bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Images to Assess Awareness and Use of Emerging Nicotine Pouch Products
Authors: Bover Manderski Michelle T , Delnevo Cristine D , Hrywna Mary
Published: January 2025

Introduction

Accurate measurement is critical for understanding the population health impact of nicotine pouches, yet precise, standardized measures of nicotine pouch use are lacking, possibly driving disparate prevalence estimates across studies. We implemented a split sample survey experiment to assess the impact of including a product image when asking about nicotine pouches.

Methods

We randomized an online sample of US adults ages 18–45 (N = 2130) recruited through the February 2023 wave of the Rutgers Omnibus Study to view either a text-only or text-plus-image description of oral nicotine pouches before being asked about awareness of the products. Participants who endorsed awareness were then asked about their use and the brands they had tried. We calculated the prevalence of awareness, ever, and current use of nicotine pouches and used chi-square tests to assess differences in responses to each question by survey condition.

Results

Participants in the image condition were more likely than those in the text condition to report awareness (40.6% vs 31.5%, p < .001) and ever use (7.2% vs 5.2%, p = .044). Among those reporting nicotine pouch use, 5.9% in the text-only condition, compared to 0% in the image condition, listed a smokeless tobacco brand as one they tried, suggesting they were misclassified by the text-only question.

Conclusion

Inclusion of product imagery can improve nicotine pouch measurement accuracy in surveys, while text-only measures may misestimate the prevalence of awareness and use. Differences in nicotine pouch prevalence estimates may be explained in part by differences in survey measures, highlighting a need to harmonize measures across studies.

Implications

In this first study to evaluate nicotine pouch measurement methods, findings suggest that existing surveillance and research efforts may be undermined by misclassification. Text-only measures of nicotine pouch awareness and use may produce biased prevalence estimates, and inclusion of product imagery can improve nicotine pouch measurement accuracy in surveys.
Unreliable emotions and ethical knowledge
Authors: Hutton James
Published: January 2025

How is ethical knowledge possible? One promising answer is Moral Empiricism: we can acquire ethical knowledge through emotional experiences. But Moral Empiricism faces a serious problem. Our emotions are unreliable guides to ethics, frequently failing to fit the ethical status of their objects, so the habit of basing ethical beliefs on one's emotions seems too unreliable to yield knowledge. I develop a new, virtue-epistemic solution to this problem, with practical implications for how we approach ethical decision-making. By exploiting a frequently overlooked connection between reliability and defeaters, I argue that an agent can have a reliable belief-forming habit despite having unreliable emotions. The upshot is that emotion-based ethical knowledge is possible even for people whose emotions are unreliable, but only if we cultivate the skill of noticing and responding to signs that a given emotion is unfitting.
Emotional priming for sustainable consumption? The effects of social media content on the valuation of chocolate
Authors: von Grafenstein Liza , Iweala Sarah , Pahl Stefan , Ruml Anette
Published: January 2025

Current consumption patterns in the Global North are unsustainable across environmental, social, and economic dimensions. To promote more sustainable consumer behavior, emotional priming on social media has become an increasingly popular tool. In this paper, we mimic social media content to test the effectiveness of emotional priming in incentivizing sustainable consumption. Specifically, we examine whether emotionally primed information about sustainability aspects in cocoa production increases consumers’ valuation for sustainably produced products in the short and medium term. To achieve this, we conducted an online panel survey of 2,161 German consumers with random assignment to one of four different treatments (unprimed information or information with emotional prime) designed as social media posts (videos). We differentiate between environmental sustainability and social responsibility, and separate the products into sustainability certification, uncertified claims, and conventional chocolate. We find statistically significant positive effects of the emotional primes on consumers’ willingness-to-pay (WTP) for products with sustainability certifications and noncertified sustainability claims in the short term. These effects can be attributed to negative emotions triggered by the primes. Two weeks after the treatments, the WTP decreases for all groups. The difference in WTP between the primed and unprimed groups diminishes in the medium term. Primed participants value sustainability certifications and claims less than those who received unprimed information.
Interacting Anomalies
Authors: Müller Karsten , Schmickler Simon N M
Published: January 2025

An extensive literature studies interactions of stock market anomalies using double-sorted portfolios. But given hundreds of known candidate anomalies, examining selected interactions is subject to a data mining critique. In this paper, we conduct a comprehensive analysis of all possible double-sorted portfolios constructed from 102 underlying anomalies. We find hundreds of statistically significant anomaly interactions, even after accounting for multiple hypothesis testing. An out-of-sample trading strategy that invests in the top backward-looking double-sort strategy generates equal-weighted (value-weighted) monthly average returns of 4% (2.7%) at an annualized Sharpe ratio of 2 (1.38), on par with state-of-the-art anomaly-based machine learning strategies.
The Fed and the Secular Decline in Interest Rates
Authors: Hillenbrand Sebastian
Published: January 2025

This paper documents a striking fact: a narrow window around Fed meetings captures the entire secular decline in U.S. Treasury yields. Yield movements outside this window are transitory and wash out over time. This is surprising because the forces behind the secular decline are thought to be independent of monetary policy. Long-term bond yields decline when the Fed cuts the short rate and when the Fed lowers its long-run forecast of the federal funds rate (the “dot plot”). These results are consistent with the view that Fed announcements provide guidance about the long-run path of interest rates.
Optimization of Bonner sphere spectrometer design applying Bayesian approach
Authors: Nguyen Ngoc-Quynh , Kurosawa Tadahiro , Le Ngoc-Thiem
Published: January 2025

