bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling early-onset cancer kinetics to study changes in underlying risk, detection, and impact of population screening
Authors: Mirzaei Navid Mohammad , Hur Chin , Terry Mary Beth , Dalerba Piero , Yang Wan
Published: December 2024

Recent studies have reported increases in early-onset cancer cases (diagnosed under age 50) and call into question whether the increase is related to earlier diagnosis from other medical tests and reflected by decreasing tumor-size-at-diagnosis (apparent effects) or actual increases in underlying cancer risk (true effects), or both. The classic Multi-Stage Clonal Expansion (MSCE) model assumes cancer detection at the emergence of the first malignant cell, although later modifications have included lag-times or stochasticity in detection to more realistically represent tumor detection requiring a certain size threshold. Here, we introduce an approach to explicitly incorporate tumor-size-at-diagnosis in the MSCE framework and account for improvements in cancer detection over time to distinguish between apparent and true increases in early-onset cancer incidence. We demonstrate that our model is structurally identifiable and provides better parameter estimation than the classic model. Applying this model to colorectal, female breast, and thyroid cancers, we examine changes in cancer risk while accounting for detection improvements over time in three representative birth cohorts (1950-1954, 1965-1969, and 1980-1984). Our analyses suggest accelerated carcinogenic events and shorter mean sojourn times in more recent cohorts. We further use this model to examine the screening impact on the incidence of breast and colorectal cancers, both having established screening protocols. Our results align with well-documented differences in screening effects between these two cancers. These findings underscore the importance of accounting for tumor-size-at-diagnosis in cancer modeling and support true increases in early-onset cancer risk in recent years for breast, colorectal, and thyroid cancer.

Significance

This study models recent increases in early-onset cancers, accounting for both true factors contributing to cancer risk and those caused by improved detection. We show that while advancement in detection has led to earlier detection, our model estimates shorter sojourn times and more aggressive carcinogenic events for recent cohorts, suggesting faster tumor progression. Further, a counterfactual analysis using this model reveals the known statistically significant reduction in colorectal cancer incidence (supporting a robust modeling approach), likely due to screening and timely removal of precancerous polyps. Overall, we introduce an enhanced model to detect subtle trends in cancer risk and demonstrate its ability to provide valuable insights into cancer progression and highlight areas for future refinement and application.
Inhibiting heme-piracy by pathogenicEscherichia coliusingde novo-designed proteins
Authors: Fox Daniel R. , Asadollahi Kazem , Samuels Imogen , Spicer Bradley , Kropp Ashleigh , Lupton Chris , Lim Kevin , Wang Chunxiao , Venugopal Hari , Dramicanin Marija , Knott Gavin , Grinter Rhys
Published: December 2024

Iron is an essential nutrient for most bacteria and is often growth-limiting during infection, due to the host sequestering free iron as part of the innate immune response. To obtain the iron required for growth, many bacterial pathogens encode transporters capable of extracting the iron-containing cofactor heme directly from host proteins. PathogenicE. coliandShigella spp. produce the outer membrane transporter ChuA, which binds host hemoglobin and extracts its heme cofactor, before importing heme into the cell. Heme extraction by ChuA is a dynamic process, with the transporter capable of rapidly extracting heme from hemoglobin in the absence of an external energy source, without forming a stable ChuA-hemoglobin complex. In this work, we utilise a combination of structural modelling, Cryo-EM, X-ray crystallography, mutagenesis, and phenotypic analysis to understand the mechanistic detail of this process. Based on this understanding we utilise artificial intelligence-based protein design to create binders capable of inhibitingE. coligrowth by blocking hemoglobin binding to ChuA. By screening a limited number of these designs, we identify several binders that inhibitE. coligrowth at low nanomolar concentrations, without experimental optimisation. We determine the structure of a subset of these binders, alone and in complex with ChuA, demonstrating that they closely match the computational design. This work demonstrates the utility ofde novo-designed proteins for inhibiting bacterial nutrient uptake and uses a workflow that could be applied to integral membrane proteins in other organisms.
Chromatin Compaction Follows a Power Law Scaling with Cell Size from Interphase Through Mitosis
Authors: Stockinger Petra , Oddone Anna , Lakadamyali Melike , Mendoza Manuel , Solon Jérôme
Published: December 2024

Coordination of mitotic chromosome compaction with cell size is crucial for proper genome segregation during mitosis. During development, DNA content remains constant but cell size evolves, necessitating a mechanism that scales chromosome compaction with cell size. In this study, we examined chromatin compaction in the developingDrosophilanervous system by analyzing the large neuronal stem cells and their smaller progeny, the ganglion mother cells. Using super-resolution 3D Stochastic Optical Reconstruction Microscopy and quantitative time-lapse fluorescence microscopy, we observed that nanoscale chromatin density during interphase scales with nuclear volume according to a power law. This scaling relationship is disrupted by inhibiting histone deacetylase activity, indicating that molecular cues rather than mechanical constraints primarily regulate chromatin compaction. Notably, this power law dependency is maintained into mitosis but the scaling exponent decreases, suggesting phase separation of chromatin events during mitotic compaction. We propose that the scaling of mitotic chromosome size relative to cell size depends on the power law behaviour of interphase chromatin volume, and that scaling of mitotic chromatin compaction is an emergent property of linear polymers undergoing phase separation with their solvent.

