants
Authors: Bernard Dominik , McGuire David , Harte Patrick , Müller Patrick
Published: January 2025

Purpose

This study investigates the relationship between perceived organizational support (POS), employee resilience and workload on burnout in the consulting sector, which is characterized by long working hours and high pressure.

Design/methodology/approach

The proposed hypotheses were tested using data collected from a sample of 169 management consultants. The key constructs were examined using the PROCESS statistical package.

Findings

The findings indicate that POS has a positive effect on exhaustion, cynicism and professional inefficacy. This effect is partially mediated by employee resilience for all three dimensions. A significant moderation between workload and POS has been found for the cynicism dimension of burnout, suggesting that the positive effect of high POS is especially useful for consultants with high workloads (exceeding 60 working hours per week).

Practical implications

These findings highlight the importance of making employees feel supported in high-pressure work environments, as this has both a direct effect on employees' mental health and an indirect effect by increasing resilience, which in turn reduces the risk of burnout.

Originality/value

The study addresses the paucity of research on the workloads of management consultants and how they navigate burnout. The findings show that both personal resources (in this case, resilience) and organizational resources (POS) have a favorable impact on preventing burnout.
ChatGPT in class: motivation, schadenfreude and student usage intentions
Authors: Hickman Thomas M. , Stoica Michael
Published: January 2025

Purpose

Integrating social comparison and social identity theories, this study aims to examine students’ emotional and behavioral responses to the use of ChatGPT in academic settings, focusing on intrinsic motivation, dissonance, envy, schadenfreude and artificial intelligence (AI) usage intentions.

Design/methodology/approach

The research design consisted of two sequential survey-based studies with undergraduate business students. Study 1, analyzed with SmartPLS, measured students’ intrinsic motivation, cognitive engagement, dispositional envy, emotional dissonance and schadenfreude experienced in response to academic dishonesty related to ChatGPT. Study 2 explored the motivations behind students’ future use of AI tools, examining ethical considerations and emotional responses.

Findings

Study 1 determined that higher levels of cognitive engagement reduce dissonance and envy among highly motivated students. Nevertheless, driven by cognitive engagement, dissonance and envy, it was established that highly motivated students experience schadenfreude when others are caught misusing ChatGPT. In contrast, low-motivated students only feel schadenfreude as a product of dissonance and envy. The focus of Study 2 was on the adoption of ChatGPT. Results indicate that future usage is driven by ethical considerations for highly motivated students, whereas less dissonance is key for low-motivated students.

Originality/value

The study’s originality lies in its exploration of schadenfreude in the context of AI use among students, highlighting how cognitive engagement and motivation influence emotional responses. Drawing on social comparison and social identity theories, it sheds new light on the dynamics of academic integrity and the emotional landscape surrounding AI tools like ChatGPT, thus filling a research gap in understanding student behavior and perceptions in higher education.
Advanced Paediatric Life Support: A 25‐year journey in Australia
Authors: Teo Stephen SS , Stanford Jane
Published: January 2025

Over twenty‐five years ago the first Advanced Paediatric Life Support (APLS) course was held in Australia. Through the lens of quality culture in educational organisations, we can identify factors which have underpinned the evolution, sustainability and success of this course.
The virtues of limits and environmental sustainability in healthcare
Authors: Symons Xavier
Published: January 2025

The spectre of human‐induced climate change has drawn attention to the need to discover new, environmentally sustainable approaches to healthcare. This article draws upon David McPherson's The Virtues of Limits (2021) to develop a virtue ethics for sustainability in healthcare. I explore how a virtuous appreciation of the value of healthcare resources can lead us to exercise stewardship in our use of those resources, whereas a failure to appreciate the value of resources can lead to irresponsible and unsustainable patterns of use. I close with some recommendations of how health systems might go about facilitating the cultivation of the virtues of sustainable health practice.
Association of prostate‐specific antigen density with prostate cancer mortality after a benign systematic prostate biopsy result
Authors: Pylväläinen Juho , Talala Kirsi , Raitanen Jani , Rannikko Antti , Auvinen Anssi
Published: January 2025

Objective

To assess the association between prostate‐specific antigen (PSA) density (PSAD) and prostate cancer mortality after a benign result on systematic transrectal ultrasonography (TRUS)‐guided prostate biopsy.

