bluuebunny/crossref_metadata_2025 huggingface dataset:
Ex-vivomouse precision cut tumour slices for modelling hepatocellular carcinoma; A 3Rs solution for at-scale drug screening
Authors: Collins Amy L , Kirkness Keara , Ramon-Gil Erik , Tzortzopoulou Eleni , Geh Daniel , Cameron Rainie , Luli Saimir , Khurram Eman , Storey Daniel , Paish Hannah , McDonald David , Filby Andrew , Borthwick Lee A , Oakley Fiona , Mann Derek , Leslie Jack
Published: September 2024

Disease modelling is vital for improving knowledge of disease mechanisms and for development of new therapeutic molecules and strategies. Modelling the intact living tumour microenvironment (TME) is increasingly considered to be vital not only for gaining a better understanding of the biology of cancer but for examining the efficacy of novel oncology drugs. To date, pre-clinical mouse models of cancer have represented the mainstay methodology for studying the evolving TME and for determining the effects of potential therapeutic molecules on tumour evolution and growth. Regarding drug screening,in vivomouse models are expensive, require the use of large cohorts of mice and involve the administration of drugs with unknown toxicities to animals which often result in adverse effects that can cause animal suffering and the discontinuation of drug investigations. Hepatocellular carcinoma (HCC) is a primary cancer of the liver for which there is an urgent need for improved systemic treatments due to the disease usually being diagnosed at an advanced stage and current treatments having limited efficacy. To provide a practical solution to the screening of drugs for their likely efficacy in HCC we have developed anex-vivomodel in which orthotopic tumours are excised from the liver and subsequently processed to generate precision-cut tumour slices (PCTS) which provide an intact culture model of the HCC-TME. We describe simplified culture conditions that maintain the viability and metabolic activity of live PCTS which maintain the architecture, cellular complexity, drug sensitivity and responsiveness to immunotherapy of the original tumour. Importantly, we show that HCC derived PCTS can be miniaturised to 96-well scale and modified to express soluble luciferase, which in combination enabled non-destructive screening of a library of 26 drugs at two doses using just 5 tumours as the source for PCTS. This screen identified two small molecules, salinomycin and rottlerin, that have potent anti-tumour activities in HCC-PCTS and subsequently validated salinomycin as effectivein vivo. In summary, we report a 3Rs (reduction, refinement and replacement) solution for study of HCC biology and for 96-well-scale screening of potential therapeutic agents in the context of an intact, metabolically active TME.
Engineered Receptors for Soluble Cell-to-Cell Communication
Authors: Piraner Dan I. , Abedi Mohamad H. , Gonzalez Maria J. Duran , Chazin-Gray Adam , Zhu Iowis , Ravindran Pavithran T. , Schlichthaerle Thomas , Huang Buwei , Lee David , Baker David , Roybal Kole T.
Published: September 2024

Despite recent advances in mammalian synthetic biology, there remains a lack of modular synthetic receptors that can robustly respond to soluble ligands and in turn activate cellular functions. Such receptors would have extensive clinical potential to regulate the activity of engineered therapeutic cells, but to date only receptors against cell surface targets have approached clinical translation. To address this gap, we developed a receptor architecture based on synNotch, called SyNthetic Intramembrane Proteolysis Receptor (SNIPR), that has the added ability to be activated by soluble ligands, both natural and synthetic, with remarkably low baseline activity and high fold activation. SNIPRs are able to access an endocytic, pH-dependent cleavage mechanism to achieve soluble ligand sensing, in addition to employing a canonical-like pathway for detecting surface-bound ligands. We demonstrate the therapeutic capabilities of the receptor platform by localizing the activity of CAR T-cells to solid tumors where soluble disease-associated factors are expressed, bypassing the major hurdle of on-target off-tumor toxicity in bystander organs. We further applied the SNIPR platform to engineer fully synthetic signaling networks between cells orthogonal to natural signaling pathways, expanding the scope of synthetic biology. Our design framework enables cellular communication and environmental interactions, extending the capabilities of synthetic cellular networking in clinical and research contexts.
Screening and identification of gene expression in large cohorts of clinical lung cancer samples unveils the major involvement of EZH2 and SOX2
Authors: Niharika  , Roy Ankan , Sadhukhan Ratan , Patra Samir Kumar
Published: September 2024

