bluuebunny/crossref_metadata_2025 huggingface dataset:
Supporting trade negotiations with sustainable development impact assessments
Authors: Rolland Sonia E
Published: December 2024

Concerns regarding equitable design of the trade governance system call for complex answers. One element of this reflection is to better assess the potential impacts of prospective trade commitments. Over the past three decades, models used to estimate potential gains from trade have overstated the gains and have failed to adequately account for the costs such as loss of tariff revenue, loss of market access, administrative costs, opportunity costs of directing government resources to trade administration, and more. This essay argues that a comprehensive approach to estimating the impacts of trade disciplines, particularly with respect to social and sustainability issues, could improve the outcomes of trade negotiations as well as the implementation of agreed-upon disciplines, particularly for developing countries. Specifically, sustainable development impact assessments could help developing countries build capacity and identify their policy needs ahead of trade negotiations as well as inform the course of negotiations. Once benefits and costs are better assessed, negotiations could focus on the allocation of these developmental and implementation impacts, particularly for the lowest-income and most capacity-constrained countries.
Tailored management strategies for IgA nephropathy based on clinical presentations
Authors: Praga Manuel , Caravaca-Fontán Fernando , Da Silva Iara , Fernández-Juárez Gema , Gutiérrez Eduardo , Sevillano Angel M , Trimarchi Hernan
Published: December 2024

The treatment landscape for IgA nephropathy (IgAN) is rapidly evolving with the introduction of novel therapies targeting diverse disease pathways. Some have already been approved in different countries, while others are under investigation in randomized controlled trials (RCTs) with encouraging results. However, almost all performed RCTs have included only patients with refractory non-nephrotic proteinuria and preserved renal function. Other clinical presentations (rapidly progressive forms, malignant hypertension, thrombotic microangiopathy, nephrotic syndrome) have received less attention and are systematically excluded from RCTs. On the other hand, certain aspects, such as the impact of hematuria or the management in special populations (e.g. pregnant patients or transplant recipients), remain underexplored. This review proposes therapeutic algorithms to guide treatment decisions in different clinical scenarios, while highlighting gaps in current research.
The Epigraphic Culture of the Greek Cities in the Roman East
Authors: Chaniotis Angelos
Published: December 2024

In this chapter, four significant aspects of the ‘epigraphic culture’ in the cities of the Roman East are discussed: innovation (the new factors that shaped the production of inscriptions and new types of inscriptions), diversity (the heterogeneous social background of the ‘producers’ of epigraphic texts), monumentalization (the presentation of literary and philosophical texts in stone inscriptions), and sophistication (the use of sophisticated rhetorical and visual media, in order to attract the attention of readers and viewers and arouse emotions). Similar phenomena are known before the Imperial period, but only sporadically. The common denominator of the main types of inscriptions in the cities of the Roman East is commemoration: the ability of inscriptions to give durability to ephemeral experiences.
Security, Military Culture, and Public Order
Authors: Fuhrmann Christopher J.
Published: December 2024

This chapter discusses the personnel who maintained security in Greek cities under Roman rule, focusing on the early Imperial period. The council and magistrates exercised their jurisdictions with enough autonomy to address routine criminality. Many Greek cities had specialized police officials; of special note are the eirenarchs and paraphylakes who patrolled the rural territory around their city. The impact of the emperor and of Roman governors is each considered in turn, with attention to pre-Imperial periods (Classical, Hellenistic, Republican) and the problem of corruption throughout. The reign of Augustus emerges as a significant turning point in Greek history, because of the imperial system he developed and its effect on Rome’s efforts to maintain public order among its Greek subjects. Finally, Roman soldiers acting as police in the Greek provinces were a significant factor in many areas. Surprisingly, Roman rule and the growth of military policing did not impede civic policing.
Indigenous Archaeologists and Cultural Heritage Professionals: Perceptions and Experiences from Australia and Aotearoa (New Zealand)
Authors: Poelina-Hunter Emily , Rika-Heke Margaret , Willika Jasmine , Pollard Kellie , Kaotea Des , Roberts Zac
Published: December 2024

Indigenous archaeologists and cultural heritage professionals live in two worlds—as practitioners of a deeply colonial discipline and as Indigenous persons who have been brought up with Indigenous values and beliefs, as well as with responsibilities to their communities. This article explores the journeys that have been undertaken by Indigenous people who are archaeologists and/or cultural heritage professionals from Australia and Aotearoa (New Zealand). Using Indigenous standpoint theory, the coauthors share honest reflections from their lived experiences as university students through to becoming working professionals.
Magnetic Resonance Spectroscopic Imaging of Brain Plasticity
Authors: Li Yao , Li Yudu , Liang Zhi-Pei
Published: December 2024

This chapter provides an overview of magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging (MRSI) and their applications in the study of brain plasticity, with a focus on key metabolic biomarkers related to neuroplasticity and recent technological advances. The fundamental principles of MRS and MRSI and their capabilities for estimating brain metabolites are first described, followed by a review of the progress of MRSI as a neuroimaging tool. MRS/MRSI studies of neuroplasticity in the developing brain, in brain injury, and in the context of neuromodulation are also discussed. The chapter concludes by pointing to recent advances in ultrafast, high-resolution whole-brain MRSI, which are expected to provide further insights into the molecular foundations of brain plasticity in future research.
Integrating bioinformatics and machine learning to unravel shared mechanisms and biomarkers in chronic obstructive pulmonary disease and type 2 diabetes
Authors: Jiran Shen , Jiling Wang , Sijing Zhou , Binbin Zhang , Pulin Li , Rui Han , Guanghe Fei , Chao Cao , Ran Wang
Published: December 2024

Background

Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) are on the rise. While there is evidence of a link between the two diseases, the pathophysiological mechanisms they share are not fully understood.