Statement of Significance

Understanding how chromatin compaction changes with cell size is essential for understanding the mechanisms ensuring accurate genome segregation during cell division. In this study, we combine Voronoi tessellation analysis of Stochastic Optical Reconstruction Microscopy and image processing methods based on fluorescence intensity spectrum analysis of live confocal images to measure chromatin volume in interphase and mitosis in cells of different sizes. This work reveals that chromatin density inDrosophilaneuronal cells follows a power law relationship with nuclear volume from interphase through mitosis, suggesting a fundamental principle underlying chromosome scaling across different cell sizes. We show that this scaling is regulated by molecular cues, such as histone deacetylase activity, and is conserved through a potential phase separation during mitosis, providing new insights into the biophysical processes that govern chromatin organization. This work broadens our understanding of chromosome biology and will have implications for understanding size-dependent chromatin dynamics in other organisms.
Pharmacological concentrations of vitamin C inhibit hypochlorous acid generation by myeloperoxidase, and oxidized vitamin C inhibits critical thiol proteins and growth of Jurkat cells
Authors: Peskin Alexander V , Magon Nicholas J , Bozonet Stephanie M
Published: December 2024

The controversy surrounding vitamin C treatment for cancer is addressed, specifically why only high doses are effective and why the outcomes are inconsistent. Our data suggest that the bona fide cause of toxicity was oxidized vitamin C rather than hydrogen peroxide. We found that vitamin C at millimolar concentrations, directly inhibits hypochlorous acid generation by myeloperoxidase, through competition with chloride rather than by scavenging the hypochlorous acid that is formed. Products of vitamin C oxidation reacted with the thiols of peroxiredoxin 2 and GAPDH, but failed to react with the cysteine of p16INK4a. The growth and viability of Jurkat cells were affected by oxidized vitamin C. These experiments were conducted in the presence of catalase, demonstrating that the biological effects were due to the products of vitamin C oxidation and not hydrogen peroxide. These findings may have practical implications for the treatment of cancer and diseases in which the deleterious effects of neutrophil activation are observed. For intravenous administration of pharmacological vitamin C to have a beneficial effect, its concentration in the blood must be maintained at millimolar levels and this can only be achieved via maintenance infusion. As a proof-of-concept, our data suggest that to enhance anticancer therapy interventions, it is crucial to implement treatments that facilitate the oxidation of vitamin C in the bloodstream.

Progress in the art of healing has always been induced by progress in basic knowledge.

Albert Szent-Gyorgyi (Woods Hole, Mass., USA, 1973)

Graphical abstract
Design of a Water-Soluble CD20 Antigen with Computational Epitope Scaffolding
Authors: Yao Zhiyuan , Kuhlman Brian
Published: December 2024

The poor solubility of integral membrane proteins in water frequently hinders studies with these proteins, presenting challenges for structure determination and binding screens. For instance, the transmembrane protein CD20, which is an important target for treating B-cell malignancies, is not soluble in water and cannot be easily screened against potential protein binders with techniques like phage display or yeast display. Here, we usede novoprotein design to create a water-soluble mimic of the CD20 dimer (“soluble CD20”). Soluble CD20 replaces the central transmembrane helix of CD20 with a water-soluble helix that dimerizes to form a coiled coil that structurally matches the dimer interface of native CD20 and presents the central extracellular loop of CD20 in a binding competent conformation. Unlike peptides derived from CD20, soluble CD20 binds tightly to monoclonal antibodies that recognize quaternary epitopes on the extracellular face of CD20. We demonstrate that soluble CD20 is easy to produce, remains folded above 60°C, and is compatible with binder screening via yeast display. Our results highlight the ability of computational protein design to scaffold conformational epitopes from membrane proteins for use in binding and protein engineering studies.

Importance

This study demonstrates that computational protein design can be used to create water soluble variants of transmembrane proteins. The water-soluble CD20 mimic created here is compatible with high throughput binding screens and should be useful for developing next generation anti-CD20 therapeutics.
The Epidemiology of Scrub typhus in Thiruvarur, Tamil Nadu
Authors: Farhat SK , Nataraj M , Behara Sujit Kumar , Rajalakshmi A , Sweta S , Jeevitha Sathya , Binduja S , Shanti S , Srivastava P.K. , Vellingiri Balachandar , Malik Mansi , Krishnan Jayalakshmi
Published: December 2024

National Vector-Borne Disease Control Programme (NVBDCP) under the National Center for Vector Borne Diseases Control (NCVBDC), Govt. of India, Delhi has put forth efforts to combat diseases transmitted by vectors, under the overarching umbrella of the National Health Mission (NHM). NCVBDC focuses mainly on six Vector Borne Diseases (VBD) but at the state and district level the VBD officials have to deal with all the VBDs covered under NCVBDC or outside the purview of NCVBDC. The advancement in modern technologies has increased attention to neglected tropical diseases, emphasizing their importance in public health discussions. Scrub typhus, a rickettsial infection with a harmless bite of infected chigger mite on humans, transmits the gram-negative bacteria Orientia tsutsugamushi causing the infection with rising mortality and morbidity rates across the globe. The living environment of the people plays a pivotal role in scrub typhus disease transmission. Rodents are the major reservoirs carrying the vector mites with additionally the environment, sanitation and hygiene as a crucial factor in the spread of scrub typhus.