Lung adenocarcinoma (LUAD), the primary subtype of Non-Small Cell Lung Cancer (NSCLC), accounts for 80% to 85% of cases. Due to suboptimal screening method, LUAD is often detected in late stage, leading to aggressive progression and poor outcomes. Therefore, early disease prognosis for the LUAD is high priority. In order to identify early detection biomarkers, we conducted a meta-analysis of mRNA expression TCGA and GTEx datasets from LUAD patients. A total of 795 differentially expressed genes (DEGs) were identified by exploring the Network-Analyst tool and utilizing combined effect size methods. DEGs refer to genes whose expression levels are significantly different (either higher or lower) compared to their normal baseline expression levels. KEGG pathway enrichment analysis highlighted the TNF signaling pathway as being prominently associated with these DEGs. Subsequently, using the MCODE and CytoHubba plugins in Cytoscape software, we filtered out the top 10 genes. Among these, SOX2 was the only gene exhibiting higher expression, while the others were downregulated. Consequently, our subsequent research focused on SOX2. Further transcription factor-gene network analysis revealed that enhancer of zeste homolog 2 (EZH2) is a significant partner of SOX2, potentially playing a crucial role in euchromatin-heterochromatin dynamics. Structure of SOX2 protein suggest that it is a non-druggable transcription factor, literature survey suggests the same; hence, we drove our focus to investigate on potential drug(s) targeting EZH2. Molecular docking analyses predicted most probable inhibitors of EZH2. We employed several predictive analysis tools and identified GSK343, as a promising inhibitor of EZH2.
A microinjection protocol for the greater waxworm moth,Galleria mellonella
Authors: Pearce James , Housden Amy , Senior Nicola , Champion Olivia , Prior Joann , Titball Richard , Wakefield James
Published: September 2024

A limitation to the non-vertebrate 3Rs modelGalleria mellonellahas been the lack of genetic toolkit. A common requirement for genetic tractability is a method to introduce exogenous material to the unicellular embryo, the most common of which is microinjection. This short article describes a detailed method for rearingGalleria mellonellato collect large amounts of staged embryos and to dechorionate and microinject embryos with limited mortality.

Research Highlights

Scientific Benefits

Microinjection allows the introduction of a wide variety of substances, such as DNA, RNA or drugs intoGalleriaembryos, providing the technology needed for genetic engineering, gene editing and functional studies in this important model organism.

3Rs Benefits

Galleriais being increasingly used as a partial animal replacement model, especially in the field of infection biology. However, uptake has been limited by the lack of genetic and molecular tools. This protocol takes a step towards removing these barriers by providing a means to introduce substances that can create transgenic or genetically engineeredGalleria.

Practical Benefits

Protocol for injecting substances intoGalleria,using for the most part easily accessible equipment.

Current Applications

Generating stable transgenic and gene-editedGallerialines.

Potential Applications

Any technique requiring the introduction of substances toGalleriaembryos. This includes applying existing techniques such as pBac-mediated transgenesis or CRISPR/Cas-based gene-editing to this organism,in order to generate engineered strains ofGalleria. It could also include injection of synthetic mRNAs encoding proteins fused to fluorescent genes (such as GFP) in order to visualise their dynamics in living embryos; and the injection of drugs that perturb particular cell or developmental processes in order to learn more about earlyGalleriadevelopment.
Predictive filtering of sensory response via orbitofrontal top-down input
Authors: Tsukano Hiroaki , Garcia Michellee M. , Dandu Pranathi R. , Kato Hiroyuki K.
Published: September 2024

Habituation is a crucial sensory filtering mechanism whose dysregulation can lead to a continuously intense world in disorders with sensory overload. While habituation is considered to require top-down predictive signaling to suppress irrelevant inputs, the exact brain loci storing the internal predictive model and the circuit mechanisms of sensory filtering remain unclear. We found that daily neural habituation in the primary auditory cortex (A1) was reversed by inactivation of the orbitofrontal cortex (OFC). Top-down projections from the ventrolateral OFC, but not other frontal areas, carried predictive signals that grew with daily sound experience and suppressed A1 via somatostatin-expressing inhibitory neurons. Thus, prediction signals from the OFC cancel out behaviorally irrelevant anticipated stimuli by generating their “negative images” in sensory cortices.
The lysosomal membrane protein LAMP2B mediates microlipophagy to target obesity-related disorders
Authors: Sakai Ryohei , Aizawa Shu , Lee-Okada Hyeon-Cheol , Hase Katsunori , Fujita Hiromi , Kikuchi Hisae , Inoue Yukiko U. , Inoue Takayoshi , Kabuta Chihana , Yokomizo Takehiko , Hashimoto Tadafumi , Wada Keiji , Mano Tatsuo , Koyama-Honda Ikuko , Kabuta Tomohiro
Published: September 2024

Lifestyle diseases, such as obesity, diabetes, and metabolic syndrome, are leading health problems, most of which are related to abnormal lipid metabolism. Lysosomes can degrade lipid droplets (LDs) via microautophagy. Here, we report the molecular mechanism and pathophysiological roles of microlipophagy, regulated by the lysosomal membrane protein LAMP2B. Our study revealed that LAMP2B interacts with phosphatidic acid, facilitating lysosomal-LD interactions and enhancing lipid hydrolysis via microlipophagy depending on endosomal sorting complexes required for transport. Correlative light and electron microscopy demonstrated direct LDs uptake into lysosomes at contact sites. Moreover, LAMP2B overexpression in mice prevents high-fat diet-induced obesity, insulin resistance, and adipose tissue inflammation; liver lipidomics analysis suggested enhanced triacylglycerol hydrolysis. Overall, the findings of this study elucidated the mechanism of microlipophagy, which could be promising for the treatment of obesity and related disorders.
Dual-energy electron storage ring
Authors: Dhital B. , Derbenev Y. S. , Hutton A. , Zhang H. , Krafft G. A. , Zhang Y. , Lin F. , Morozov V. S.
Published: September 2024