The design of Bonner Sphere Spectrometer (BSS) was optimized using Bayesian approach for two different measurement purposes in the ISO 8529 neutron standard field of 241Am-Be source as follows: (i) for the best estimation of neutron fluence spectrum and (ii) for the best estimation of neutron ambient dose equivalent, H*(10). As results, two optimal sets of BSS system (with sequential specific diameters) were proposed: (i) for the first problem, an optimal BSS system with a maximum of six different diameters is needed to obtain neutron fluence spectrum with the standard uncertainties in each energy bin as low as reasonably achievable and (ii) for the second problem, if one would just like to achieve the output H*(10) with a standard uncertainty <10%, only two optimal BSS measurements are needed.
Interpersonal Brain Synchronization in Social Pain Contexts: An fNIRS-Based Exploration of Empathy
Authors: Lian Tao , Jiao Zhibin , Song Juan , Zhang Peng
Published: January 2025

Social pain is a common occurrence in interpersonal interactions, yet limited research has explored the neural mechanisms underlying both social pain and social pain empathy. Existing studies often focus on the neural processes of individuals experiencing pain, referred to as “subjects,” or those empathizing with them, known as “observers.” This study examines the neural mechanisms involved in the process of social pain empathy from the perspective of interpersonal brain synchronization (IBS). To do so, we employed functional near-infrared spectroscopy (fNIRS) to simultaneously scan the brains of both subjects and observers in social pain scenarios created using the Cyberball paradigm. The study’s findings indicate that in social pain contexts, the IBS among dyads composed of subjects and observers was significantly enhanced in the dorsolateral prefrontal cortex (dlPFC) compared to non-social pain contexts. This brain region is associated with emotion regulation. Furthermore, we found that this enhancement depended on the observers’ levels of rejection sensitivity. This study provides the inaugural exploration into the neural mechanisms underlying social pain empathy through the lens of IBS.
Gendered wealth and the challenges of child support in India
Authors: Garnaik Upasana
Published: January 2025

In this paper, I examine the challenges in the legal processes of securing child support in India. Drawing from a qualitative study of family disputes—including ethnographic observations in courts, mediation centers, and legal offices, as well as in-depth interviews and archival research, I reveal how gendered institutional practices shape child support negotiations, often to the detriment of women. I make three significant contributions. First, while much research has focused on judicial decision making in family law disputes, I turn my attention to mediation, a growing method of dispute resolution, to show how this private ordering of family law often places women in financially precarious positions. Second, building on the concept of relational work, I show how mediators perform institutional gendered relational work and persuasive relational work in their roles as facilitators and reinforce inequality by reproducing gendered expectations and constructing notions of parenthood. Third, I demonstrate how women’s privileged class status does not necessarily guarantee favorable outcomes. Instead, gendered institutional dynamics intersect with systemic failure to perpetuate the gendered wealth gap, pushing women into debt, economic dependence, and financial insecurity. By analyzing these processes, this paper underscores how legal processes create persistent barriers to economic equality contributing to the gendered wealth gap and provides critical insights into the economic conditions of separated and divorced women.
The intergenerational reproduction of self-direction at work: Revisiting Class and Conformity
Authors: Burger Kaspar , Mele Francesca , Johnson Monica Kirkpatrick , Mortimer Jeylan , Han Xiaowen
Published: January 2025

In his path-breaking monograph, Class and Conformity, Melvin Kohn reasoned that parents prepare their children for the same conditions of work that they themselves experience. Kohn and his colleagues’ research focused on the influence of parental self-direction at work on parental child-rearing values and practices, as well as the self-directed values of children. The intergenerational transmission of occupational self-direction from parents to the succeeding generation of adult children, strongly implied by Kohn’s analysis, has not been empirically tested. Using two-generation longitudinal data from the Youth Development Study (N = 1139), we estimate a structural equation model to assess the intergenerational continuity of occupational self-direction. We find evidence supporting a key inference of Kohn’s analysis: that self-direction at work, a primary feature of jobs of higher social class standing, is transmitted across generations via self-directed psychological orientations, operationalized here as intrinsic work values. Intrinsic values also significantly predicted second-generation educational attainment, contributing further to the reproduction of socioeconomic inequality. The findings enhance understanding of the intergenerational transmission of advantage.
Adult Human Heart ECM Improves Human iPSC-CM Function via Mitochondrial and Metabolic Maturation
Authors: Gulberk Ozcebe S , Tristan Mateo , Zorlutuna Pinar
Published: January 2025

Myocardial infarction can lead to the loss of billions of cardiomyocytes, and while cell-based therapies are an option, immature nature of in vitro-generated human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) is a roadblock to their development. Existing iPSC differentiation protocols don’t go beyond producing fetal iCMs.

Recently, adult extracellular matrix (ECM) was shown to retain tissue memory and have some success driving tissue-specific differentiation in unspecified cells in various organ systems. Therefore, we focused on investigating the effect of adult human heart-derived ECM on iPSC cardiac differentiation and subsequent maturation. By preconditioning iPSCs with ECM, we tested whether creating cardiac environments around iPSCs would drive iPSCs toward cardiac fate and which ECM components might be involved.