Patients and Methods

This retrospective study used data from the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC) collected between 1996 and 2020. We identified men aged 55–71 years randomised to the screening arm with PSA ≥4.0 ng/mL and a benign systematic TRUS‐guided biopsy result. The cumulative prostate cancer mortality of men stratified by a PSAD cutoff of 0.15 ng/mL/cm3 was modelled with competing risk functions. The ability of PSAD, PSA, and base variables (age at biopsy, DRE result, socioeconomic status, 5α‐reductase inhibitor usage, family history, and Charlson Comorbidity Index (CCI)) to predict prostate cancer death was compared using c‐statistics and a likelihood ratio test.

Results

After excluding 10 men without PSA data within 2 years of the biopsy and 65 without prostate volume data, 2276 men were eligible for inclusion in the study. A total of 50 men died from prostate cancer and 1028 from other causes during a median (interquartile range) follow‐up of 17.4 (13.2–20.9) years. The cumulative prostate cancer mortality of men with PSAD <0.15 ng/mL/cm3 was significantly lower than that of men with PSAD ≥0.15 ng/mL/cm3: 0.5% (95% confidence interval [CI] 0.2%–1.1%) vs 2.0% (95% CI 1.2%–3.1%) at 15 years (Grey's test, P = 0.001). The model consisting of PSAD, PSA and the base variables predicted prostate cancer mortality (c‐statistic 0.781) significantly better than either the base variables alone (c‐statistic 0.737; likelihood‐ratio test, P = 0.003) or the base variables and PSA (c‐statistic 0.765; likelihood‐ratio test, P = 0.039).

Conclusion

Prostate cancer mortality after a benign systematic TRUS‐guided biopsy is low. In these patients, PSAD predicts prostate cancer mortality and provides additional value to other clinical variables. PSAD‐based stratification can be used to guide follow‐up strategy.
The eukaryotic elongation factor 2 kinase inhibitor, A484954, induces hypoglycaemic and hypotensive effects
Authors: Kodama Tomoko , Kameshima Satoshi , Otani Kosuke , Okada Muneyoshi , Yamawaki Hideyuki
Published: January 2025

Background and Purpose

Eukaryotic elongation factor 2 kinase (eEF2K) belongs to the Ca2+/calmodulin‐dependent protein kinase family. We previously revealed that A484954, a selective eEF2K inhibitor, caused hypotensive and diuretic effects via the production of nitric oxide (NO) in spontaneously hypertensive rats. Otsuka Long–Evans Tokushima Fatty (OLETF) rats are hypertensive because of obesity and type 2 diabetes. Because an NO synthase inhibitor was reported to increase the expression of sodium glucose co‐transporter 2 (SGLT2), we hypothesised that A484954 causes not only hypotensive but also hypoglycaemic effects via NO production in OLETF rats.

Experimental Approach

To test the hypothesis, we examined the effects of A484954 administration on hyperglycaemia and hypertension in OLETF rats. OLETF rats were given an intraperitoneal injection of A484954 (2.5 mg kg−1 day−1) for 7 days. Then, we measured blood and urinary glucose level, urine output, systolic blood pressure and ventricular contractility. We also conducted Western blotting and isometric tension measurements.

Key Results

A484954 induced a decrease in blood glucose, an increase in urinary glucose excretion, and a decrease in protein expression of kidney SGLT2. In addition, A484954 induced a decrease in systolic blood pressure, an NO‐dependent vasorelaxation, and a diuretic effect. Further, A484954 enhanced left ventricular contractility.

Conclusion and Implications

We, for the first time, revealed that (1) A484954 caused hypoglycaemic effects through increasing urinary glucose excretion via decreasing SGLT2, (2) A484954 improved diabetic complication, including hypertension, through vasorelaxation and diuresis via NO production, and (3) A484954 had a positive inotropic effect.
Treating Hematological Malignancies With OR‐2100, an Orally Bioavailable Prodrug of Decitabine
Authors: Watanabe Tatsuro , Kidoguchi Keisuke , Kimura Shinya
Published: January 2025

DNA methylation is an enzyme‐driven epigenetic modification that must be precisely regulated to maintain cellular homeostasis. Aberrant methylation status, especially hypermethylation of the promoter sites of tumor‐suppressor genes, is observed in human malignancies and is a proven target for cancer therapy. The first‐generation DNA demethylating agents, azacitidine and decitabine, are widely used for treating several hematological malignancies. In addition, orally bioavailable prodrugs of azacitidine and decitabine have recently been approved by the FDA. We have developed a silylated derivative of decitabine, OR‐2100, which is resistant to degradation by cytidine deaminase and orally bioavailable. It has efficacy against several human hematological malignancies in xenograft mouse models with less hematotoxicity than decitabine. Since DNA demethylating agents are combined with molecularly targeted drugs in clinical use and trials, we think that the less hematotoxic profile of OR‐2100 makes it suitable for use as a combination therapy. In this article, we review the therapeutic approach in hematological malignancies with the DNA demethylating agent OR‐2100.
Artificial Intelligence in Detecting and Segmenting Vertical Misfit of Prosthesis in Radiographic Images of Dental Implants: A Cross‐Sectional Analysis
Authors: Fasih Paniz , Yari Amir , Kamali Hakim Lotfollah , Kashe Nader Nasim
Published: January 2025

Objective

This study evaluated ResNet‐50 and U‐Net models for detecting and segmenting vertical misfit in dental implant crowns using periapical radiographic images.