A study was conducted from December 2023-July 2024, in the delta district of Thiruvarur covering the household participants of 730 from both rural and urban households. The statistical analysis of both quantitative and categorical variables was done using the SPSS software Version 16.0. The spacio-temporal mapping of the household areas enhanced the study with the representation of the study participants who were exposed to the risk factors but were susceptible hosts to scrub typhus. The univariate analysis showed a significant association between scrub typhus exposure with the people working in the agricultural fields, location of toilets, kitchen, presence of animals in homes, barren land and paddy fields near living areas, lack of protective implements against rodents, drying clothes on bushes, walking barefoot with more chances of being bitten by insects, mites or ticks resulting in rashes or Eschars, hospitalization due to fever, sneezing and headache. The Multivariate regression analysis showed that the association between scrub typhus exposure to the kitchen located outdoors (aOR=3.768, CI: 1.036 - 13.699, p = 0.044), people living near paddy fields (aOR=2.140, CI: 1.019-4.492, p=0.044), the use of protective implements (aOR = 0.071 (CI: 0.034 - 0.147, p < 0.001), drying clothes on bushes (aOR = 3.012 CI: 1.579 - 5.745, p = 0.001) showed strong association to exposure to scrub typhus.
Temporary fun, permanent damage: a systematic review on the effects of musical characteristics on participants’ experience and behavior during leisure activities
Authors: Daelemans Céline , Bonapart Casper , Smit Adriana L. , Stegeman Inge
Published: December 2024

Background

Excessively loud music is frequently played at leisure activities, posing significant health risks. However, the lack of consensus on consumers’ preferred music settings makes it difficult to implement preventive measures against high noise levels. Therefore, our objective is to systematically evaluate how different musical characteristics influence the experiences and behaviors of individuals engaged in leisure activities.

Methods

We conducted a search for studies examining the effects of musical characteristics on individuals at leisure activities where the musical experience is of primary focus. The search was performed using the Medline Pubmed, Embase Elsevier, Cochrane, PsychInfo, andClinicalTrial.govdatabases. The exclusion criteria included: leisure activities related to sports, studies evaluating music as a treatment, lab settings, case studies, and participants below 15 years old. The NOS, RoB2, and ROBINS-I tools were used to assess risk of bias. Results relevant to our outcomes of interest were extracted and summarized in tables.

Results

We identified 2503 studies, of which 37 studies were included for data extraction. The total number of participants in this systematic review was 16843. Among the 37 studies, 23 were observational with the remainder being experimental control trials. Risk of bias in the studies was high. Our findings indicate that musical characteristics such as low frequencies, high groove, high tempo, and live performance enhanced participants’ movements and emotions. Excessively high levels, such as those found in nightclubs, were deemed unnecessary by those exposed. These extreme volumes also caused discomfort and posed a risk to hearing health.

Interpretation

The high risk of bias makes it difficult to draw conclusions based on the data in this systematic review. Therefore, and in order to inform policy makers, we need adequate randomized controlled trials in order to assess the effects of different levels of loudness on music experience.

Funding

Dorhout Mees Stichting

Registration

PROSPERO registration: CRD42023412634
Left ventricular myocardial molecular profile of human diabetic ischaemic cardiomyopathy
Authors: Hunter Benjamin , Zhang Yunwei , Harney Dylan , McEwen Holly , Koay Yen Chin , Pan Michael , Malecki Cassandra , Khor Jasmine , Hume Robert D. , Guglielmi Giovanni , Walker Alicia , Dutta Shashwati , Rajagopal Vijay , Don Anthony , Larance Mark , O’Sullivan John F. , Yang Jean , Lal Sean
Published: December 2024