Methods

In this study, the co-expressed genes of COPD and T2DM in Gene Expression Omnibus database were identified by bioinformatics method, and the functional enrichment analysis was performed. Machine learning algorithms were used to identify biomarkers. The diagnostic value of these biomarkers was assessed by receiver operating characteristic analysis, and their relationship to immune cells was investigated by immunoinfiltration analysis. Finally, real-time quantitative polymerase chain reaction was performed.

Results

A total of five overlapping genes were obtained, focusing on pathways associated with insulin resistance and inflammatory mediators. The machine learning method identified three biomarkers: matrix metalloproteinase 9, laminin α4, and differentially expressed in normal cells and neoplasia domain containing 4 C, all of which were shown to have high diagnostic values by receiver operating characteristic analysis. Immunoinfiltration analysis showed that it was associated with a variety of immune cells. In addition, the real-time quantitative polymerase chain reaction results confirmed agreement with our bioinformatics analysis.

Conclusions

Our study sheds light on the common pathogenesis and biomarkers of both diseases, and these findings have potential implications for the development of new diagnostic and treatment strategies for COPD and T2DM.

Key message What is already known on this topic?  Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) often coexist as comorbidities. However, the exact mechanistic link between the two diseases remains complex, multifactorial, and not fully understood. What this study adds?  Three biomarkers, including matrix metalloproteinase, laminin α4, and differentially expressed in normal cells and neoplasia domain containing 4 C, were identified as key co-expression hub genes in COPD and T2DM. How this study might affect research, practice or policy?  Future studies may benefit from incorporating a larger sample set to further explore and validate the diagnostic and therapeutic effects of these core genes.
Homological stability for spaces of subsurfaces with a tangential structure
Authors: Kastenholz Thorben
Published: December 2024

Given a manifold with a boundary, one can consider the space of subsurfaces of this manifold meeting the boundary in a prescribed fashion. It is known that these spaces of subsurfaces satisfy homological stability if the manifold has at least dimension five and is simply connected. We introduce a notion of tangential structure for subsurfaces and give a general criterion for when the space of subsurfaces with a tangential structure satisfies homological stability, provided that the manifold is simply connected and has dimension $n\geq 5$. Examples of tangential structures such that the spaces of subsurface with that tangential structure satisfy homological stability are framings or spin structures of their tangent bundle or k-frames of the normal bundle, provided that $k\leq n-2$. Furthermore we introduce spaces of pointedly embedded subsurfaces and construct stabilization maps, as well as prove homological stability for these. This is used to prove homological stability for spaces of symplectic subsurfaces.
The Application of a New Framework Construction Technique in Autologous Costal Cartilage Rhinoplasty
Authors: Gu Qinhao , Li Jingyu , Fu Zexin , Wang Ji , Feng Xiao , Sun Yi , Yan Sheng , Jin Peihong , Wu Sufan
Published: December 2024

Background:

In this study, the clinical efficacy of a new framework construction technique for costal cartilage rhinoplasty was investigated.

Methods:

From January 2020 to February 2022, patients who underwent rhinoplasty in the department of plastic and reconstructive surgery of Zhejiang Provincial People’s Hospital were enrolled. The sixth costal cartilage was made into the nasal columellar support graft (strut), the nasal tip graft integrated scaffold, and the septal extension grafts. The strut and septal extension grafts were sutured to construct the framework. Adobe Photoshop 6.0 was used to measure a series of aesthetic indices preoperatively and at 9 months postoperatively, including the nasal length, tip projection, nasofrontal angle, columellar/lobular angle, and nasolabial angle. The visual analog scale score and rhinoplasty outcome evaluation score were used to assess patient satisfaction. A paired t test was used for data analysis, and a P value of less than 0.05 was considered to indicate statistical significance.

Results:

A total of 65 patients aged 19–43 years (average age 26.0 y) were enrolled. No short-term complications occurred. All patients were followed up for 9–23 months. There were statistically significant differences in all measurements (P < 0.05), which suggested that the aesthetic defects of the nose were corrected and that no obvious deflection or rotation of the nasal tip occurred. The visual analog scale score and rhinoplasty outcome evaluation score indicated a significant improvement in patient satisfaction (P < 0.05).

