bluuebunny/crossref_metadata_2025 huggingface dataset:
Age-Related Patterns of DNA Methylation Changes
Authors: Chen Kevin , Wang Wenshu , Suryadevara Hari Naga Sai Kiran , Peng Gang
Published: December 2024

DNA methylation is a dynamic process that adds methyl groups to DNA molecules, which plays an important role in gene expression regulation, genome stability, and aging. Epigenetic clocks developed over the past decade have used DNA methylation values at specific CpG sites combined with factors such as environmental influences and lifestyle factors to predict biological age with remarkable accuracy. However, these epigenetic clocks, built using conventional penalized regression models, have several limitations: (1) they assume consistent linear changes in methylation with age, even though methylation patterns may vary at different ages; (2) the selected CpGs in these clocks often lack specific biological significance; and (3) there is minimal overlap among the selected CpGs across different clocks, suggesting that only a small subset of a larger group of age-correlated CpGs is used to build an effective clock. Using data from 4,899 samples across 22 GEO datasets, we first analyzed the methylation patterns of 1,868 CpGs from 9 widely used epigenetic clocks and observed the expected consistently linear patterns in a subcluster. Next, we applied our own CpG selection method, which does not assume a lifelong linear correlation between DNA methylation and age. we divided the lifespan into overlapping age windows— [0, 20], [5, 25], [10, 30] …, [55, 75], [60, 80]— and identified CpGs that showed strong correlations with age within each specific window. Most CpGs were selected in young and old age windows, while few were selected in the middle-aged windows, indicating fast DNA methylation changes during child development and aging. Among the 12,903 unique CpGs selected within any of the windows, we performed clustering and uncovered from main patterns: (1) increase before 20 years old, (2) decrease before 20 years old, (3) increase before 20 and then decrease after 60, and (4) decrease before 20 and then increase after 60. Comparing this to the clock CpGs, both sets contained CpGs that decreased during adolescence. When examining gender differences, we noted that female samples had notably slowed methylation changes in old age windows compared to male samples, possibly due to hormonal changes during menopause. These findings suggest that age-related methylation changes are more complex than previously thought, with implications for refining epigenetic clocks and redefining the way researchers study aging. Future research should explore the biological mechanisms behind these non-linear and sex-specific patterns.
FSTL3 is a biomarker of poor prognosis and is associated with immunotherapy resistance in ovarian cancer
Authors: Chauvin Maeva , Tromelin Estelle , Roche Julien , Lancia Hyshem H , Meinsohn Marie-Charlotte , Coletti Caroline , Phuong Nguyen Ngoc Minh , Lafont Virginie , Michaud Henri-Alexandre , Mishra Ranjan , Gros Laurent , Bonnefoy Nathalie , Pépin David
Published: December 2024

High-grade serous ovarian carcinoma (HGSOC), is associated with high mortality rates due to late-stage diagnosis and limited treatment options. We investigated the role of FSTL3 in ovarian cancer progression both as a prognostic biomarker and as a potential therapeutic target.

We measured levels of follistatin (FST) and follistatin-like 3 (FSTL3) in 96 ovarian cancer patient ascites samples and found that FSTL3 overexpression was more predominant than FST and associated with poorer survival outcomes. Mice implanted with an HGSOC syngeneic cell line bearing common alterations in ovarian cancer (KRASG12V, P53R172H, CCNE1oe, AKT2oe) had increasing levels of FST and FSTL3 in serum during tumor growth. Further alteration of this model to generate a knockout of FST (KPCA.FSTKO) and an overexpression of human FSTL3 (KPCA.FSTKO_hFSTL3), revealed that FSTL3 expression was associated with a more fibrotic tumor microenvironment, correlating with an increased abundance of cancer-associated myofibroblasts (myCAFs), and cancer cells with a more mesenchymal phenotype. Tumors overexpressing FSTL3 had less immunocyte infiltration and a significantly reduced intratumoral T-cell abundance (CD4+, CD8+). FSTL3 overexpression completely abrogated tumor response to PPC treatment (Prexasertib combined with PD-1 and CTLA-4 blockade) compared to controls, suggesting that FSTL3 may be involved in immunotherapy resistance.

In conclusion, this study suggests a role for FSTL3 as a prognostic marker and as therapeutic target in HGSOC, where it may play a role in promoting a mesenchymal tumor phenotype, maintaining an immunosuppressive tumor microenvironment, and driving immunotherapy resistance.

Highlights

High FSTL3 levels are associated with poor outcomes in ovarian cancer.