We report novel high- and low- abundance proteomes of young, adult, and aged human hearts, with relative abundances to total proteins and each other. We found that adult ECM had extracellular galactin-1, fibronectin, fibrillins, and perlecan (HSPG2) which are implicated in normal heart development. We also showed preconditioning iPSCs with adult cardiac ECM resulted in enhanced cardiac differentiation, yielding iCMs with higher functional maturity, more developed mitochondrial network and coverage, enhanced metabolic maturity, and shift towards more energetic profile.

These findings demonstrate the potential use of cardiac ECM in iCM maturation and as a promising strategy for developing iCM-based therapies, disease modeling, and drug screening studies. Upon manipulating ECM, we concluded that the beneficial effects observed were not solely due to the ECM proteins, which might be related to the decorative units attached.
Policy in practice: Cystic Fibrosis Australia and Phage Australia surveys: understanding clinical needs and attitudes towards phage therapy in the cystic fibrosis community
Authors: Lynch Stephanie , Sinclair Holly , Khatami Ameneh , Mileham Nicki , Sacher Jessica C , Zheng Jan , Lin Ruby C Y , Iredell Jonathan
Published: January 2025

Cystic fibrosis (CF) is the most prevalent serious inherited disease in Australia, imposing significant health risks. CF is characterized by chronic lung inflammation and recurrent pulmonary infections that increase morbidity and premature mortality rates. The emergence of antimicrobial resistance (AMR) places further challenges on the treatment and management of CF, necessitating research into alternative strategies for treatment of bacterial infections. Bacteriophage therapy, involving bacterial-specific viruses, is a potential avenue for AMR infections in patients with CF. Existing literature supports the feasibility of phage therapy in CF but there has been a gap in investigating attitudes of the CF community including affected individuals and their caregivers, regarding phage therapy. Understanding perspectives and needs of the CF community is essential for successful implementation and acceptance of novel therapies including phage therapy. We conducted a survey that encompasses responses from 112 consumers from across Australia, comprising people living with CF (38.4%), parents of affected children (49.6%), carers (6.4%), and family members (3%). The findings showed a significant reliance on antibiotics with 51.4% requiring oral, 43.4% nebulized, and 11.4% intravenous antibiotics within the preceding 2 weeks. Respondents highlighted the availability of new treatments, duration of hospitalizations and costs associated with treatment as important priorities to address. Despite an awareness of phage therapy among 62.4% of respondents, 86.4% expressed interest in obtaining more information, primarily from medical staff (66.7%). Notably, 96.0% of respondents expressed willingness to participate in phage therapy trials. The results of this survey highlighted the CF community’s strong interest in advanced therapeutic approaches, specifically phage therapy. The findings reveal a notable recognition and acceptance of phage therapy as a viable treatment option for pulmonary infections associated with CF. This study addresses UN Sustainable Development Goal 3: Good Health and Wellbeing by advancing knowledge on alternative therapeutic strategies for managing AMR in CF. By exploring community attitudes towards bacteriophage therapy, the research promotes informed development and implementation of innovative, targeted treatments for CF-associated infections. These findings support the sustainable management of AMR, fostering better health outcomes and reducing reliance on traditional antibiotics, thereby contributing to long-term health resilience.
An arginine switch drives the stepwise activation of β-arrestin
Authors: Ji Jeong Seok , Yun Yaejin , Stepniewski Tomasz Maciej , Yoon Hye-Jin , Min Kyungjin , Park Ji Young , Chung Chiwoon , Chung Ka Young , Selent Jana , Lee Hyung Ho
Published: January 2025

β-arrestins (βarrs) play a crucial role in regulating G protein-coupled
receptor (GPCR) signaling and trafficking. Canonically, interactions of βarr
with the phosphorylated intracellular GPCR-tail induce a multi-step
conformational transition that results in the activation of βarr. Depending on
the specific interaction pattern with the receptor, βarrs adopt multiple
conformational states, each tightly linked to a specific functional outcome of
βarr recruitment. Despite its physiological relevance, the structural
determinants of βarr activation remain poorly understood. Using a combination of
molecular dynamics simulations, biochemical and cell-based experiments, we
reveal how specific interactions with a prototypical GPCR promote the unbinding
of the βarr2 C-tail—a crucial step in arrestin activation. Importantly, we
observe that the expulsion of the C-tail is promoted by the displacement of a
conserved arginine residue (Arg394) within the βarr polar core, which we dub
“the arginine switch.” Our study uncovers a previously unknown molecular switch
that, upon engagement, destabilizes the polar core as a crucial step in the
GPCR-induced βarr activation.
Melchior: A Hybrid Mamba-Transformer RNA Basecaller
Authors: Litman Elon
Published: January 2025