Conclusions:

This new framework construction technique for costal cartilage rhinoplasty can reduce the risk of framework deflection and nasal tip rotation and provide a satisfactory nasal columellar shape.
Interleukin 8-CXCR2–mediated neutrophil extracellular trap formation in biliary atresia associated with neutrophil extracellular trap–induced stellate cell activation
Authors: Luo Yuhuan , Fraser Lisa , Jezykowski Julia , Gupta Nitika A. , Miethke Alexander G. , Taylor Sarah A. , Alonso Estella M. , Horslen Simon , Kohli Rohit , Molleston Jean P. , Kamath Binita M. , Guthery Stephen L. , Loomes Kathleen M. , Magee John C. , Rosenthal Phillip , Valentino Pamela , Sokol Ronald J. , Mack Cara L. ,   on behalf of the Childhood Liver Disease Research Network
Published: December 2024

Background and Aims:

Biliary atresia (BA) entails an inflammatory sclerosing lesion of the biliary tree, with prominent fibrosis in infancy. Previous studies revealed that neutrophil-activating IL-8 and neutrophil extracellular traps (NETs) positively correlated with bilirubin and the risk of liver transplant. The aims of this study were to determine the mechanism of NET formation (NETosis) in BA and whether NETs induce stellate cell activation.

Approach and Results:

BA and other liver disease control plasma and tissue were obtained at diagnosis and transplant. Elastase, NETs, and IL-8 were quantified by ELISA for plasma and by immunohistochemistry for liver tissue. FACS analysis of neutrophils co-cultured with BA or control plasma measured BA-specific NETosis. Stellate cell activation from co-culture studies of stellate cells with NETs was measured by real-time quantitative PCR, ELISA, and FACS. Liver neutrophils and NETs, and plasma elastase, NETs, and IL-8, were significantly increased in BA at diagnosis and transplant. Normal neutrophils co-cultured with BA plasma had increased NETosis and activation of CXCR2, an IL-8 receptor; CXCR2 inhibition decreased NET production. Immunohistochemistry identified increased NET expression of profibrogenic tissue factor and IL-17. NETs co-cultured with stellate cells resulted in stellate cell activation based on increased ACTA2 and COL1A1 mRNA, collagen protein, and cell surface expression of actin, collagen1A, and platelet-derived growth factor receptor-beta.

Conclusions:

Patients with BA have persistent IL-8-CXCR2–mediated NETosis that correlates with biomarkers of injury and fibrosis, and NETs induce stellate cell activation, suggesting a role for NETs in the immunopathogenesis of disease. Future investigations should focus on therapeutic agents that inhibit NETs in BA.
Minimally invasive glaucoma surgery in angle closure
Authors: Chan Nicole Shu-Wen , Sng Chelvin C.A.
Published: December 2024

Purpose of review

This review discusses the evidence on the efficacy, safety and role of minimally invasive glaucoma surgery (MIGS) in eyes with angle closure glaucoma. While cataract surgery remains the most established surgical treatment for primary angle closure glaucoma (PACG), the intraocular pressure (IOP) may remain elevated after cataract surgery despite open angles due to trabecular meshwork damage from chronic iridotrabecular contact.

Recent findings

There is emerging evidence that combining cataract surgery with MIGS in eyes with PACG, though an off-label indication for some MIGS devices, can achieve greater IOP and glaucoma medication reduction than cataract surgery alone.

Trabecular bypass MIGS procedures and less destructive forms of ciliary body treatment have been shown to be effective in PACG and are safer alternatives to traditional incisional surgeries. Evidence for the use of subconjunctival MIGS and suprachoroidal MIGS in angle closure eyes is lacking at present, and further investigation is indicated.
Prosthesis and health-related factors of mobility in people with nontraumatic unilateral transtibial amputation
Authors: Alavi Tahereh , Jalali Maryam , Farahmand Behshid , Babaee Taher
Published: December 2024

Background:

Numerous factors can affect mobility of individuals with lower limb amputation, including prosthesis-dependent, physical and psychological determinants.

Objective:

This study aimed to investigate the prosthesis and health-related factors of mobility in people with nontraumatic unilateral transtibial amputation.

Study Design:

Cross-sectional observational study.

Methods:

Individuals with nontraumatic unilateral transtibial amputation who are using a prosthetic leg were included. All participants were asked to fill out the Prosthesis Evaluation Questionnaire, 12-Item Short-Form Health Survey (SF-12), Comprehensive Lower Limb Amputee Socket Survey, and 12-item Prosthetic Limb Users Survey of Mobility. The relationships between the variables of interest and mobility were investigated using correlation coefficient analyses. Multiple regression analysis was run to investigate the impact of a set of predictor variables on mobility.

Results:

A total of 168 people with lower limb amputation were included. Mobility had a significant association with age, comorbidity, occupation, Prosthesis Evaluation Questionnaire score, physical and mental component scores of SF-12, subscales of the Comprehensive Lower Limb Amputee Socket Survey, educational status, amputation cause, time since amputation, time since using the prosthesis, and socket insert type. In the final model of multiple regression analysis, the Physical Component Summary score of SF-12 showed the strongest predictor of mobility (beta = 0.40, p < 0.001).

Conclusions:

Nonprosthetic factors play a significant role in mobility of people with nontraumatic unilateral transtibial amputation. Although some predictors, such as age and time since amputation, are immutable, clinicians may still enhance the mobility of this population through the utilization of health-related factors, such as improving their physical activity.
Cognitive Impairment and Brain Metabolic Changes in Post-Acute Sequelae of COVID-19
Authors: Rozenblum Laura , Debroucker Thomas , Habert Marie-Odile , Soret Marine , Desarnaud Serge , Lemercier Valérie Causse , Guedj Eric , Marshall Esaie , Salmon Dominique , Kas Aurélie
Published: December 2024

Purpose

Neurological symptoms often prominent in post-acute sequelae of COVID-19 (PASC) necessitate deeper understanding. Our objective was to investigate brain metabolism in PASC and examine correlations with neurological symptoms during both the acute and chronic stages.