Abstract

Ischaemic cardiomyopathy is the most common cause of heart failure and often coexists with diabetes mellitus which worsens patient symptom burden and outcomes. Yet, their combined effects are seldom investigated and are poorly understood. To uncover the influencing molecular signature defining ischaemic cardiomyopathy with diabetes, we performed multi-omic analyses of ischaemic and non-ischaemic cardiomyopathy with and without diabetes against healthy age-matched donors. Tissue was sourced from pre-mortem human left ventricular myocardium. Fatty acid transport and oxidation proteins were most down-regulated in ischaemic cardiomyopathy with diabetes relative to donors. However, the down-regulation of acylcarnitines, perilipin, and ketone body, amino acid and glucose metabolising proteins indicated lipid metabolism may not be entirely impaired. Oxidative phosphorylation, oxidative stress, myofibrosis, and cardiomyocyte cytoarchitecture also appeared exacerbated principally in ischaemic cardiomyopathy with diabetes. These findings indicate diabetes confounds the pathological phenotype in heart failure, and the need for a paradigm shift regarding lipid metabolism.
Potent antitumor activity of a designed interleukin-21 mimic
Authors: Chun Jung-Ho , Lim Birkley S. , Roy Suyasha , Walsh Michael J. , Abhiraman Gita C. , Zhangxu Kevin , Atajanova Tavus , Revach Or-Yam , Clark Elisa C. , Li Peng , Palin Claire A. , Khanna Asheema , Tower Samantha , Kureshi Rakeeb , Hoffman Megan T. , Sharova Tatyana , Lawless Aleigha , Cohen Sonia , Boland Genevieve M. , Nguyen Tina , Peprah Frank , Tello Julissa G. , Liu Samantha Y. , Kim Chan Johng , Shin Hojeong , Quijano-Rubio Alfredo , Jude Kevin M. , Gerben Stacey , Murray Analisa , Heine Piper , DeWitt Michelle , Ulge Umut Y. , Carter Lauren , King Neil P. , Silva Daniel-Adriano , Kueh Hao Yuan , Kalia Vandana , Sarkar Surojit , Jenkins Russell W. , Garcia K. Christopher , Leonard Warren J. , Dougan Michael , Dougan Stephanie K. , Baker David
Published: December 2024

Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a broad range of affinities while dampening suppressive regulatory T (Treg) cell responses, but current approaches achieve these goals with limited success. Here, we report ade novoIL-21 mimic, 21h10, designed to have augmented stability and high signaling potency in both humans and mice. In multiple animal models and inex vivohuman melanoma patient derived organotypic tumor spheroids (PDOTS), 21h10 showed robust antitumor activity. 21h10 generates significantly prolonged STAT signalingin vivocompared with native IL-21, and has considerably stronger anti-tumor activity. Toxicities associated with systemic administration of 21h10 could be mitigated by TNFα blockade without compromising antitumor efficacy. In the tumor microenvironment, 21h10 induced highly cytotoxic antitumor T cells from clonotypes with a range of affinities for endogenous tumor antigens, robustly expanding low-affinity cytotoxic T cells and driving high expression of interferon-𝛾 (IFN-𝛾) and granzyme B compared to native IL-21, while increasing the frequency of IFN-𝛾+Th1 cells and reducing that of Foxp3+Tregs. As 21h10 has full human/mouse cross-reactivity, high stability and potency, and potentiates low-affinity antitumor responses, it has considerable translational potential.
Single-cell analysis reveals multi-faceted features of B cell development together with age-associated B cell subpopulations
Authors: Yang Xiujia , Tang Haipei , Lan Chunhong , He Weiting , Chen Sen , Zeng Huikun , Liu Danfeng , Wu Haoyu , Wang Wenjian , Zhang Zhenhai
Published: December 2024

The development and maturation of B lymphocytes involve intricate orchestrated processes, where dedicated gene regulations (GR) take place within specific microenvironments shaped by both extracellular matrix and neighboring cells. Despite extensive investigations aimed at deepening our comprehension of these mechanisms, there remains a dearth of high-dimensional and integrated analysis concerning B cell heterogeneity, gene regulation, and external factors implicated in B cell development. In this study, we scrutinized single-cell transcriptomic data and B cell receptor (BCR) sequencing data obtained from B cells and their surrounding counterparts in the bone marrow, tonsil, and peripheral blood. A full picture of the GR dynamics, the heterogeneity of conventional B cells and cell-cell interactions (CCIs) along B cell development axis was depicted. We found immature B cells represent the most quiescent stage characterized by the least number of expressed genes and low RNA velocity. The homeostatic proliferation and activation of naïve B cells is niche-confined and individualized, respectively. Two development models for memory B cell subpopulations seem not mutually exclusive and warrant in-depth investigation. Moreover, CCI analysis reveals a pivotal role of myeloid cells and two dominant and stage-dependent CCI categories, TNF and adhesion signaling, in B cell development. Besides, we unexpectedly identified two age-associated B cell subpopulations that respectively express S100A8/S100A9 and C1q and experimentally confirmed the secretion of S100A8/A9 from human B cellsin vitro, suggesting a senescence-associated secretion phenotype. Our integrated analysis provides valuable insights into GR dynamics, the evolution of B cells, and potential intercellular communication networks involved in B cell development and revealed novel phenotypes of age-associated B cell aberrance. This study serves as a valuable resource for in-depth exploration of the intricacies of B cell biology.
MuSpAn: A Toolbox for Multiscale Spatial Analysis
Authors: Bull Joshua A , Moore Joshua W , Mulholland Eoghan J , Leedham Simon J , Byrne Helen M
Published: December 2024