Abstract

Sequence transduction from raw nanopore signals is notoriously difficult because the signal level does not naturally correspond to a single base, but rather many adjacent nucleotides. Thus, we introduce Melchior, an RNA basecaller that uses a hybrid Mamba-Transformer backbone to achieve global visual context at a lower computational complexity. This is in contrast to temporal convolutions, which collate features by fusing both spatial and channel features in the local receptive field. Melchior is also able to exploit the full complementarity between local and global features, unlike Vision Transformers, which have empirically been observed to ignore local features. Augmenting a selective structured state-space sequence model with self-attention unlocks unprecedented performance gains, particularly in homopolymer regions, by modeling fine-grained details in both short and long-range spatial dependencies.
A Fine-tuned ProtGPT2 (transformer model) for Predicting more Virulent
SARS-CoV-2 variants and understanding its virulence by biophysical
methods
Authors: Dhamodharan Sam Paul , Jeyaraj Abraham Rebairo , Siddalingappa Rashmi , Venkatachalam Rajakannan , Kothandan Gugan
Published: January 2025

The emergence of Variants of Concern (VOCs) of SARS-COV2 with increased
virulence and transmissibility has been linked to multiple mutations in the RBD
region, altering their antigenic properties. In this study, we used a
specialized ProtGPT2 model trained on the SARS-COV2 spike protein to forecast
probable mutations on the spike protein that have not yet emerged. Upon
prediction, we systematically studied the stability of single-site and multisite
mutations using unbiased molecular dynamics simulations. Binding free energies
were used to study the physicochemical significance of the mutations and their
affinity to human ACE2 receptor. Our results show that there are specific
hot-spots that mutate in the spike protein that enhance binding affinity through
electrostatic and improved non-bonded interactions and highlight the role of
specific energetic contributions in viral adaptation and infectivity. Our
analysis revealed that the reduction of a disulphide bridge within sites 480-488
lowered the binding free energy and increased the flexibility of the loop
region, enhancing its interface interaction with ACE, leading to a more virulent
variant than Omicron.
Folic acid-containing supplement use among females aged 15-55 in the Canadian Community Health Survey 2015-2018
Authors: Hopperton Kathryn , Loukine Lidia , Luong The Minh , Nguyen Loan , Bertinato Jesse , Bonvalot Yvette , Cooper Marcia , Luo Wei , MacFarlane Amanda J , McCrea Jennifer , Nicholson Carley , Rana Huma , Vercammen Kelsey , Yuan Jane , Brule Shawn , Weiler Hope A
Published: January 2025

Introduction: In Canada, those who are or who could become pregnant are recommended to consume a daily multivitamin containing 400 mcg of folic acid to help prevent neural tube defects. Objectives: To report the prevalence and determinants of folic acid-containing supplement use among females of childbearing age in Canada. Methods: Data were combined from cycles 2015/16 and 2017/18 of the maternal experiences module of the cross-sectional Canadian Community Health Survey, which was completed by females aged 15-55 years. Representative weighted estimates (means/percentages, 95% CI) were generated for folic acid-containing supplement use among all pregnant, non-pregnant, and lactating respondents. For those who had given birth in the preceding 5 years, estimates were also generated for supplement use in the 3 months before and first 3 months of their most recent pregnancy, and pre-pregnancy awareness of the link between folic acid and some birth defects. We examined associations with sociodemographic factors using multivariable logistic regression. Results: Overall, 16.5% (15.9-17.0%) of non-pregnant, 80.3% (77.1-83.5%) of pregnant, and 58.4% (54.8-61.9%) of lactating females aged 15-55 reported using a folic acid-containing supplement. Among those who had given birth in the preceding 5 years, 63.7% (62.2-65.1%) consumed a folic acid-containing supplement in the 3 months prior to pregnancy, while 89.9% (88.8-90.9%) did so during the first trimester. Lower prevalence of supplement use before or during pregnancy was reported among the 23.7% (22.4-25.1%) of respondents unaware of the relationship between folic acid and birth defects. Younger age, single marital status, lower educational attainment, income below the median, and smoking were associated with lower odds of awareness or supplement use. Conclusion: While most females living in Canada reported using folic-acid containing supplements prior to and during pregnancy, use of these supplements among non-pregnant females of childbearing age is low, and sociodemographic inequalities exist.
Three annotated chromosome-levelde novogenome assemblies ofLomentospora prolificansprovide evidence for a chromosomal translocation event
Authors: Grossman Nina T , Fan Yunfan , Zimin Aleksey V. , Wear Maggie P. , Jedlicka Anne , Dziedzic Amanda , Liporagi-Lopes Livia , Timp Winston , Casadevall Arturo
Published: January 2025

Lomentospora prolificansis a fungal pathogen responsible for serious, often fatal, illness in patients with compromised immune systems. Treatment is rarely successful becauseL. prolificansis inherently resistant to all major classes of antifungal drugs. In this study we publish three chromosome-levelde novogenome assemblies, including the first complete-level assembly ofL. prolificans, along with genome annotations. The L. prolificans genome is packaged in 11 nuclear chromosomes and one mitochondrial chromosome, has 36.7-37.1 Mb, and encodes for a putative 7357-7640 genes. The length and composition of contigs in one stain varied from those of the other two strains, supporting the hypothesis that a chromosomal translocation took place. These assemblies were confirmed with pulsed-field gel electrophoresis. The availability of more complete genomes will hopefully help the search for new antifungal drugs and provides insights into the evolutionary history of this pathogenic fungus.
Hybrid zone analysis using coalescent-based estimates of introgression and migration
Authors: Leaché Adam D. , Davis Hayden R. , Singhal Sonal
Published: January 2025