A dual-energy electron storage ring is a novel concept initially proposed to cool hadron beams at high energies. The design consists of two closed rings operating at significantly different energies: the low-energy ring and the high-energy ring. These two rings are connected by an energy recovery linac (ERL) that provides the necessary energy difference. The ERL features superconducting radio-frequency (SRF) cavities that first accelerate the beam from the low energy EL to the high energy EH and then decelerate the beam from EH to EL in the next pass. The different SRF cavities in the ERL section can be adjusted based on the applications. In this paper, we present a possible layout of a dual-energy electron storage ring. The preliminary optics of the ring is designed to optimize chromaticity correction, dynamic aperture, momentum aperture, beam lifetime, radiation damping, and intrabeam scattering effects. The primary focus of this paper is on the stability conditions and beam dynamics studies associated with this storage ring.

Published by the American Physical Society
2024
Order and chaos in the
SU(2)
matrix model: Ergodicity and classical phases
Authors: Bhatt Chaitanya , Nenmeli Vijay , Vaidya Sachindeo
Published: September 2024

We study the classical nonlinear dynamics of the SU(2) Yang-Mills matrix model introduced in [] as a low-energy approximation to two-color QCD. Restricting to the spin-0 sector of the model, we unearth an unexpected tetrahedral symmetry, which endows the dynamics with an extraordinarily rich structure. Among other things, we find that the spin-0 sector contains coexisting chaotic subsectors as well as nested chaotic “basins”, and displays alternation between regular and chaotic dynamics as energy is varied. The symmetries also grant us a considerable amount of analytic control which allows us to make several quantitative observations. We see that the classical spin-0 sector has a rich phase structure, arising from ergodicity breaking. Surprisingly, we find that many of these classical phases display numerous similarities to previously discovered phases of the spin-0 sector [], and we explore these similarities in a heuristic fashion.

Published by the American Physical Society
2024
Measurements of extended magnetic fields in laser-solid interaction
Authors: Griff-McMahon J. , Malko S. , Valenzuela-Villaseca V. , Walsh C. A. , Fiksel G. , Rosenberg M. J. , Schaeffer D. B. , Fox W.
Published: September 2024

Magnetic fields generated from a laser-foil interaction are measured with high fidelity using a proton radiography scheme with x-ray fiducials. In contrast to prior findings under similar experimental conditions, this technique reveals the self-generated, Biermann-battery fields extend beyond the edge of the expanding plasma plume to a radius of over 3.5 mm by t=+1.4 ns. An analysis of two monoenergetic proton populations confirms that proton deflection is dominated by magnetic fields far from the interaction (>2 mm) and electric fields are insignificant. The results are not captured in state-of-the-art magnetohydrodynamics simulations and suggest the need to consider additional physics mechanisms for the magnetic field generation and transport in laser-solid interactions.

Published by the American Physical Society
2024
Additional reviews, perceived credibility and consumer online purchasing behavior: a study of university students in China
Authors: Wang Xulong , Bai Xuejiao , Zhao Liming
Published: September 2024

Purpose

This study explores the link between additional reviews, credibility, and consumers’ online purchasing behavior.

Design/methodology/approach

We employ a 2 × 2 between-subjects design to measure subjects’ purchasing behavior with versus without additional reviews and with important versus non-important attributes. A total of 529 valid questionnaires are collected from university students across 30 Chinese provinces.

Findings

The addition of negative reviews to a positive initial review enhances consumers’ perceived credibility of the reviewer and the overall review content. This effect is positively moderated by the attribute importance in additional reviews. Moreover, we find that as the time interval increases, consumers’ perceived credibility gradually increases but eventually decreases after reaching a certain threshold. In addition, the attribute importance in additional reviews negatively moderates the impact of perceived credibility on consumer purchasing behavior.

Originality/value

Existing studies on first and subsequent reviews mainly focus on the difference in perceived usefulness between the two. They do not examine how additional reviews affect potential customers’ perceived credibility and their purchase decision-making. This study bridges the gap between the word-of-mouth literature and marketing practices.
Paymob: transforming digital payments in Egypt and the region for a cashless society
Authors: Ismail Ayman , Ghalwash Seham , Ballesteros-Sola Maria , Dahawy Ahmed
Published: September 2024

Learning outcomes

After completion of the case study, the students will be able to analyze the FinTech industry in emerging markets, distinguish the growth strategies for startups in the hyper-growth phase, using the Ansoff matrix, evaluate and select geographical markets for expansion (foreign country selection) and understand the liability of foreignness concept.