The generation of spatial data in biology has been transformed by multiplex imaging and spatial-omics technologies, such as single cell spatial transcriptomics. These approaches permit a detailed mapping of cell populations and phenotypes within the tissue context, which reveals that tissues are complex ecosystems that include multiple organisational structures over different length scales. Quantitative methods for maximising the information that can be retrieved from these images have not kept pace with technological advances in platforms, and no standard methodology has emerged for spatial data analysis. Proposed pipelines are often tailored to individual studies, leading to a fragmented landscape of available methods, and no clear guidance about which statistical tools are best suited to a particular research question. In response to these challenges, we present MuSpAn, a Multiscale Spatial Analysis package designed to provide straightforward access to well-established and cutting-edge mathematical tools for analysing spatial data. MuSpAn provides easy to use, flexible, and interactive access to quantitative methods developed from mathematical fields that include spatial statistics, topological data analysis, network theory, geometry, probability and ecology. Users can construct custom pipelines from tools across these fields to address specific biological problems, or conduct unbiased exploration of data for discovery spatial biology. In summary, MuSpAn is an extensive platform which enables multiscale analysis of spatial data, ranging from the subcellular to the tissue-scale.
Establishing reliable blood biomarkers for trimethylamine N-oxide status in rodents: effects of oral choline challenge, dietary choline and fasting conditions
Authors: Din Ahmad Ud , Sweet Michael G. , McAmis Ashley M. , Ratliff Juanita G. , Pon Velayutham Anandh Babu , Neilson Andrew P.
Published: December 2024

Circulating concentrations of the gut microbial-mammalian metabolite trimethylamine N-oxide (TMAO) is linked to atherosclerosis risk. TMAO biosynthesis begins when dietary choline is converted to trimethylamine (TMA) by gut microbial TMA lyase. TMA is transported to the liver, where flavin-containing monooxygenases convert it to TMAO. While dietary modifications regulate TMAO production, the impact of different intake methods, including oral gavage, dietary supplementation, and conditions such as fasting versus non-fasting, has not been fully explored. Twelve female Sprague-Dawley rats were divided into three diet groups (n= 4 per group): no-choline (0% choline), low-choline (0.08% choline), and high-choline (1% choline). Choline and TMAO fasting and non-fasting blood concentrations, and their kinetics following an acute choline challenge, were assessed before and after a 2-week dietary intervention with the distinct choline dietary levels. Fasting choline was under tight control, with little effect of dietary choline. Non-fasting choline was more variable, with high dietary choline reflected in higher blood choline. Greater levels of dietary choline were reflected in significantly greater levels of TMAO, particularly for non-fasting levels. Kinetic profiling demonstrated additional information regarding the appearance and clearance of these compounds from blood. These results suggest that acute oral choline gavage is likely most suitable for studies targeting acute (direct) inhibitors, whereas a choline-rich diet with assessment of fasting and non-fasting blood levels is more suitable for studying alterations to TMAO production capacity. Future research should examine the impact on atherosclerosis biomarkers and microbiome diversity to deepen the understanding of TMAO regulation and its cardiovascular implications.
MCSPACE: inferring microbiome spatiotemporal dynamics from high-throughput co-localization data
Authors: Uppal Gurdip , Urtecho Guillaume , Richardson Miles , Comba Isin Y. , Lee Jeongchan , Moody Thomas , Wang Harris H. , Gerber Georg K.
Published: December 2024

Recent advances in high-throughput approaches for estimating co-localization of microbes, such as SAMPL-seq, allow characterization of the biogeography of the gut microbiome longitudinally and at unprecedented scale. However, these high-dimensional data are complex and have unique noise properties. To address these challenges, we developed MCSPACE, a probabilistic AI method that infers from microbiome co-localization data spatially coherent assemblages of taxa, their dynamics over time, and their responses to perturbations. To evaluate MCSPACE’s capabilities, we generated the largest longitudinal microbiome co-localization dataset to date, profiling spatial relationships of microbes in the guts of mice subjected to serial dietary perturbations over 76 days. Analyses of these data and an existing human longitudinal dataset demonstrated superior benchmarking performance of MCSPACE over existing methods, and moreover yielded insights into spatiotemporal structuring of the gut microbiome, including identifying temporally persistent and dynamic microbial assemblages in the human gut, and shifts in assemblages in the murine gut induced by specific dietary components. Our results highlight the utility of our method, which we make available to the community as an open-source software tool, for elucidating dynamics of microbiome biogeography and gaining insights into the role of spatial relationships in host-microbial ecosystem function.
Genome-wide characterization of hypothiocyanite stress response ofEscherichia colireveals a potential role for RclB and RclC in lowering cell envelope permeability
Authors: Meredith Julia D. , Gray Michael J.
Published: December 2024

Oxidative stress is one of the major methods of microbial population control and pathogen clearing by the mammalian immune system. The methods by which bacteria are able to escape damage by host-derived oxidants such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) have been relatively well described, while other oxidants’ effect on bacteria and their genetic responses are not as well understood. Hypothiocyanite/hypothiocyanous acid (-OSCN/HOSCN) is one such antimicrobial oxidant. In this study, we used RNA-sequencing to characterize the global transcriptional response ofEscherichia colito treatment with HOSCN and observed that the response is different from the responses ofE. colito other oxidants such as H2O2, superoxide, or HOCl, and distinct from the responses of other bacteria such asStreptococcus pneumoniaeandPseudomonas aeruginosato HOSCN. Furthermore, we found that deletion of the genes encoded downstream of HOSCN reductaserclAinE. coli,rclBandrclC,has a transcriptional effect onompCand may play a role in membrane permeability to HOSCN.