Methods

Eighty-seven adults experiencing PASC with neurocognitive symptoms were recruited in the PERSICOR prospective study and examined using brain [18F]FDG PET/CT. Comprehensive clinical variables including neurocognitive symptoms were evaluated. PET images were compared voxel-wise with SPM12 software (P < 0.05, false discovery rate corrected) and volume-of-interest basis (BrainVisa software) with those of 55 healthy controls recruited before COVID-19 pandemic. We also investigated differences in brain metabolism according to the time interval after acute COVID-19. The correlation between brain metabolism and neurocognitive symptoms was assessed.

Results

Frequently reported neurological symptoms included concentration difficulties (79%) and immediate/working memory impairments (66%). Significant hypometabolism was identified in regions previously identified in PASC: left fusiform gyrus (33% of patients), amygdala (23% on left, 28% on right), parahippocampal area (25% left, 24% right), and vermis (22%). The most substantial metabolism decreases were observed in the pons (5.5% decrease in the whole patient group vs controls) and right amygdala (−4.2%). Concentration and memory impairments correlated with decreased metabolism in prefrontal and mesial/inferior temporal areas, respectively (P < 0.01 for both). A shorter interval between PET imaging and the acute phase of COVID-19 correlated with reduced glucose metabolism in the brainstem, thalamus, mesiotemporal lobe, frontobasal cortex, and olfactory bulb (P < 10−3).

Conclusions

This study underscores the links between neurological symptoms and cerebral hypometabolism in specific regions in PASC. These findings illuminate the complex neuropathophysiological mechanisms of PASC and pave the way for potential therapeutic interventions.
Temporal contact patterns and the implications for predicting superspreaders and planning of targeted outbreak control
Authors: Pung Rachael , Firth Josh A. , Russell Timothy W. , Rogers Tim , Lee Vernon J. , Kucharski Adam J.
Published: December 2024

Directly transmitted infectious diseases spread through social contacts that change over time, but outbreak models typically make simplifying assumptions about network structure and dynamics. To assess how common assumptions relate to real-world interactions, we analysed 11 networks from five settings and developed metrics, capturing crucial epidemiological features of these networks. We developed a novel metric, the ‘retention index’, to characterize the distribution of retained contacts over consecutive time steps relative to fully static and dynamic networks. In workplaces and schools, contacts in the same department formed most of the retained contacts. In contrast, no clear contact type dominated the retained contacts in hospitals, thus reducing overall risk of disease introduction would be more effective than control targeted at departments. We estimated the contacts repetition over multiple days and showed that simple resource planning models overestimate the number of unique contacts by 20%–70%. We distinguished the difference between ‘superspreader’ and infectious individuals driving ‘superspreading events’ by measuring how often the individual represents the top 80% of contacts in the time steps over the study duration. We showed an inherent difficulty in identifying ‘superspreaders’ reliably: less than 20% of the individuals in most settings were highly connected for multiple time steps.
Effects of Disease on Renal Blood Flow Regulation: Assessing Autoregulation Disruption
Authors: Maddineni Bhavishya , Versypt Ashlee N. Ford
Published: December 2024

The functioning of kidneys on blood flow regulation was investigated, particularly under diseased conditions such as chronic kidney disease, which includes conditions of diabetic nephropathy and other glomerular damage. A mathematical model was developed to better understand how variations based on the glomerular filtration rate impact key kidney function outputs, such as afferent arteriolar diameter, smooth muscle activation, and the chloride ion concentration at the macula densa. We have analyzed these factors by considering the dynamics of the mathematical model of ordinary and partial differential equations to study blood flow control in the kidney, which has provided new insights into the maintenance of autoregulation. By simulating the processes of renal blood flow—specifically through the afferent arteriole and glomerulus, and detailing the process of chloride transport within the renal tubule—the model offers a comprehensive view of how the kidney regulates glomerular filtration rate amidst fluctuating systemic blood pressures and disease-specific changes. Central to this model are the myogenic response that adjusts afferent arteriole muscle tone in reaction to pressure changes and the tubuloglomerular feedback, which controls arteriole size based on chloride levels at the macula densa. The model’s simulations reveal the robustness of renal autoregulation across a spectrum of chronic kidney disease stages, showing stability under normal conditions but indicating a breakdown in regulation with advanced chronic kidney disease. This breakdown is attributed to disruptions in the vascular and feedback systems. The findings from this model shed light on the progression of renal dysfunction in chronic kidney disease and underscore the potential for developing targeted treatments to maintain kidney health.
Test-retest reliability of auditory MMN measured with OPM-MEG
Authors: Demko Laszlo , Iglesias Sandra , Mellor Stephanie , Brand Katja , Kalberer Alexandra , Köchli Laura , Marino Stephanie , Zimmermann Noé , Heinzle Jakob , Stephan Klaas Enno
Published: December 2024