Case overview/synopsis

In 2015, Islam Shawky, Alain Al-Hajj and Mostafa Menessy founded Paymob in Egypt, a FinTech start-up providing technological and financial solutions to consumers and merchants in the country. The company had grown into one of Egypt’s most prominent digital payment providers by deploying infrastructure and technologies that empower the underserved with access to financial services. In 2021, Paymob had gained a lot of support from venture capital investors that ended with closing the largest in Egypt Series A fund of $18.5m led by Dubai-based venture capital firm Global Ventures. Although Paymob had already reached great success in Egypt, the founders’ vision was to become the regional leader of digital payments, focusing on small and medium-sized enterprises. So, they are considering regional markets similar to Egypt’s, such as the Kingdom of Saudi Arabia, a call with a lot of structure but a lot of competition, and Pakistan, a market with much less competition but relatively unstructured. The founders found themselves in early 2022 deciding between these two markets in preparation for the next round of Series B $50m funding.

Complexity academic level

This case study can be useful for courses in executive education.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 3: Entrepreneurship.
Enhancing new service development effectiveness: the role of customer participation and the moderating effects of empowerment and satisfaction
Authors: Kamali Mehran , Zarea Hadi , Parackal Mathew , Su Zhan
Published: September 2024

Purpose

The purpose of this paper is to investigate the role of Customer Participation (CP) in the effectiveness of New Service Development (NSD) by examining the moderating roles of Customer Empowerment (CE) and Customer Satisfaction (CS). The research reduces the risk of failure of the NSD process and/or improves the NSD processes used by companies through the consideration of the results in the practical dimension.

Design/methodology/approach

This study investigates the effects of CP at different stages of NSD using a quantitative approach. Data were collected through an online survey questionnaire. Smart PLS was used to analyse the data collected from 509 newsreaders and users of the news agency’s application.

Findings

The model confirmed that CE has an impact on the effectiveness of NSD in the idea generation and commercialization stages, but not in the development stage. Empowerment and customer satisfaction did not influence the three stages of NSD indirectly but directly. The results show that CP, CS and CE do not always have a direct or indirect effect on the development of new services. Therefore, in order to design new service development projects, media news companies need to determine the level of user cooperation.

Research limitations/implications

The lack of objective data, especially on company performance, forces researchers to use questionnaires to analyse NSD effectiveness. Another limitation is that newspaper users answered the questionnaires, which creates “common method variance.”

Practical implications

Researchers on NSD effectiveness must use questionnaires due to a lack of objective data, especially on company performance. Another limitation is “common method variance” from newspaper users answering questionnaires.

Originality/value

This paper is a response to a perceived need for an examination of how new service development can be successful and effective.
When and how it is good for fashion to look typical: visual prototypicality affecting product valuation and brand preference
Authors: Lee Eun-Jung
Published: September 2024

Purpose

Although visual prototypicality in fashion is an observed phenomenon, empirical examinations of the link between fashion products' design prototypicality and consumer evaluations still need to be included. The present study analyzes the influence of the visual prototypicality of fashion products on consumer-perceived product values and brand preference.

Design/methodology/approach

An online survey adopting the fashion product images with significantly differing levels of visual prototypicality was used to collect data from 456 US consumers. The hypothesized relationships among visual prototypicality, product values and brand preference were analyzed through multi-group analysis.

Findings

Perceived visual typicality of fashion product designs significantly increased the hedonic and utilitarian value of the product and only indirectly increase brand preference. The hypothesized positive relationship between visual prototypicality and the product’s social value was found to be significant only in the low-price levels but became insignificant in the high-price levels.

Originality/value

The findings of this study contribute to the extant literature by first providing an initial analysis of the mechanism of visual prototypicality in the fashion product design field. The results confirm that visual prototypicality indirectly influences consumers' brand evaluations by the product’s perceived value. This relationship was previously assumed but not empirically proven only in non-fashion product categories. The study also presents additional new points, further enriching the understanding of visual typicality. Additionally, the results show the complex relationship between the visual prototypicality of fashion product designs and the perceived social value of the product, which varies depending on the price range.
Dynamic game research of food agricultural products supply chain based on blockchain traceability technology
Authors: Ma Junhai , Fan Jie , Zhu Meihong , Chen Jiecai
Published: September 2024

Purpose

Food quality and safety issues have always been imperative topics discussed by people. The anti-tampering of blockchain technology and the transparency of information make it possible to improve food traceability and safety quality. How to effectively apply blockchain traceability technology to food safety has great research significance for improving food safety and consumer quality trust.

Design/methodology/approach

The paper aims to analyze the differences in product quality levels and market participants’ profits before and after the use of blockchain-driven traceability technology in the food agricultural product supply chain (SC) in the dynamic game frameworks of supplier-led and retailer-led modes, respectively, and explores the willingness, social welfare and consumer surplus of each member of the agricultural product SC to participate in the blockchain. Besides, We investigate the SC performance improvement with the mechanism of central centralized decision-making and revenue-sharing contract, compared to the SC performance in dynamic games.