Hybrid zones can serve as natural experiments allowing us to investigate the evolutionary consequences of introgression between distinct populations with divergent genomic backgrounds. Modeling hybrid zones using a coalescent framework can provide critical insights into the historical demography of populations, including population divergence times, population sizes, introgression proportions, migration rates, and the timing of hybrid zone formation. We used coalescent analyses to test whether a hybrid zone between Plateau Fence Lizard (Sceloporus tristichus) populations in Arizona formed recently because of human-induced landscape alterations or originated during Pleistocene climatic shifts. Introgression analysis places the divergence time between the parental populations at approximately 140 kya and their secondary contact and hybridization at approximately 10 kya at the end of the Pleistocene. Introgression proportions for hybrid populations are correlated with their geographic distance from the parental populations, a pattern that is repeated with admixture proportions and hybrid index values. The multispecies coalescent with migration model supports asymmetric migration rates with a bias for gene flow moving towards the northern end of the hybrid zone. The direction of this asymmetry is consistent with spatial cline analyses that suggest a slow but steady northward shift of the center of the hybrid zone. When analyzing hybrid populations sampled along a linear transect, coalescent methods can provide novel insights into the evolutionary history of hybrid zone formation that complement existing spatial and genomic methods.
SqueezeCall: Nanopore basecalling using a Squeezeformer network
Authors: Zhu Zhongxu
Published: January 2025

Nanopore sequencing, a novel third-generation sequencing technique, offers significant advantages over other sequencing approaches, owing especially to its capabilities for direct RNA sequencing, real-time analysis, and long-read length. During nanopore sequencing, the sequencer measures changes in electrical current that occur as each nucleotide passes through the nanopores. A basecaller identifies the base sequences according to the raw current measurements. However, due to variations in DNA and RNA molecules, noise from the sequencing process, and limitations in existing methodology, accurate basecalling remains a challenge. In this paper, we introduce SqueezeCall, a novel approach that uses an end-to-end Squeezeformer-based model for accurate nanopore basecalling. In SqueezeCall, convolution layers are used to down sample raw signals and to model local dependencies. A Squeezeformer network is employed to capture the global context. Finally, a connectionist temporal classification (CTC) decoder generates the DNA sequence by a beam search algorithm. Inspired by the Wav2vec2.0 model, we masked a proportion of the time steps of the convolution outputs before feeding them to the Squeezeformer network and replaced them with a trained feature vector shared between all masked time steps. Experimental results demonstrate that this method enhances our model’s ability to resist noise and allows for improved basecalling accuracy. We trained SqueezeCall using a combination of three types of loss: CTC-CRF loss, intermediate CTC-CRF loss, and KL loss. Ablation experiments show that all three types of loss contribute to basecalling accuracy. Experiments on multiple species further demonstrate the potential of the Squeezeformer-based model to improve basecalling accuracy and its superiority over a recurrent neural network (RNN)-based model and Transformer-based models.
End-to-end prediction of clinical outcomes in head and neck squamous cell carcinoma with foundation model-based multiple instance learning
Authors: Rabasco Meneghetti Asier , Ligero Hernández Marta , Kuehn Jens-Peter , Löck Steffen , Itzel Carrero Zunamys , Perez-Lopez Raquel , Bressem Keno , Brinker Titus K. , Pearson Alexander T. , Truhn Daniel , Nebelung Sven , Kather Jakob Nikolas
Published: January 2025

Background

Foundation models (FMs) show promise in medical AI by learning flexible features from large datasets, potentially surpassing handcrafted radiomics. Outcome prediction of head and neck squamous cell carcinomas (HNSCC) with FMs using routine imaging remains unexplored.

Purpose

To evaluate end-to-end FM-based multiple instance learning (MIL) for 2-year overall survival (OS), locoregional control (LRC), and freedom from distant metastasis (FFDM) prediction and risk group stratification using pretreatment CT scans in HNSCC.

Materials and Methods

We analyzed data of 2485 patients from three retrospective HNSCC cohorts (RADCURE, HN1, HN-PET-CT), treated between 2004 and 2017 with available pre-treatment CTs and primary gross tumor volume (GTVp) segmentations. The RADCURE cohort was split into training (n=1464) and test (N=606), with HN1 (n=131) and HN-PET-CT (n=284) as additional test cohorts. FM-based MIL models (2D, multiview and 3D) for 2-year endpoint prediction and risk stratification wre evaluated based on area under the receiver operator curve (AUROC) and Kaplan-Meier (KM) with hazard ratios (HR), compared with radiomics and assessed for multimodal enhancement with clinical baselines.

Results

2D MIL models achieved 2-year test AUROCs of 0.75-0.84 (OS), 0.66-0.75 (LRC) and 0.71-0.78 (FFDM), outperforming multiview and 3D MIL (AUROCs: 0.50-0.77, p≥0.15) and comparable or superior to radiomics (AUROCs: 0.64-0.74, p≥0.012). Significant stratification was observed (HRs: 2.14-4.77, p≤0.039). Multimodal enhancement of 2-year OS/FFDM (AUROCs: 0.82-0.87, p≤0.018) was observed for patients without human papilloma virus positive (HPV+) tumors.