In this paper, we report results from an investigation of auditory mismatch responses as measured by magnetoencephalography (MEG) based on optically pumped magnetometers (OPM). Specifically, as part of a quality control study, we examined the reliability and validity of auditory mismatch negativity (MMN) recordings, obtained with a newly installed OPM-MEG system. Based on OPM-MEG data from 30 healthy volunteers, measured twice with an established auditory MMN paradigm with frequency deviants, we examined the following questions:

First, we focused on construct validity and examined whether OPM-MEG measurements of MMN responses (in terms of event-related fields, ERFs) were qualitatively comparable to previous MMN findings from studies using EEG or MEG based on superconducting quantum interference devices (SQUIDs). In particular, we examined whether significant MMN responses measured by OPM-MEG occurred in a comparable time window and showed a similar topography as in previous EEG/MEG studies of MMN. Second, we quantified test-retest reliability of MMN amplitude and latency over two separate measurement sessions.

The results of our analyses show that MMN responses recorded with OPM-MEG are in good agreement with previously reported MMN results in terms of timing and topography. Furthermore, the comparison of group-level MMN topographies and timeseries shows excellent consistency across the two measurement sessions. Our quantitative test-retest reliability analyses at the sensor level indicate good reliability for MMN amplitude, but poor reliability for MMN latency.

Overall, our findings suggest that OPM-MEG measurements of auditory MMN (i) are comparable to results from EEG and SQUID-based MEG and (ii) show good test-retest reliability for amplitude measures at the sensor level. Notably, these results were achieved in an “out of the box” state of the OPM-MEG system, shortly after installation and without further optimisation. The reason for the insufficient reliability for MMN latency we observed is currently under investigation and represents an important target for future improvements.
Axon initial segment plasticity caused by auditory deprivation degrades time difference sensitivity in a model of neural responses to cochlear implants
Authors: Jing Anna , Xi Sylvia , Fransazov Ivan , Goldwyn Joshua H.
Published: December 2024

Synaptic and neural properties can change during periods of auditory deprivation. These changes may disrupt the computations that neurons perform. In the brainstem of chickens, auditory deprivation can lead to changes in the size and biophysics of the axon initial segment (AIS) of neurons in the sound source localization circuit. This is the phenomenon of axon initial segment (AIS) plasticity. Individuals who use cochlear implants (CIs) experience periods of hearing loss, and so we ask whether AIS plasticity in neurons of the medial superior olive (MSO), a key stage of sound location processing, would impact time difference sensitivity in the scenario of hearing with cochlear implants. The biophysical changes that we implement in our model of AIS plasticity include enlargement of the AIS and replacement of low-threshold Potassium conductance with the more slowly-activated M-type Potassium conductance. AIS plasticity has been observed to have a homeostatic effect with respect to excitability. In our model, AIS plasticity has the additional effect of converting MSO neurons from phasic firing type to tonic firing type. Phasic firing is known to have greater temporal sensitivity to coincident inputs. Consistent with this, we find AIS plasticity degrades time difference sensitivity in the auditory deprived MSO neuron model across a range of stimulus parameters. Our study illustrates a possible mechanism of cellular plasticity in a non-peripheral stage of neural processing that could impose barriers to sound source localization by bilateral cochlear implant users.
Improved prediction of antimicrobial resistance inKlebsiella pneumoniaeusing machine learning
Authors: Sevilla-Fortuny Jordi , González-Candelas Fernando , García-González Neris
Published: December 2024

Klebsiella pneumoniaeis an important cause of healthcare-associated infections, with high levels of antimicrobial resistance (AMR) to critical antibiotics such as carbapenems and third-generation cephalosporins (3GCs). Accurate antimicrobial susceptibility detection is essential for guiding appropriate treatment. In this study, we evaluated the efficacy of machine learning (ML) models for predicting AMR phenotypes inK. pneumoniaeparticularly for antibiotics for which rule-based approaches fail. We analyzed a dataset of 5,907K. pneumoniaegenomes from public databases and a genomic surveillance project in Spanish hospitals. ML models were trained to predict AMR phenotypes using genomic features, and their performance was compared to ResFinder, which implements a conventional rule-based approach. Models were evaluated based on predictive accuracy across antibiotics. Additionally, we conducted a detailed analysis of the genomic features associated with AMR identified by ML to identify new putative AMR determinants. ResFinder exhibited low prediction accuracy for amikacin, fosfomycin, and piperacillin/tazobactam, whereas ML models significantly improved the prediction accuracy for these antibiotics. Moreover, we provide insights into why rule-based methods failed in these cases, specifically related to the genesacc(6)-Ib-cr,fosA, andblaOXA-1, respectively. Finally, we found possible genetic factors related to resistance for each antibiotic. Our findings underscore the value of ML models in AMR prediction based on genome information forK. pneumoniae, especially in challenging cases where traditional methods have low success rates. Continued evaluation and refinement of ML approaches are essential for applying these methods to enhance AMR detection in clinical and public health contexts.