Findings

The results are obtained as follow: The adoption of blockchain traceability technology can help improve the quality of food agricultural products, consumer surplus and social welfare, but the application and popularization of technology is hindered by traceability technology installment costs. Compared with the supplier leadership model, retailer-led food quality level, customer surplus and social welfare are higher.

Research limitations/implications

How to effectively apply blockchain traceability technology to food safety has great research significance for improving food safety and consumer quality trust.

Practical implications

Food quality and safety issues have always been hot topics discussed by people. The anti-tampering of blockchain technology and the transparency of information make it possible to improve food traceability and safety quality.

Social implications

The research results enrich the theories related to food safety and quality, and provide a valuable reference for food enterprises involved in the decision-making exploration of blockchain technology.

Originality/value

Based on the characteristics of blockchain technology, the demand function is adjusted and the product loss risk of channel members is transferred through a Stackelberg game SC composed of agricultural products suppliers and retailers.

Highlights:

•

We introduce two features of blockchain: quality trust and product information tracking.

•

The willingness of each member of the supply chain to use blockchain for product traceability was explored.

•

The overall traceability effect of the retailer-led blockchain is better than that of the manufacturer-led blockchain.

•

The cost of blockchain technology is a barrier to its adoption.

•

Blockchain brings higher consumer surplus and social welfare.
Compassion, value creation and digital learning orientation in social entrepreneurs
Authors: Satar Mir Shahid
Published: September 2024

Purpose

Social value creation (SVC) is the primary emphasis for unifying the various issues in contemporary social entrepreneurship (SE) literature and practice since it highlights the fundamental problem of sustainability in SE business. Accordingly, SVC as an outcome of SE represents the primary drive of social entrepreneurs (SEs). However, SEs encounter multi-dimensional challenges as they work to build their SE businesses and create social value. In the current context of digitally transforming entrepreneurship scenario, this study investigates the role of SE compassion and digital learning orientation (DLO) for SVC ability of SEs.

Design/methodology/approach

The study utilized a quantitative survey approach for primary data collection from social entrepreneurs in Saudi Arabia. A total of 158 valid replies from social entrepreneurs were obtained for the study. Using SmartPLS (3.0), partial least square structural equation modeling was used to analyze the data.

Findings

The results validated a model of SVC in which the SE compassion and DLO positively impact the SVC ability in SEs. However, the impact of DLO in moderating the SE compassion - SVC relationship in SEs was not proven.

Practical implications

The study established the role of SE compassion in explaining the distinctive SVC ability in SEs. Meanwhile, given the expanding necessity for SEs to leverage digital technologies for SE missions, the study provides implications for nurturing positive outcomes in terms of SE compassion and DLO outcomes among SEs. This organized knowledge can help entrepreneurs, educators and policymakers better incorporate these concerns in SE education, and social enterprises and entrepreneurs’ developmental initiatives.

Originality/value

This work is pioneering in that it conceptualizes and tests a theoretical framework that links SE compassion, DLO, and SVC in SEs. Meanwhile, the study is the first to operationalize the DLO in entrepreneurs. The study thus generates fresh insights about SVC in SE amid the digitally transforming entrepreneurship scenario.
Do uncertain outcomes matter for ticket prices? Examination of the National Football League's secondary ticket market
Authors: Lee Yo Han , Sung Yoon Tae , Jung Hoyoon
Published: September 2024

Purpose

This study examines the impact of outcome uncertainty on the National Football League (NFL) secondary ticket market prices. As a demand-driven market, it is essential to comprehend how resellers respond to outcome uncertainty, one of the consumer demand factors in sports.

Design/methodology/approach

Using real-time ticket prices and money lines as a proxy of the probabilities of winning, this study employs a regression analysis and examines 33,554 price observations from the NFL’s secondary ticket market partner, StubHub.

Findings

The result shows a positive relationship between outcome uncertainty and secondary market ticket prices, indicating that resellers adjust the prices in response to the level of outcome uncertainty and put more value on games with greater uncertainty. This finding confirms the demand-driven nature of the secondary ticket market, as outcome uncertainty is one of the demand factors in sports.

Originality/value

This study links the uncertainty of outcome hypothesis with secondary ticket market pricing and fills a gap in the literature by providing an important perspective on games with uncertainty in the secondary ticket market. Outcome uncertainty has limited understanding in relation to secondary ticket market pricing despite its relationship with consumer demand. The positive relationship between outcome uncertainty and the ticket prices, grounded in real-time price data and win probability from sport betting markets, enhances our understanding of price determinations in the secondary ticket market.
Seasonal acclimation of photosynthetic thermal tolerances in six woody tropical species along a thermal gradient
Authors: Kullberg Alyssa T. , Feeley Kenneth J.
Published: September 2024

Extreme heat events are becoming increasingly common, and the short‐term acclimation of photosynthesis will have a large impact on plant performance. Trees in lowland tropical forests, which are hypothesized to have limited abilities to tolerate rising temperatures, may need to rely on short‐term acclimation of their more plastic traits, like photosynthetic thermal tolerance, to persist in the face of increasingly variable climates.