Conclusion

FM-based MIL demonstrates promise in HNSCC risk prediction, showing similar or superior performance to radiomics and enhancing clinical baselines in non-HPV+ patients.

Key Results

First end-to-end study using both foundation models and multiple instance learning for outcome prediction in head and neck squamous cell carcinoma.

Multiple instance learning approaches predict clinically-relevant 2-year endpoints and stratify patients across external cohorts with similar or better performance than handcrafted radiomics.

Multimodal inclusion of clinical and multiple instance learning information improve clinical baseline models in patients without human papillomavirus positive tumors.
Factors influencing the prescription of first-line treatment for type 2 diabetes mellitus: a systematic review
Authors: Moreira Helena , Moreira Fernando , Jesus Ângelo , Monteiro-Soares Matilde , Santos Paulo
Published: January 2025

Introduction

Understanding and predicting prescription preferences for type 2 diabetes mellitus, a heterogeneous and complex condition that affects over 10% of the global adult population, can improve prescribing practices, guide policymakers in promoting evidence-based medicine, and help tailor first-line treatments to individual characteristics or specific subgroups, improving patient outcomes. This study aimed to identify factors influencing metformin prescription, the first-line therapy recommended in Western guidelines, and to assess factors leading to its avoidance and their alignment with evidence-based medicine. It also explores factors associated with initial combination therapy, a newer and controversial approach compared to stepwise therapy.

Methods

We performed a systematic search in PubMed, Scopus and Web of Science for observational analytical studies evaluating factors associated with metformin or combination therapy initiation. Quality assessment was done using the Joanna Briggs Institute critical appraisal checklists. (PROSPERO registry numberCRD42023438313).

Results

Thirty studies were included, evaluating 105 variables, mostly (62%) assessed in one study. The 25 variables using combination therapy as outcome were mostly (72%) evaluated also in one study. Initial metformin prescription was strongly associated with the age of individuals with diabetes, glycated haemoglobin levels, body mass index, and renal complications, while combination therapy was mainly linked with glycated haemoglobin levels and comorbidities. Findings also highlighted a discrepancy between clinical practice and evidence-based recommendations. However, concerns were raised regarding both the internal and external validity of the included studies.

Conclusion

Our systematic review, that offers insights into real-world clinical practices, indicated that there is a misalignment between clinical practices and evidence-based recommendations supporting the need for interventions of this field.
Wastewater-integrated pathogen surveillance dashboards enable real-time, transparent, and interpretable public health risk assessment and dissemination
Authors: Msomi Nosihle S. , Levy Joshua I. , Matteson Nathaniel L. , Ndlovu Nkosenhle , Ntuli Phindile , Baer Adam , Mabasa Victor , Gwala Sipho , Singh Natasha , Subramoney Kathleen , Phalane Emmanuel , Macheke Mokgaetji , Motloung Mantshali , Mangena Thabo , Monametsi Lethabo , Rabotapi Lebohang , Maposa Sibonginkosi , Birmingham Amanda , Zeller Mark , Karthikeyan Smruthi , Harris Simon , Knight Rob , Laurent Louise C. , Andersen Kristian G. , McCarthy Kerrigan , Yousif Mukhlid
Published: January 2025

Timely pathogen surveillance and reporting is essential for effective public health guidance. Web dashboards have become a key tool for communicating public health information to stakeholders, health care workers, and the broader community. Over the SARS-CoV-2 pandemic, wastewater surveillance has increasingly been incorporated into public health workflows for outbreak monitoring and response, enabling community-representative and low-cost monitoring to supplement clinical surveillance. However, the methods used for visualization and dissemination of clinical and wastewater surveillance data differ across programs and best practices are yet to be defined. In this work, we demonstrate data workflows and dashboards used to perform wastewater-based public health surveillance in tandem with clinical data across local and national scales, leveraging custom-built, reproducible, and open-source software. Using a centralized data aggregation and analysis hub approach, we establish multiple data pipelines for data storage, wrangling, and standardized analyses, and deploy custom-built web dashboards that allow for immediate public release. We find that our approach is effective across scales, computing architectures, and dissemination strategies, and provides an adaptable model to incorporate additional pathogens and epidemiological data.
Physical confinement regulates transition in nematode motility
Authors: Dey Saheli , Sreepadmanabh M , Kundu Sayan , Arun Ashitha B , Koushika Sandhya P , Thutupalli Shashi , Hewitt Duncan , Bhattacharjee Tapomoy
Published: January 2025