IMPORTANCE

Understanding how bacteria sense and respond to oxidative stress provides insights into how our bodies interact with the microbial population within us. In this study, we have characterized the genetic response ofE. colito important immune oxidant hypothiocyanite and investigated the role of therclABCgenes in that response.
Matrix porosity is associated withStaphylococcus aureusbiofilm survival during prosthetic joint infection
Authors: Bhattacharya Mohini , Scherr Tyler D. , Lister Jessica , Kielian Tammy , Horswill Alexander R.
Published: December 2024

Biofilms are a cause of chronic, non-healing infections.Staphylococcus aureusis a proficient biofilm forming pathogen commonly isolated from prosthetic joint infections that develop following primary arthroplasty. Extracellular adhesion protein (Eap), previously characterized in planktonic or non-biofilm populations as being an adhesin and immune evasion factor, was recently identified in the exoproteome ofS. aureusbiofilms. This work demonstrates that Eap and its two functionally orphaned homologs EapH1 and EapH2, contribute to biofilm structure and prevent macrophage invasion and phagocytosis into these communities. Biofilms unable to express Eap proteins demonstrated increased porosity and reduced biomass. We describe a role for Eap proteinsin vivousing a mouse model ofS. aureusprosthetic joint infection. Results suggest that the protection conferred to biofilms by Eap proteins is a function of biofilm structural stability that interferes with the leukocyte response to biofilm-associated bacteria.
A systematic review and meta-synthesis of factors that influence clinical decision making for organ support interventions within the critical care unit
Authors: Matsumoto Kenki , Fazzini Brigitta , Malcolm Hannah , Eldridge Jack , Puthucheary Zudin , Osman Magda , Stephens Timothy J
Published: December 2024

Background

The critical care unit is a dynamic environment that necessitates a high volume of daily clinical decisions regarding organ support. It is known that decision-making varies significantly between clinicians, even where internationally accepted treatment guidance exists and overall the processes and influences on clinical decision-making are poorly understood. Our aim was to summarise the evidence on the decision-making process and the factors that influence organ support decisions in the critical care setting and 2) conduct a meta-synthesis to generate a model of medical decision-making, illustrating how different factors interact and affect the process.

Methods

We conducted a systematic search on three databases (PubMed, Embase and CINAHL) to find relevant papers exploring factors that influenced organ support decisions made by critical care clinicians. A meta-synthesis was then completed on included papers. The data were collated into a common format and cross-compared. This enable the generation of distinct themes/subthemes that were synthesised to develop a higher order interpretation.

Results

33 studies (from 8967 citations) met the inclusion criteria. 21 of these only included nurses, 7 only doctors and 5 were interprofessional. 11 factors that influenced a clinician’s decision-making were identified: experience; professional and personal risk; uncertainty; characteristics of individuals; senior support; team hierarchy; decision making by colleagues; protocols, guidelines and evidence; time and workload; hospital structure; and clinical condition. These were grouped into four themes: human, team, system and patient factors. From our interpretation of the data, we found decision-making is often linear and primarily dictated by disease factors (i.e. patient’s clinical parameters). However, the identified human, team and system factors can place strain on decision-makers and make clinical scenarios more complex. There is scope however to modify these to optimise critical care decision-making.

Conclusion

While decision-making surrounding organ support is complex and dynamic, we identified recurring themes that influenced these decisions across different professions and environments. Further studies should focus on understanding how different decision-making processes directly affect patients’ outcomes.
HCN1 channels in GABAergic amygdalar neurons underpin male-biased aggressive behaviors
Authors: Li Kaiyuan , Zhu Zhenggang , Wang Quan , Pan Lina , Miao Lu , Deng Guochuang , Wu JinRong , Lou Huifang , Zeng Ling-Hui , Liu Yijun , Li Xiao-ming , Duan Shumin , Sun Li , Yu Yan-qin
Published: December 2024

Aggression behaviors typically vary between sexes, but the molecular mechanisms driving these disparities in neural coding are unclear. We found that aggression selectively activates GABAergic neurons in the posterior substantia innominata (pSI), an extend amygdala region critical for aggressive behaviors in both sexes of mice, with males exhibiting higher neuronal activity during the attack. Utilizing single-nucleus RNA sequencing, we characterized the diverse molecular landscape of pSI neurons, revealing significant differences in ion channels and hormone regulator genes that may underpin sex-specific aggression. Male GABAergic pSI neurons exhibited remarkable hyperexcitability due to increased Ih currents. Strikingly, modulating HCN1 expression not only adjusted this hyperexcitability but also influenced sexual dimorphism in aggression: silencing HCN1 in the GABAergic pSI neurons reduced male aggression, while its overexpression markedly heightened aggression in females. Furthermore, testosterone was shown to intensify aggression by upregulating HCN1 and remodeling pSI circuits. These findings provide detailed sex-specific molecular mechanisms underlying social behaviors.
Ventral tegmental area GABA neurons integrate positive and negative valence
Authors: Stelzner Margaret E. , Wolff Amy R. , Saunders Benjamin T.
Published: December 2024