Importance

To combat antimicrobial resistance (AMR), the rapid and accurate identification of resistance phenotypes is essential for guiding appropriate therapy. In this study, we demonstrate the significant potential of machine learning (ML) to improve AMR prediction inKlebsiella pneumoniaeusing genomic data. Our findings reveal that gold standard rule-based methods for predicting AMR from genomic data underperform for antibiotics such as amikacin, fosfomycin, and piperacillin/tazobactam. In this study, we identified the genomic determinants that mislead resistance predictions in rule-based methods providing insights that can refine existing rule-based approaches. Moreover we used ML models that improved the prediction accuracy for these antibiotics and used these models to uncover potential new AMR-associated genes that contribute to a deeper understanding of resistance mechanisms. While these findings are specific toK. pneumoniae, the ML approach is broadly applicable to other pathogens facing similar challenges, enabling improved AMR prediction without reliance on prior knowledge.
The multi-scale complexity of human genetic variation beyond continental groups
Authors: Palma-Martínez María J. , Posadas-García Yuridia S. , López-Ángeles Brenda E. , Quiroz-López Claudia , Lewis Anna C. F. , Bird Kevin A. , Lasisi Tina , Zaidi Arslan A. , Sohail Mashaal
Published: December 2024

Traditional clustering and visualization approaches in human genetics often operate under frameworks that assume inherent, discrete groupings1,2. These methods can inadvertently simplify multifaceted relationships, functioning to entrench the idea of typological groups3. We introduce a network-based pipeline and visualization tool grounded in relational thinking4, which constructs networks from a variety of genetic similarity metrics. We identify communities at multiple resolutions, departing from typological models of analysis and interpretation that categorize individuals into a (predefined) number of sets. We applied our pipeline to a dataset merged from the 1000 Genomes and Human Genome Diversity Project5, revealing the limitations of traditional groupings and capturing the complexities introduced by demographic events and evolutionary processes. This method embraces the context-specificity of genetic similarities that are salient depending on the question, markers of interest, and study individuals. Different numbers of communities are revealed depending on the resolution chosen and metric used, underscoring a fluid spectrum of genetic relationships and challenging the notion of universal categorization. We provide a web application (https://sohail-lab.shinyapps.io/GG-NC/) for interactive visualization and engagement with these intricate genetic landscapes.
Juvenile fluoxetine treatment affects the maturation of the medial prefrontal cortex and behavior of adolescent female rats
Authors: Kryst Joanna , Chocyk Agnieszka , Solarz-Andrzejewska Anna , Majcher-Maślanka Iwona
Published: December 2024

Background

Serotonin is strongly involved in the regulation of brain development. An early-life imbalance in brain serotonin levels may influence the proper formation of neuronal circuits and synaptic plasticity. One of the factors that can affect serotonin concentrations is exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, the first-line pharmacological treatment for depression and anxiety in the pediatric population. Women are more prone to depression and anxiety from a young age. The safety of early-life FLX treatment is still questionable. We hypothesized that juvenile FLX treatment influences the brain maturation and behavior of adolescent females.

Methods

On postnatal days (PNDs) 20–28, juvenile female rats were injected once daily with FLX. Five days later, anxiety- and fear-related behaviors and the response to amphetamine were assessed. On PND 40, the numbers of neurons and glial cells in the medial prefrontal cortex (mPFC) and hippocampus were estimated via stereological methods. Additionally, the mRNA expression of cell survival/apoptosis and synaptic plasticity markers was evaluated via RT‒qPCR.

Results

Juvenile FLX attenuated anxiety-like behaviors, impaired fear memory and blunted the locomotor response to amphetamine in adolescent females. Simultaneously, FLX increased the regional volume and the numbers of neurons and astrocytes in specific subregions of the mPFC but not in the hippocampus. Additionally, FLX-treated females presented increased expression of genes regulating cell survival and reduced mRNA levels of AMPA glutamate receptors in the mPFC.

Conclusions

Juvenile FLX affects the maturation of the mPFC; therefore, this psychotropic drug should be used with caution in young people.
From North to South: Transmission Dynamics of H1N1pdm09 Swine Influenza A Viruses in Italy
Authors: Giovanetti Marta , Cella Eleonora , Soliani Laura , Prosperi Alice , Mescoli Ada , Nucci Ambra , della Ventura Carla , Junqueira Dennis Maletich , Trovão Nídia S. , Branda Francesco , Carrera Maya , Lelli Davide , Rosignoli Carlo , Faccini Silvia , Fiorentini Laura , Guarneri Flavia , Zehender Gianguglielmo , Ciccozzi Massimo , Chiapponi Chiara , Moreno Ana
Published: December 2024