Here, we investigated seasonal acclimation of thermal tolerances in plant species of the moist Amazon. Specifically, we measured the photosynthetic thermal tolerances of six common woody Amazonian species at the beginning and at the end of the dry season to determine the species' abilities to acclimate to intra‐annual changes to climate. In addition, we used the natural thermal gradient present at our research site to test the acclimation of individual plants to maximum air temperatures not currently observed elsewhere in the moist lowland Amazon (up to ~43°C).

Between seasons, there were significant overall increases in the thermal tolerances of three species (i.e. higher thermal tolerances in the hotter dry season), suggesting that leaf megathermy is prominent in these species. Also, three species acclimated their thermal tolerances to microsite‐level differences in seasonal temperature maxima, suggesting closer fidelity between leaf and air temperatures (i.e. limited homeothermy) for these species.

Our results show that some woody species from the moist Amazon can acclimate their thermal tolerances over short time‐scales, although acclimation is likely insufficient to overcome thermal stress during extreme temperature events. Some species may therefore be more sensitive to heatwaves than others, which could impact survival and composition of tropical lowland forests into the future.

Read the free Plain Language Summary for this article on the Journal blog.
Age truncation due to disease shrinks metapopulation viability for amphibians
Authors: Heard Geoffrey W. , Scroggie Michael P. , Hollanders Matthijs , Scheele Ben C.
Published: September 2024

Metapopulations often exist in a fragile balance between local extinctions and (re)colonisations, in which case emerging threats that alter species vital rates may drastically increase metapopulation extinction risk.

We combined empirical data with metapopulation simulations to examine how demographic shifts associated with amphibian chytrid fungus (Batrachochytrium dendrobatidis, Bd) have altered metapopulation viability for threatened amphibians in Australia.

Comparing the ages of museum specimens collected before Bd emerged in Australia with individuals from geographically matched remnant populations revealed significant truncation of age structures post‐Bd, with a halving of annual adult survival probabilities.

Spatially realistic metapopulation modelling demonstrated that reduced adult survival led to major reductions in the parameter space over which persistence was possible for the focal species, with contractions to landscapes with higher landscape connectivity, lower environmental stochasticity and considerably higher recruitment rates.

Metapopulation persistence post‐Bd required greater landscape connectivity than pre‐Bd. This arises from a landscape‐level analogue of compensatory recruitment at the population level, in which higher (re)colonisation rates can offset more frequent local extinctions, enabling persistence of amphibians susceptible to Bd.

Interactions between recruitment rate, environmental stochasticity and landscape connectivity were also more important for metapopulation persistence post‐Bd. Higher recruitment was required to mitigate the impacts of environmental stochasticity, and higher landscape connectivity was required to mitigate the impacts of environmental stochasticity and poor recruitment. Increased reliance on these interdependencies shrunk the parameter space over which metapopulations could persist post‐Bd.

Our study demonstrates that emerging threats that alter species vital rates can drastically reduce the capacity of certain environments to support metapopulations. For our focal species, reductions in adult survival rates due to Bd produced major reductions in the conditions under which persistence was possible, providing a mechanistic insight into the processes underpinning observed range and niche contractions of amphibians impacted by this pathogen.

More broadly, our study illustrates how environmentally mediated host resilience can enable persistence following the emergence of novel pathogens. This pathway to persistence is worthy of greater attention on both conceptual and applied grounds.
A Comparative Analysis of International Drug Price Negotiation Frameworks: An Interview Study of Key Stakeholders
Authors: SYVERSEN ISELIN DAHLEN , SCHULMAN KEVIN , KESSELHEIM AARON S. , FELDMAN WILLIAM B.
Published: September 2024

Policy Points

Health care systems around the world rely on a range of methods to ensure the affordability of prescription drugs, including negotiating prices soon after drug approval and relying on formal clinical assessments that compare newly approved therapies with existing alternatives.

The negotiation framework established under the Inflation Reduction Act is far more limited than other frameworks explored in this study. Adding elements from these frameworks could lead to more effective price negotiation in the United States.

Context

In 2022, Congress passed the Inflation Reduction Act, which allowed Medicare, for the first time, to begin negotiating the prices for certain high‐cost brand‐name prescription drugs. Many other industrialized countries negotiate drug prices, and we sought to compare and contrast key features of the negotiation process across several health systems. We focused, in particular, on the criteria for selecting drugs for price negotiation, procedures for negotiation, factors that influence negotiated prices, and how prices are implemented.

Methods

We included four G7 countries in our analysis (Canada, France, Germany, and the United Kingdom [England]), two Benelux countries (Belgium and the Netherlands), and one Scandinavian country (Norway) with long‐established frameworks for drug price negotiation. We also analyzed the Veterans Affairs Health System in the United States. For each system, we gathered relevant legislation, government publications, and guidelines to understand negotiation frameworks, and we reached out to key drug price negotiators in each system to conduct semistructured interviews. All interviews were recorded, transcribed, and coded, and data were analyzed based on an internal assessment tool that we developed.