How do worms navigate their complex natural surroundings? Undulatory microswimmers such as nematodes typically inhabit environments such as soil, vegetable matter, and host tissues. While the natural habitats of nematodes are often three-dimensional granular niches with spatiotemporally varying visco-elasto-plastic material properties that impose physical constraints on their motion, current knowledge about nematode motility patterns broadly comes from investigating model organisms such asCaenorhabditis eleganseither inside liquid cultures or the surface of soft agar pads. How nematodes move through 3D granular niches across different degrees of physical confinement remains poorly understood due to a lack of optically transparent 3D granular matrices. We bridge this gap by engineering an optically transparent granular matrix to directly visualise and quantitatively analyse nematode motion. Importantly, nematodes can freely move through this matrix by generating a minimal yield stress; once the nematode moves away, the matrix self-heals to ensure the material properties remain invariant. Using these platforms, we observe that the propulsive speed of nematodes shows a non-monotonic relation with the yield stress of their microenvironment. This non-monotonicity emerges as nematodes optimize for efficient navigation at higher yield stress, wherein, their forward propulsive speed matches the wave speed along their body. This regulation of locomotory behaviour is purely dictated by the physical interaction of the nematode with its environment without involving soft-touch sensory neurons. Remarkably, predictions from a slender body theory of undulatory motion exactly capture the scaling behaviour for both efficiency and mode of motion as obtained from the experimental data. Finally, in a phase space described by non-dimensional propulsive efficiency and a non-dimensional time scale of motility, we capture a gait transition from poorly efficient thrashing under low confinement to more efficient crawling under high confinement. Thus, our work establishes a new regulatory paradigm describing how distinct modes of undulatory motion emerge under different degrees of physical confinement.
A cyanobacterial screening platform for Rubisco mutant variants
Authors: Hoffmann Ute A. , Schuppe Anna Z. , Knave Axel , Sporre Emil , Brismar Hjalmar , Englund Elias , Syrén Per-Olof , Hudson Elton P.
Published: January 2025

Rubisco is the main entry point of inorganic carbon into the biosphere and a central player in the global carbon system. Its relatively low catalytic constant as well as its tendency to also accept O2as a substrate have made it a common target of enzyme engineering. We have developed an enzyme engineering and screening platform for Rubisco using the model cyanobacteriumSynechocystissp. PCC 6803. Starting with the Form II Rubisco fromGallionella,we first show that the enzyme can replace the native Form I Rubisco inSynechocystisand that growth rates become sensitive to CO2and O2levels. We address the challenge of designing a zero-shot input library, without prior experimental knowledge, by coupling the phylogenetically-guided model EVmutation with “in silicoevolution”. Starting with this targeted mutagenesis library, we used competitive growth coupled to deep sequencing to compare the properties of Rubisco protein variants under different cultivation conditions. We identified an amino acid exchange which increased the thermostability ofGallionellaRubisco and conveyed resilience to detrimental exchanges. The establishment of this platform is a first step towards high-throughput screening of Rubisco variants inSynechocystisand creating optimized enzyme variants to accelerate the Calvin-Benson-Bassham cycle in cyanobacteria and possibly chloroplasts.
Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer
Authors: Villarreal Oscar E. , Xu Yixin , Tran Ha , Machado Annette , Prescod Dionne , Anderson Amanda , Minelli Rosalba , Peoples Mike , Martinez Alejandro Hernandez , Lee Hey Min , Wong Chi Wut , Fowlkes Natalie , Kanikarla Preeti , Sorokin Alexey , Alshenaifi Jumanah , Coker Olu , Lin Kangyu , Bristow Chris , Viale Andrea , Shen John Paul , Parseghian Christine , Marszalek Joseph R. , Corcoran Ryan , Kopetz Scott
Published: January 2025

MAPK pathway inhibitors (MAPKi) are increasingly used in the treatment of advanced colorectal cancer, but often produce short-lived responses in patients. Although acquired resistance byde novomutations in tumors have been found to reduce response in some patients, additional mechanisms underlying the limited response durability of MAPK targeting therapy remain unknown. Here, we denote new contributory tumor biology and provide insight on the impact of tumor plasticity on therapy response. Analysis of MAPKi treated patients revealed activation of stemness programs and increased ASCL2 expression, which are associated with poor outcomes. Greater ASCL2 with MAPKi treatment was also seen in patient-derived CRC models, independent of driver mutations. We find ASCL2 denotes a distinct cell population, arising from phenotypic plasticity, with a proliferative, stem-like phenotype, and decreased sensitivity to MAPKi therapy, which were named adaptive plasticity tumor (APT) cells. MAPK pathway suppression induces the APT phenotype in cells, resulting in APT cell enrichment in tumors and limiting therapy response in preclinical and clinical data. APT cell depletion improved MAPKi treatment efficacy and extended MAPKi response durability in mice. These findings uncover a cellular program that mitigates the impact of MAPKi therapies and highlights the importance of addressing tumor plasticity to improve clinical outcomes.
Optimized protocols for commonly-used murine models of heart failure with preserved ejection fraction
Authors: McIntosh Bailey , Elbassioni Ali Mohamed , Raheem Anmar , McDonald Eilidh , Nicklin Stuart A. , Koay Yen Chin , Cameron Ewan R. , Loughrey Christopher M. , O’Sullivan John F.
Published: January 2025

Background

HFpEF is a leading cause of death worldwide and clinically relevant preclinical models are required to identify new therapeutic targets. The most clinically representative murine models of heart failure with preserved ejection fraction (HFpEF) in common use include a “2-hit” model combining metabolic stress with hypertension (high-fat diet [HFD] + N(gamma)-nitro-L-arginine methyl ester [L-NAME]) and a “3-hit” model that includes age as an additional “hit” (age + HFD + deoxycorticosterone pivalate [DOCP]). However, both models have reproducibility challenges, and sub-strain and sex dependency. Here we optimize both preclinical models to overcome these challenges.