The influenza A H1N1pdm09 virus continues to be a significant pathogen, posing potential risks to both animal and human health due to its zoonotic potential. Italy, which has one of the largest swine populations in Europe, plays a crucial role in monitoring the evolution of influenza viruses in livestock. This study aims to address the existing knowledge gaps regarding the genetic diversity and transmission dynamics of H1N1pdm09 circulating in Italian swine populations. Utilizing whole genome sequencing and dynamic modeling, we conducted a comprehensive analysis of virus samples collected from swine farms across Italy. Our results reveal that multiple independent viral introductions have occurred into the country, with most cases resulting in self-limited infections and limited onward transmission. However, six distinct transmission clusters were identified, suggesting instances of sustained viral spread. These clusters were found across multiple regions of Italy, highlighting the broad geographic distribution of virus lineages. Our findings indicate that while many introductions led to localized containment, certain virus lineages were able to spread within specific regions of Italy. Through a detailed examination of selective pressures, we observed that most viral genes are under strong purifying selection in both swine and human hosts, as reflected by dN/dS ratios well below 1. The hemagglutinin (HA) gene exhibited a notably higher dN/dS ratio in swine (∼0.28) compared to humans (∼0.22), indicating slightly relaxed selection in swine. In contrast, other genes, such as neuraminidase (NA) and non-structural protein (NS), showed similarly strong purifying selection across both hosts. These results reflect a general trend of selective pressures affecting multiple viral components, rather than emphasizing specific genes. Our study emphasizes the importance of ongoing genomic surveillance in detecting viral circulation and mitigating risks to both animal and public health. Italy’s efforts contribute significantly to global influenza monitoring and highlight the importance of a One Health approach that integrates human, animal, and environmental health. These findings provide essential data to inform public health policies and enhance preparedness against future zoonotic influenza outbreaks.
Approach-Avoidance Bias in Virtual and Real-World Simulations: Insights from a Systematic Review of Experimental Setups
Authors: Grasso-Cladera Aitana , Madrid-Carvajal John , Walter Sven , König Peter
Published: December 2024

Background

Approach and avoidance bias (AAB) describes automatic behavioral tendencies to react toward environmental stimuli regarding their emotional valence. Traditional setups have provided evidence but often lack ecological validity. The study of the AAB in naturalistic contexts has recently increased, revealing significant methodological challenges. This systematic review evaluates the use of virtual reality (VR) and real-world setups to study the AAB, summarizing methodological innovations and challenges.

Methods

We systematically reviewed peer-reviewed articles employing VR and real-world setups to investigate the AAB. We analyzed experimental designs, stimuli, response metrics, and technical aspects to assess their alignment with research objectives and identify limitations.

Results

This review included 21 studies revealing diverse methodologies, stimulus types, and novel behavioral responses, highlighting significant variability in design strategies and methodological coherence. Several studies used traditional reaction time measures yet varied in their application of VR technology and participant interaction paradigms. Some studies showed discrepancies between simulated and natural bodily actions, while others showcased more integrated approaches that preserved their integrity. Only a minority of studies included control conditions or acquired (neuro)physiological data.

Conclusions

VR offers a potential ecological setup for studying the AAB, enabling dynamic and immersive interactions. Our results underscore the importance of establishing a coherent framework for investigating the AAB tendencies using VR. Addressing the foundational challenges of developing baseline principles that guide VR-based designs to study the AAB within naturalistic contexts is essential for advancing the AAB research and application. This will ultimately contribute to more reliable and reproducible experimental paradigms and develop effective interventions that help individuals recognize and change their biases, fostering more balanced behaviors.
B-Cells Extracellular Vesicles Shape Melanoma Response to Immune Checkpoint Therapy
Authors: Al Hrout Ala’a , Balayev Agshin , Cervantes-Gracia Karla , Gkelis Konstantinos , Benke Stephan , Matínez Gómez Julia M. , Silina Karina , Levesque Mitchell P. , Chahwan Richard
Published: December 2024

The immune tumor microenvironment (TME) is increasingly recognized as a dynamic ecosystem where B cells play pivotal roles in modulating therapeutic responses, particularly in the context of immune checkpoint blockade (ICB) therapy. While B cells have traditionally been viewed as bystanders in tumor immunity, recent evidence suggests they may actively influence anti-tumor immunity, albeit with conflicting reports regarding their pro-tumor or anti-tumor roles. This study explores the crucial roles played by B cells and their secreted extracellular vesicles (EVs) in shaping melanoma responses to ICB therapy. We show a significant enrichment of B cells in ICB therapy responders compared to non-responders, pre-treatment, through retrospective analyses of melanoma patient tumors. Functional assays demonstrate that B cell depletion impairs T cell-mediated tumor cytotoxicity, underscoring the importance of B cells in anti-tumor responses. To investigate the clinical relevance, EVs were isolated from melanoma patient tumors, and fractioned into tumor and immune subpopulations. MiRNA profiling of CD19+ EVs identifies miR-99a-5p as a top candidate, among several others, upregulated in responders. Functional assays show that miR-99a-5p silencing in B cells diminishes T cell-mediated anti-tumor activity, suggesting its role in promoting B cell-mediated immune responses. Mechanistically, miR-99a-5p influences B cell maturation within the TME by mediating class-switch recombination. Our findings highlight the important role of B cells and their derived EVs in shaping the efficacy of melanoma immunotherapy, paving the way for novel therapeutic strategies targeting B cell-related pathways.