Findings

All eight systems negotiate the prices of brand‐name prescription drugs soon after approval and rely on formal clinical assessments that compare newly approved drugs with existing therapies. Systems in our study differed on characteristics such as whether the body performing clinical assessments is separate from the negotiating authority, how added health benefit is assessed, whether explicit willingness‐to‐pay thresholds are employed, and how specific approaches for priority disease areas are taken.

Conclusions

High‐income countries around the world adopt different approaches to conducting price negotiations on brand‐name drugs but coalesce around a set of practices that will largely be absent from the current Medicare negotiation framework. US policymakers might consider adding some of these characteristics in the future to improve negotiation outcomes.
Fingerprint localisation for fine‐scale wildlife tracking using automated radio telemetry
Authors: Tyson Chris , Fragueira Rita , Sansano‐Sansano Emilio , Yu Hui , Naguib Marc
Published: September 2024

Automated radio telemetry systems are one of the most widely applicable methods for tracking wildlife at fine spatiotemporal scales. A growing trend is for these systems to apply large networks of receivers to detect radio signal strength (RSS) from radio‐tagged individuals. Analytical methods to derive position estimates using RSS localisation, however, are relatively underdeveloped in the field of wildlife tracking. Here, we apply approaches from indoor positioning systems to develop a new method, radio fingerprinting, for localising radio‐tagged animals in structurally complex, outdoor environments. This method characterises the RSS patterns at known locations to generate a radio map of the study area, which is then used to predict the location of new RSS patterns.

We conducted field tests to evaluate the localisation accuracy of radio fingerprinting relative to multilateration, a commonly used method for RSS localisation. To do so, we established an experimental receiver network covering multiple habitat types and compared the localisation accuracy of radio fingerprinting to multilateration. Additionally, we evaluated how a variety of features characteristic of typical tracking data sets affected the accuracy of both methods.

While both methods had a similar median error under ideal conditions (~30 m), radio fingerprint localisation method offered several advantages over multilateration. Multilateration localisation estimates were highly affected by missed detections from the nearest receiver to the test point, which occurred in 30% of cases. In these cases, the median error was 103 m, over a 3.5‐fold increase. Distance to the nearest receiver also biased multilateration estimates with error increasing as the distance increased. Additionally, errors from multilateration estimates were higher in more densely vegetated areas. In contrast, fingerprinting position estimates were largely robust to each of these scenarios.

Automated radio telemetry enables the fine‐scale, continuous tracking of range‐resident animals. We present radio fingerprinting as a localisation method in outdoor environments where standard localisation methods are error‐prone due to habitat heterogeneity and missed detections. This approach can be applied to any automated radio telemetry hardware and to any study system where a radio map can be generated.
Spatio‐temporal occupancy models with INLA
Authors: Belmont Jafet , Martino Sara , Illian Janine , Rue Håvard
Published: September 2024

Modern methods for quantifying, predicting and mapping species distributions have played a crucial part in biodiversity conservation. Occupancy models have become a popular choice for analysing species occurrence data due to their ability to separate out the observational error induced by imperfect detection of a species, and the sources of bias affecting the occupancy process. However, the spatial and temporal variation in occupancy that is not accounted for by environmental covariates is often ignored or modelled through simple spatial structures as the computational costs of fitting explicit spatio‐temporal models is too high. In this work, we demonstrate how Integrated Nested Laplace Approximation (INLA) may be used to fit complex spatio‐temporal occupancy models and how the R‐INLA package can provide a user‐friendly interface to make such complex models available to users.

We show how occupancy models, provided some simplification on the detection process is assumed, can be framed as latent Gaussian models and, as such, benefit from the powerful INLA framework. A large selection of complex modelling features, and random effect models, including spatio‐temporal models, have already been implemented in R‐INLA. These also become available for occupancy models, providing the user with an efficient, reliable and flexible toolbox.

We illustrate how INLA provides a flexible and computationally efficient framework for developing and fitting complex occupancy models using two complex case studies. Through these, we show how different spatio‐temporal models that include spatial‐varying trends, smooth terms and spatio‐temporal random effects can be fitted to aggregated detection/non‐detection data. At the cost of limiting the complexity of the detection model structure, INLA can incorporate a range of rather complex structures in the ecological process of interest and hence, extend the functionality of occupancy models.

The limitations of occupancy models in terms of scalability for large spatio‐temporal data sets remain a challenge and an active area of research. INLA‐based occupancy models provide an alternative inferential and computational framework to fit complex spatio‐temporal occupancy models. The need for new and more flexible computationally efficient approaches to fit such models makes INLA an attractive option for addressing complex ecological problems, and a promising area of research.
An ultraviolet light data logger for studies of organismal ecology and physiology
Authors: Lattanzio Matthew S.
Published: September 2024

Monitoring environmental conditions over time is essential for understanding how species regulate those conditions to satisfy their physiological needs. Variation in ultraviolet (UV) light exposure, for instance, is crucial for numerous taxa, influencing behaviour as well as essential physiological processes like vitamin D3 synthesis. Yet, despite these considerations, no commercially available data loggers exist to record UV exposures over time, preventing inquiry into this important but neglected fitness demand.