Ventral tegmental area (VTA) dopamine (DA) neurons are classically linked to Pavlovian reward learning and reinforcement. Intermingled VTA GABA neurons are positioned to regulate dopaminergic and striatal systems, but we lack critical insight into how this population contributes to conditioned motivation in different learning contexts. Recording DA and GABA neurons across multiple conditioning paradigms, we found that GABA neurons not only actively encode appetitive and aversive cues and outcomes separately, but uniquely integrate salient events of both valences to guide reward seeking.
Superresolution Imaging Reveals the Spatial Organization of CD81 Microdomains in Regulating Membrane Signaling on Jurkat T Cell Microvilli
Authors: Ramseier Neal T. , Jing Haoran , Anderson Jesse , Hu Ying S.
Published: December 2024

Tetraspanin proteins are closely associated with high-curvature membrane structures and play key roles in organizing membrane domains and regulating membrane signaling in immune cells. However, their specific roles in regulating T cell membrane signaling, particularly within the microvilli often characteristic of these cells, remain poorly understood. Here, we used Jurkat T cells as a model system and investigated CD81 as a member of the tetraspanin family. Using total internal reflection fluorescence (TIRF) microscopy and structured illumination microscopy (SIM), we identified an enrichment of the tetraspanin CD81 microdomains along the actin-rich membrane microvilli. At the distal end of the microvilli, SIM images revealed the spatial colocalization of CD81 with T cell receptors (TCR) and CD63, implying a potential role for CD81 in regulating TCR signaling in conjunction with CD63. Spatial analysis of CD81 and CD63 microdomains from the dual-color SIM data revealed their preference for associating with each other. Cluster analysis of direct stochastic optical reconstruction microscopy (dSTORM) data revealed thatin vitroT cell activation results in reduced domain sizes and increased domain separation of CD81. These findings provide visual evidence of the spatial organization and rearrangement of CD81 on the T cell microvilli, highlighting its potential role in signal regulation on specialized membrane protrusions.
Changing economic environment and expected return proxies
Authors: Yang Huan , Cai Jun , Webb Robert
Published: December 2024

Purpose

We aim to examine two issues. First, we intend to identify the best performing expected return proxies. Second, we investigate whether the expected return proxies for individual stocks can track the corresponding realized returns during extremely good or extremely bad times of the economic environment related to business conditions, stock market valuation and broad market performance.

Design/methodology/approach

We construct four sets of expected return proxies, including: (1) characteristic-based proxies; (2) standard risk-factor-based proxies; (3) risk-factor-based proxies that allow betas to vary with firm characteristics and (4) macroeconomic-variable-based proxies. First, we estimate expected returns for individual stocks using newly developed methods and evaluate the performance of these expected return proxies based on the minimum variance criterion of Lee et al. (2020). Second, we regress expected return proxies and realized returns on indicator variables that capture the extreme phases of the economic environment. Then we compare the estimated coefficients from these two sets of regressions and see if they are similar in magnitude via formal hypothesis testing.

Findings

We find that characteristic-based proxies and risk-factor-based proxies that allow betas to vary with firm characteristics are the two best performing proxies. Therefore, it is important to allow betas to vary with firm characteristics in constructing expected return proxies. We also find that model-based expected return proxies do a reasonably good job capturing actual returns during extremely bad and extremely good phases of business cycles measured by leading economic indicators, consumer confidence and business confidence. However, there is a large gap between the adjustment of model-based expected returns and realized returns during extreme episodes of stock market valuation or broad market performance.

Originality/value

We examine four types of expected return proxies and use the newly developed methodology as in Lee et al. (2020) to see which one is the best. In addition, we document whether model-based expected returns from individual stocks adjust partially or fully to keep pace with actual returns in response to changing economic conditions. No prior studies have examined these two issues.
Risk assessment of poverty-returning based on hybrid q-rung orthopair fuzzy EDAS and prospect theory
Authors: He Jifeng , Gao Luhong , Zeng Shouzhen
Published: December 2024

Purpose

Accurately identifying the risk of poverty-returning is a complex and critical challenge in current poverty alleviation efforts. However, there is currently no study on evaluation methods for the risk of poverty-returning. This study aims to establish a robust and systematic approach for an evaluation framework for the risk of poverty-returning.

Design/methodology/approach

Based on relevant assessment criteria, a maximum deviation method was established to identify the weights of the indicators. A complex evaluation methodology using prospect theory (PT), a q-rung orthopair fuzzy set (QrOFS) and evaluation relying on distance from average solution [EDAS] (QrOFS-PT-EDAS) was developed to evaluate the poverty-returning risks. Some policy recommendations to reduce the risk of poverty-returning have also been put forward.

Findings

His study identifies the risk factors of poverty relapse from nine aspects, including natural disasters, accidents and policy-driven poverty relapse. In addressing the evaluation challenge arising from uncertain decision-making, the QrOFS aligns more with people’s thinking habits and expression methods in complex environments. The proposed hybrid evaluation framework accurately measures the poverty-returning risk, which is beneficial for the formulation of policy recommendations.