Methods

In this study we optimized both models: (1) The 2-hit model was optimised to reproduce HFpEF (defined as the induction and maintenance of obesity, hypertension, diastolic dysfunction, left ventricular hypertrophy, lung congestion, and exercise intolerance) in both C57BL/6N and 6J mice using increasing L-NAME doses (0.5 g/L to 1.75 g/L) and protocol lengths (7 weeks to 13 weeks); and (2) The 3-hit model used 12-week-old C57BL/6N and 6J mice and two aging protocols were compared: HFD for 7 months, or healthy chow for 5 months then high fat diet for 7 months. After HFD, mice received an intraperitoneal injection of DOCP to induce hypertensionviasodium retention. To enhance and prolong the effect of DOCP, mice received 1% NaCl drinking water at the time of injection until sacrifice, henceforth called “4-hit”. To ensure the phenotype was maintained, a second bolus of DOCP was administered 8 weeks after the first.

Results

For the 2-hit protocol, HFpEF was successfully induced in C57BL/6J mice when exposed to a 13-week L-NAME protocol with gradually increasing dosage from 1.0 g/L to 1.75 g/L. C57BL/6N mice showed the desired parameters after 7-weeks of 0.5 g/L L-NAME, which were not augmented by increased dosage or time administered. For the 4-hit mice, after addition of 1% NaCl drinking water following DOCP administration, a clear HFpEF phenotype was observed in C57BL/6N and 6J mice in both male and females, and maintained for up to 12 weeks.

Conclusions

Our modifications ensure the 2-hit model is equally effective in both commonly used J and N substrains of C57BL/6 mice. Our 4-hit model overcomes the challenges of the 3-hit model, enhances reproducibility and robustness, which we demonstrate across sexes and substrains. Both of these new protocols will enhance clinically relevant mechanistic studies on HFpEF.
Winter rye root growth and plasticity in response to nitrogen and phosphorus omission under field conditions
Authors: Nyameasem John Kormla , Seidel Sabine J. , Hadir Sofia , Lopez Gina , Bauke Sara L. , Hernandez-Ochoa Ixchel M.
Published: January 2025

Nitrogen (N) and phosphorus (P) deficiencies can significantly reduce crop yield. Despite their importance, the impacts of N and P deficiencies under field conditions on cereal roots, particularly winter rye, remain poorly understood. This study investigates the effects of N and P deficiencies on winter rye growth and root architecture under field conditions. A sampling campaign was conducted during the 2022 season at the long-term fertilizer experiment Dikopshof, Germany. Four fertilizer treatments were chosen: (1) fully fertilized with manure (NPKCa+m+s), (2) fully fertilized without manure (NPKCa), (3) N omitted (_PKCa), and (4) P omitted (N_KCa). Shoot biomass was assessed at five growth stages, alongside with topsoil root biomass, number of nodal roots and tillers, and root angle. The results showed that shoot and root biomass were highest in the NPKCa+m+s treatment and lowest under N omission. Although the treatment ranking of root traits varied between dates, a trend for an enhanced number of roots in the N and P omission treatments was observed around flowering. P omission fostered an increased number of tillers and N omission caused steeper root angles compared to other treatments. These findings demonstrate the strong impact of the environment and development stage on root phenotypic plasticity.
Transcriptome mining reveals diversity and evolution of iflaviruses in Lepidoptera
Authors: van Valkengoed Devin , Bryon Astrid , Ros Vera I.D. , Kupczok Anne
Published: January 2025

Insects are associated with a wide variety of diverse RNA viruses, including iflaviruses, a group of positive stranded RNA viruses that mainly infect arthropods. Whereas some iflaviruses cause severe diseases in insects, numerous iflaviruses that were detected in healthy populations of butterflies and moths (order: Lepidoptera) do not show apparent symptoms. Compared to other hosts, only few iflavirus genomes for lepidopteran hosts could be found in publicly available databases and we know little about the occurence of iflaviruses in natural and laboratory lepidopteran populations. To expand the known diversity of iflaviruses in Lepidoptera, we developed a pipeline that automatically reconstructs complete virus genomes from public transcriptome data, yielding 1,548 complete virus genomes from 55 different lepidopteran species. To include incompletely assembled genomes, we developed a reference-based patching approach, resulting in 240 patched genomes. By including publicly available genomes, we inferred a phylogeny consisting of 139 non-redundant iflavirus genomes. Of these, 65 represent novel complete genomes, of which 39 might even belong to novel virus species. Our analysis expanded virus host range, where highly similar viruses were found in the transcriptomes of different lepidopteran species, genera or even families. Additionally, we find two groups of lepidopteran species depending on the diversity of viruses that infect them: some species were only infected by closely related viruses, whereas other species are infected by highly diverse viruses from different regions of the phylogeny. Finally, we show that the evolution of one virus species,Iflavirus betaspexiguae, is impacted by recombination within the species, which is also supported by the co-occurrence of multiple strains within data sets. Our analysis demonstrates how data mining of publicly available sequencing data can be used at a large scale to reconstruct intra-family viral diversity which serves as a basis to study virus host range and evolution. Our results contain numerous novel viruses and novel virus-host associations, including viruses for relevant insect pests, highlighting the impact of iflaviruses in insect ecology and as potential biological control agents in the future.