To overcome this challenge, I designed the first UV data logger, custom built on the open‐source Arduino platform. This device logs UV exposures (in voltage or converted to UV index) and date‐time information for each UV reading, at user‐defined intervals. The integration of a low‐power timer into the assembly, and its weather‐resistant housing, enables long‐term use (at least several months). The cost of one device (including housing) is under £45/$55 USD.

Calibration and performance tests reveal that this device is reliable under various weather conditions and produces accurate UV readings under both artificial lighting and sunlight. Both the device and its customised housing can be easily replicated and expanded upon (e.g. inclusion of additional sensors).

Overall, this device represents a crucial first step in our ability to better characterise UV exposure patterns in habitats for physiological ecology studies. Exposure to UV light is adaptive for many types of organisms, both in the wild and in captivity (e.g. zoos and private hobbyists), and so I expect a broad array of scientific and public users alike to benefit from using this device.
CASIN exerts anti‐aging effects through RPL4 on the skin of naturally aging mice
Authors: Zhang Yijia , Wang Xueer , Huang Jianyuan , Zhang Xinyue , Bu Lingwei , Zhang Yarui , Liang Fengting , Wu Shenhua , Zhang Min , Zhang Lu , Zhang Lin
Published: September 2024

Skin aging has been associated with the onset of various skin issues, and recent studies have identified an increase in Cdc42 activity in naturally aging mice. While previous literature has suggested that CASIN, a specific inhibitor of Cdc42 activity, may possess anti‐aging properties, its specific effects on the epidermis and dermis, as well as the underlying mechanisms in naturally aging mice, remain unclear. Our study revealed that CASIN demonstrated the ability to increase epidermal and dermal thickness, enhance dermal‐epidermal junction, and stimulate collagen and elastic fiber synthesis in 9‐, 15‐, and 24‐month‐old C57BL/6 mice in vivo. Moreover, CASIN was found to enhance the proliferation, differentiation, and colony formation and restore the cytoskeletal morphology of primary keratinocytes in naturally aging skin in vitro. Furthermore, the anti‐aging properties of CASIN on primary fibroblasts in aging mice were mediated by the ribosomal protein RPL4 using proteomic sequencing, influencing collagen synthesis and cytoskeletal morphology both in vitro and in vivo. Meanwhile, both subcutaneous injection and topical application exhibited anti‐aging effects for a duration of 21 days. Additionally, CASIN exhibited anti‐inflammatory properties, while reduced expression of RPL4 was associated with increased inflammation in the skin of naturally aging mice. Taken together, our results unveil a novel function of RPL4 in skin aging, providing a foundational basis for future investigations into ribosomal proteins. And CASIN shows promise as a potential anti‐aging agent for naturally aging mouse skin, suggesting potential applications in the field.
Optimizing β‐lactam‐containing antibiotic combination therapy for the treatment of Buruli ulcer
Authors: D'Agate Salvatore , Velickovic Peter , García‐Barrios Noelia , Ramón‐García Santiago , Della Pasqua Oscar
Published: September 2024

Aims

The current treatment for Buruli ulcer is based on empirical evidence of efficacy. However, there is an opportunity for shortening its duration and improving response rates. Evolving understanding of the pharmacokinetic–pharmacodynamic relationships provides the basis for a stronger dose rationale for antibiotics. In conjunction with modelling and simulation, it is possible to identify dosing regimens with the highest probability of target attainment (PTA). This investigation aims to: (i) assess the dose rationale for a new combination therapy including amoxicillin/clavulanic acid (AMX/CLV) currently in clinical trials; and (ii) compare its performance with alternative dosing regimens including rifampicin, clarithromycin and AMX/CLV.

Methods

In vitro estimates of the minimum inhibitory (MIC) concentration were selected as a measure of the antibacterial activity of different drug combinations. Clinical trial simulations were used to characterize the concentration vs. time profiles of rifampicin, clarithromycin and amoxicillin in a virtual cohort of adult and paediatric patients, considering the effect of baseline covariates on disposition parameters and interindividual variability in exposure. The PTA of each regimen was then assessed using different thresholds of the time above MIC.

Results

A weight‐banded dosing regimen including 150–600 mg rifampicin once daily, 250–1000 mg clarithromycin and AMX/CLV 22.5 mg/kg /1000 mg twice daily ensures higher PTA than the standard of care with AMX/CLV 45 mg/kg/2000 mg once daily.

Conclusion

The higher PTA values support the proposed 4‐drug combination (rifampicin, clarithromycin, AMX/CLV) currently under clinical investigation. Our findings also suggest that higher rifampicin doses might contribute to enhanced treatment efficacy.