Methods

Periapical radiographs of dental implant crowns were classified by two experts based on the presence of vertical misfit (reference group). The misfit area was manually annotated in images exhibiting vertical misfit. The resulting datasets were utilized to train the ResNet‐50 and U‐Net deep learning models. Then, 70% of the images were allocated for training, while the remaining 30% were used for validation and testing. Five general dentists categorized the testing images as “misfit” or “fit.” Inter‐rater reliability with Cohen's kappa index and performance metrics were calculated. The average performance metrics of dentists and artificial intelligence (AI) were compared using the paired‐samples t test.

Results

A total of 638 radiographs were collected. The kappa values between dentists and AI ranged from 0.93 to 0.98, indicating perfect agreement. The ResNet‐50 model achieved accuracy and precision of 92.7% and 87.5%, respectively, whereas dentists had a mean accuracy of 93.3% and precision of 89.6%. The sensitivity and specificity for AI were 90.3% and 93.8%, respectively, compared to 90.1% and 95.1% for dentists. The Dice coefficient yielded 88.9% for the ResNet‐50 and 89.5% among the dentists. The U‐Net algorithm produced a loss of 0.01 and an accuracy of 0.98. No significant difference was found between the average performance metrics of dentists and AI (p > 0.05).

Conclusion

AI can detect and segment vertical misfit of implant prosthetic crowns in periapical radiographs, comparable to clinician performance.
The Alteration of Brain Network Topology in Tinnitus Transition From Recent‐Onset to Chronic
Authors: Xie Jiapei , Zhang Weidong , Wei Wei , Bai Yan , Shen Yu , Meng Nan , Wang Xinhui , Wang Meiyun
Published: January 2025

The occurrence and persistence of tinnitus result from the interaction of multiple neural networks. This study aims to explore the alterations in brain network topology associated with the transition of tinnitus from recent‐onset to chronic. Twenty‐eight patients with chronic tinnitus, 28 patients with recent‐onset tinnitus and 28 sex‐ and age‐matched healthy controls (HC) were enrolled in this study. We performed a graph theory analysis to identify aberrant brain network topologies and calculated the correlation between differential brain regions and clinical indicators. Compared with the recent‐onset tinnitus group, patients with chronic tinnitus showed decreased global efficiency (Eg, decreased by 3.7%, p < 0.001), local efficiency (Eloc, decreased by 1.8%, p = 0.031) and small‐worldness (decreased by 13.8%, p = 0.007) and increased characteristic path length (Lp, increased by 6.8%, p = 0.001). Additionally, ANOVA revealed significant differences in the AUC of degree centrality (DC), nodal efficiency (Ne), nodal clustering coefficient (NCp) and nodal local efficiency (Nle) among the three groups in brain regions such as the superior temporal gyrus, inferior temporal gyrus, anterior cingulate cortex, precuneus, middle occipital gyrus, inferior occipital gyrus, fusiform gyrus, cuneus and putamen (q < 0.05, FDR corrected). Notably, several of these regions were associated with tinnitus duration, distress and loudness. The topological properties of several brain networks were altered in patients with chronic tinnitus compared to those with recent‐onset tinnitus, providing new insights into the neural mechanisms of tinnitus chronification. These findings could inform the development of targeted interventions aimed at mitigating the progression from recent‐onset to chronic tinnitus.
Yearling laryngeal function grades II.2 and below are not associated with reduced performance
Authors: Hardwick Josephine L. , Ahern Benjamin J. , Crawford Kylie L. , Allen Kate J. , Anderson Brian H. , Rose Kim J. , Franklin Samantha H.
Published: January 2025

Background

The relationship between Thoroughbred yearling laryngeal function (YLF) grade and race performance is unclear.

Objectives

To determine the effect of YLF on future race performance.

Study design

Retrospective cohort study.

Methods

Post‐sale endoscopic recordings were reviewed from Australian yearling sales in 2018–2019. Race performance was evaluated for career and as 2‐, 3‐ and ≥4‐year‐olds. Multivariable generalised linear modelling examined the association between YLF and performance, with risk estimates presented as coefficients (95% CI).