Originality/value

A scientific and comprehensive assessment system index for poverty-returning is constructed. A hybrid QrOFS-PT-EDAS framework is presented to make the evaluation results more scientific and objective. Several strategic recommendations for reducing the poverty-returning risk are presented. This study offers a novel framework for assessing poverty-returning issues that can be extended to many other areas.
Nonlinear moderating effects of individual social engagement in freemium strategies on digital content platforms
Authors: Xue Hanbing , Du Qianzhou , Liu Jin , Li Yongjun
Published: December 2024

Purpose

This study aims to investigate the moderating effects of individual social engagement on the effectiveness of freemium strategies in digital content platforms.

Design/methodology/approach

This study involved conducting a randomized field experiment with 74,758 consumers on a prominent e-book platform in China, comparing the effects of offering the first 50 chapters for free against no free content. Additionally, a causal random forest machine learning algorithm was applied to analyze data and optimize strategies based on individual social engagement levels.

Findings

This study indicates freemium strategies on digital content platforms can increase consumer willingness to pay but may reduce social community participation. These effects are moderated by consumers' prior social engagement, with excessive interaction leading to diminishing returns.

Practical implications

The study offers actionable insights for digital content managers, showing how tailored freemium strategies can effectively balance consumer engagement and revenue generation. The findings suggest that platforms can significantly enhance profitability by moderating free content offerings based on detailed analysis of consumer engagement histories.

Originality/value

This study enhances the understanding of freemium strategies by showcasing their dual impact on consumer willingness to pay and social engagement, and detailing the complex, non-linear effects of individual social engagement, which challenges the traditional linear assumptions in existing literature. Additionally, it provides insights for implementing mixed marketing strategies on digital platforms, where multiple strategies often interact, guiding the effective management of these complexities.
The Effectiveness of Polynucleotides in Esthetic Medicine: A Systematic Review
Authors: Lampridou Smaragda , Bassett Sian , Cavallini Maurizio , Christopoulos George
Published: December 2024

Background

Polynucleotides (PN), popular in biorevitalization, show promise in the current sphere of esthetic medicine due to their regenerative properties, previously used in wound healing. Currently, research investigates their use in esthetic medicine. The aim of this review was to synthesize the existing literature, focusing on the effectiveness of PN in esthetic medicine, which is concentrated on skin rejuvenation by providing patients with multiple benefits and the least side effects.

Methods

A systematic electronic search was conducted in Embase, Medline, and Cochrane to identify primary research studies evaluating the effectiveness of polynucleotides in esthetic medicine, published in English between January 01, 2010, and January 01, 2024. A narrative synthesis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. The quality of evidence was assessed using the Critical Appraisal Skills Programme checklists. PROSPERO Registration: CRD42024588712.

Results

Nine studies, of low and moderate quality, were included in this review, describing a population of 219 patients receiving PN treatment. A variation was present regarding procedural characteristics, such as injection areas and techniques. Polynucleotide injections have shown promising outcomes in reducing wrinkles, improving skin texture, and enhancing elasticity, with statistically significant results in several studies. While side effects are generally mild and transient, patient satisfaction is moderate to high, suggesting PN treatment as a well‐tolerated and effective cosmetic intervention.

Conclusion

Polynucleotides offer promising potential in esthetic medicine; however, there is limited consensus regarding their optimal use. Rigorous, high‐quality studies are essential to validate the effectiveness and safety of PN.
Trends and variation in issuance of high‐cost narcolepsy drugs by NHS England organisations and regions from 2019 to 2022
Authors: van Someren Frederick , Wiedemann Milan , Warren‐Gash Charlotte , Sykorova Martina , Mistry Hema , Miller Michelle A. , Leschziner Guy , Nolte Ellen , Belot Aurélien , Smith Ian E. , Quinnell Tim , Eriksson Sofia H. , Strongman Helen
Published: December 2024

Clinicians and people with narcolepsy report varied access to higher‐cost narcolepsy treatments in England associated with variations in national and local commissioning. There are no publicly available data quantifying use of these drugs to support policy decisions. We therefore aimed to describe national, regional and local prescribing trends for higher‐cost narcolepsy drugs using new national databases. We used the English prescribing dataset and secondary care medicines data to quantify volumes of high‐cost narcolepsy drugs issued between 01 January 2019 and 31 December 2022. Volumes were converted to World Health Organisation defined daily doses, to estimate the monthly number of defined daily doses of sodium oxybate, pitolisant and solriamfetol issued by each integrated care board and region. We compared national, integrated care board, and regional level issuance of each drug over time. Analysis of almost 6000 primary care prescriptions and 2000 cumulative months of secondary care pharmacy stock data, issued across 41/42 integrated care boards in England, revealed a 49.1% increase in issuance of high‐cost narcolepsy drugs between 2019 and 2022. In 2022, sodium oxybate accounted for 52.66% of issuance, pitolisant 43.09% and solriamfetol 4.25%, with 22.31% of defined daily doses issued in primary care. Three integrated care boards (NHS Southeast London, NHS Cumbria and North‐East, NHS Cheshire and Merseyside) predominate, issuing 56.33% of all defined daily doses. Variations between integrated care boards and regions differ substantially by drug and route of issuance. Our findings describe substantial variation in the use of specialist narcolepsy drugs in England, and highlight the untapped potential of using large, public domain datasets to publicly review higher‐cost drug prescribing.