Graphical abstract (created with Biorender)
Deficient cell-cell cohesion is linked with lobular localization in simplified models of lobular carcinomain situ(LCIS)
Authors: Christgen Matthias , Caetano Rodrigo A. , Eisenburger Michael , Traulsen Arne , Altrock Philipp M.
Published: December 2024

Lobular carcinomain situ(LCIS) is a precursor of invasive lobular carcinoma of the breast. LCIS cells lack cell-cell cohesion due to the loss of E-cadherin. LCIS cells grow in mammary lobules rather than in ducts. The etiology of this pattern, especially its dependence on cellular cohesion, is incompletely understood. We simulated passive intra-glandular scattering of carcinomain situ(CIS) cells in an ultra-simplified hollow mold tissue replica (HMTR) and a discrete-time mathematical model featuring particles of variable sizes representing single cells (LCIS-like particles) or groups of cohesive carcinoma cells (DCIS-like particles). The HMTR features structures reminiscent of a mammary duct with associated lobules. The discrete mathematical model characterizes spatial redistribution over time and includes transition probabilities between ductal or lobular localizations. Redistribution of particles converged toward an equilibrium depending on particle size. Strikingly, equilibrium proportions depended on particle properties, which we also confirm in a continuous-time mathematical model that considers controlling lobular properties such as crowding. Particles of increasing size, representing CIS cells with proficient cohesion, showed increasingly higher equilibrium ductal proportions. Our investigations represent two conceptual abstractions implying a link between loss of cell-cell cohesion and lobular localization of LCIS, which provide a much-needed logical foundation for studying the connections between collective cell behavior and cancer development in breast tissues. In light of the findings from our simplified modeling approach, we discuss multiple avenues for near-future research that can address and evaluate the redistribution hypothesis mathematically and empirically.
Acute Myeloid Leukemia Skews Therapeutic WT1-specific CD8 TCR-T Cells Towards an NK-like Phenotype that Compromises Function and Persistence
Authors: Mazziotta Francesco , Martin Lauren E. , Eagan Daniel N. , Bar Merav , Kinsella Sinéad , Paulson Kelly G. , Voillet Valentin , Lahman Miranda C. , Hunter Daniel , Schmitt Thomas M. , Duerkopp Natalie , Yeung Cecilia , Tang Tzu-Hao , Gottardo Raphael , Asano Yuta , Wilcox Elise C. , Lee Bo , Zhang Tianzi , Lopedote Paolo , Penter Livius , Wu Catherine J , Milano Filippo , Greenberg Philip D. , Chapuis Aude G.
Published: December 2024

Acute myeloid leukemia (AML) that is relapsed and/or refractory post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. In a prior study, we demonstrated that AML relapse in high-risk patients was prevented by post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8+T cells engineered to express a high-affinity Wilms Tumor Antigen 1 (WT1)-specific T-cell receptor (TTCR- C4). However, in the present study, infusion of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4did not clearly improve outcomes in fifteen patients with active disease post-HCT. TCRC4-transduced EBV-specific T cells persisted longer post-transfer than CMV-specific T cells. Persisting TTCR-C4skewed towards dysfunctional natural killer-like terminal differentiation, distinct from the dominant exhaustion programs reported for T-cell therapies targeting solid tumors. In one patient with active AML post-HCT, a sustained TTCR-C4effector-memory profile correlated with long-term TTCR-C4persistence and disease control. These findings reveal complex mechanisms underlying AML-induced T-cell dysfunction, informing future therapeutic strategies for addressing post-HCT relapse.
Identification of novel plasma proteomic biomarkers of Dupuytren Disease
Authors: Hummer Blake , Sebastiani Paola , Leshchyk Anastasia , Gurinovich Anastasia , Bager Cecilie , Karsdal Morten , Nielsen Signe , Eaton Charles
Published: December 2024

Dupuytren Disease (DD) is a chronic progressive disease that can cause disabling hand deformities. The most common treatments have high rates of complications and early recurrence. Dupuytren lacks a staging biomarker profile to develop preventive therapeutics to improve long-term outcomes. This multi-omic study aimed to create a DD blood proteomic biomarker profile by comparing DD plasma to a healthy control group. We measured circulating collagen metabolism peptides and found normal Collagen I synthesis but impaired Collagen I degradation in DD. We measured 6995 serum protein aptamers and identified 68 proteins with statistically significant differences from the control group. We developed two Diagnostic Proteomic Risk Scores (DPRS) based on hypothesis-free and hypothesis-based analyses. In independent data, our hypothesis-free and the hypothesis-based DPRS distinguished Dupuytren from control subjects with 76.5% and 70.6% accuracy, respectively. Our hypothesis- based DPRS also distinguished DD subjects with different disease progression rates based on subject age at the time of their first corrective procedure (p=0.0018). This pilot study is the first to provide evidence that Collagen I accumulation in DD is due to impaired degradation rather than increased collagen synthesis. It also describes novel DPRS that have potential use as diagnostic and staging biomarker panels for Dupuytren disease.
Limited durability of protection conferred by XBB.1.5 vaccines against Omicron-associated severe outcomes among community-dwelling adults aged ≥50 years, Ontario, Canada, September 2023 to June 2024
Authors: Lee Nelson , Nguyen Lena , Nasreen Sharifa , Austin Peter C. , Brown Kevin A. , Buchan Sarah A , Grewal Ramandip , Schwartz Kevin L , Tadrous Mina , Wilson Kumanan , Wilson Sarah E , Kwong Jeffrey C
Published: December 2024

We estimated XBB.1.5 vaccine effectiveness against hospitalization/death among adults aged ≥50 years. Compared with non-XBB.1.5 vaccinees, the initial protection of 64% (95%CI, 57%−69%) was reduced when JN/KP-sublineages became predominant, and quickly declined. No significant protection was observed >6 months post-vaccination. Short durability of protection poses unique challenges for COVID-19 vaccination.