Results

The YLF in 5175 examinations was graded I in 29.8% (n = 1542); II.1 in 49.0% (n = 2537), II.2 in 16.5% (n = 855), III.1 in 3.9% (n = 200), III.2 in 0.8% (n = 39) and III.3 in <0.04% (n = 2). Additional endoscopic abnormalities included ventroaxial luxation of the corniculate process (VLAC, n = 77, 1.5%); arytenoid mucosal lesions (n = 392, 7.6%) and intermittent dorsal displacement of the soft palate (iDDSP, n = 1264, 24.4%). Median (IQR) career earnings were: grade I $45 095 ($15 565, $113 220); grade II.1 $45 315 ($15 915, $107 490), grade II.2 $38 610 ($14 326, $95 218), grade III.1 $32 765 ($8565, $86 030) and grade III.2 $35 810 ($3700, $65 770). There was no difference in career earnings for YLF grades II.2 and III.1, compared with referent grade I/II.1, whereas grade III.2 earned less overall (−$46 015 (95% CI: −$89 994, −$2036), p = 0.04). Earnings in ≥4‐year‐olds were less for grades III.1 (−$35 076 (−$56 129, −$14 024), p = 0.001) and III.2 (−$53 219, (−$76 062, −$30 375) p < 0.001).

Main limitations

Lack of follow‐up data due to retrospective nature of study. Exclusion of unraced horses and those with no prize money from analysis.

Conclusions

Ninety‐five percent of the yearling population had grades I, II.1 or II.2 YLF and minimal difference in race performance was identified between them. Horses with grade III.1 YLF performed similarly to grades I/II.1 in their early careers but had reduced race performance at ≥4‐year‐old.
Fine‐tuned calcium homeostasis is crucial for murine erythropoiesis
Authors: Zhang Shujing , Zhang Yuanzhen , Li Yanxia , Zhang Zhiyue , Li Hui , Xu Miaomiao , Lu Zhiyuan , Li Yuan , Zhao Baobing
Published: January 2025

Intracellular calcium (Ca2+) is a crucial signaling molecule involved in multiple cellular processes. However, the functional role of Ca2+ in terminal erythropoiesis remains unclear. Here, we uncovered the dynamics of intracellular Ca2+ levels during mouse erythroid development. By using the calcium ionophore ionomycin, we found that low Ca2+ levels are required for the expansion of erythroid progenitors, whereas higher Ca2+ levels led to the differentiation and proliferation of early‐stage erythroblasts. Intracellular Ca2+ levels were then gradually reduced, which is required for the nuclear condensation and polarisation at the late stage of erythroid differentiation. However, elevated Ca2+ levels in late‐stage erythroblasts, achieved by using ionomycin, promoted erythroid enucleation via calmodulin (CaM)/calcium/calmodulin‐dependent protein kinase kinase 1 (CaMKK1)/AMPK signaling. These data suggest that the reduction of intracellular Ca2+ plays a double‐edged role at the late stage of erythroid differentiation, which is beneficial for nuclear condensation but compromises terminal enucleation. Our study highlighted the importance of the fine‐tuned regulation of intracellular Ca2+ during terminal erythropoiesis, providing cues for the efficient generation of mature and enucleated erythrocytes in vitro.
Effectiveness of a Strobing Light System for Deflecting Downstream Migrating European Silver Eels (Anguilla anguilla)
Authors: Lenihan Eamonn S. , McCarthy T. Kieran , Lawton Colin
Published: January 2025

Anthropogenic structures, such as dams, delay, injure and kill during downstream migrating silver‐phase Anguillid eels. To enhance spawner escapement from rivers, efforts are being made to develop devices that guide eels towards safe passage routes. We tested the ability of a strobing light array to deflect downstream migrating European silver eels (Anguilla anguilla) by comparing the distribution of eel catches in a series of nets when lights were on (treatment periods) and off (control periods). Deflection efficiency of the light array was 80.6% (95% CL = 74.3%–85.3%), estimated by comparing the proportion of the total biomass captured in nets located immediately downstream of the light array during control and treatment periods. Eels caught during treatment periods (Mean ± S.E.; 452 ± 11 mm) were significantly smaller than those caught during control periods (538 ± 8 mm), which suggested that smaller eels were less capable of avoiding the light array. Future research should determine specifications for operation of strobe light arrays, including effects of light intensity and strobe rate, angle of array deployment, and effects of environmental factors on deflection efficiency.