Serum levels of FSTL3 increase during tumor growth and reflect tumor burden and therapy response.

Overexpression of FSTL3 in cancer cells promotes a fibrotic tumor microenvironment and immunocyte exclusion.

Overexpression of FSTL3 in tumors induces resistance to Chk1 and immune checkpoint inhibitor combination therapy.

Graphical abstract
The coordination of cell proliferation and cell-division orientation controls Arabidopsis radial style development
Authors: Jamil Iqra , Koh Samuel W.H. , Cheema Jitender , Moubayidin Laila
Published: December 2024

The biological mechanisms responsible for correct shape acquisition at the apex of the female reproductive organ, the gynoecium, remain poorly understood, despite its fundamental importance for successful plant reproduction and seed production. This process involves a rare bilateral-to-radial symmetry transition in Arabidopsis thaliana, orchestrated in part by the transcription factor SPATULA (SPT). Here, we show that SPT negatively controls cell proliferation, promoted by the hormone cytokinin, to enhance the robustness of cell-division orientation by orchestrating a coherent feed-forward loop that converges on the cell-cycle regulators CYCLIN-P3;1 (CYCP3;1) and CYCP3;2. While cytokinin induces both P-type cyclins, SPT represses their expression. Overexpression of CYCP3s disrupts style radial symmetry, causing the split-style phenotype and hypersensitivity to cytokinin observed in the spt mutant. Finally, we demonstrate a genetic link connecting the machinery of cell-division orientation, controlled by auxin, with the cell-proliferation input induced by cytokinin. Thus, our work reveals how the antagonistic auxin-cytokinin interaction scales up symmetry from the cellular to the organ level.
FLEXIBILITY IN GENE COEXPRESSION AT DEVELOPMENTAL AND EVOLUTIONARY TIMESCALES
Authors: Fischer Eva K , Song Youngseok , Zhou Wen , Hoke Kim L
Published: December 2024

The explosion of next-generation sequencing technologies has allowed researchers to move from studying single genes, to thousands of genes, and thereby to also consider the relationships within gene networks. Like others, we are interested in understanding how developmental and evolutionary forces shape the expression of individual genes, as well as the interactions among genes. To this end, we characterized the effects of genetic background and developmental environment on brain gene coexpression in two parallel, independent evolutionary lineages of Trinidadian guppies (Poecilia reticulata). We asked whether connectivity patterns among genes differed based on genetic background and rearing environment, and whether a gene’s connectivity predicted its propensity for expression divergence. In pursuing these questions, we confronted the central challenge that standard approaches fail to control the Type I error and/or have low power in the presence of high dimensionality (i.e., large number of genes) and small sample size, as in many gene expression studies. Using our data as a case study, we detail central challenges, discuss sample size guidelines, and provide rigorous statistical approaches for exploring coexpression differences with small sample sizes. Using these approaches, we find evidence that coexpression relationships differ based on both genetic background and rearing environment. We report greater expression divergence in less connected genes and suggest this pattern may arise and be reinforced by selection.
Stable isotope fingerprinting can directly link intestinal microorganisms with their carbon source and captures diet-induced substrate switchingin vivo
Authors: Mordant Angie , Blakeley-Ruiz J. Alfredo , Kleiner Manuel
Published: December 2024

Diet has strong impacts on the composition and function of the gut microbiota with implications for host health. Therefore, it is critical to identify the dietary components that support growth of specific microorganismsin vivo. We used protein-based stable isotope fingerprinting (Protein-SIF) to link microbial species in gut microbiota to their carbon sources by measuring each microbe’s natural13C content (δ13C) and matching it to the13C content of available substrates. We fed gnotobiotic mice, inoculated with a 13 member microbiota, diets in which the13C content of all components was known. We varied the source of protein, fiber or fat to observe13C signature changes in microbial consumers of these substrates. We observed significant changes in the δ13C values and abundances of specific microbiota species, as well as host proteins, in response to changes in13C signature or type of protein, fiber, and fat sources.

Using this approach we were able to show that upon switching dietary source of protein, fiber, or fat (1) some microbial species continued to obtain their carbon from the same dietary component (e.g., protein); (2) some species switched their main substrate type (e.g., from protein to carbohydrates); and (3) some species might derive their carbon through foraging on host compounds. Our results demonstrate that Protein-SIF can be used to identify the dietary-derived substrates assimilated into proteins by microbes in the intestinal tract; this approach holds promise for the analysis of microbiome substrate usage in humans without the need of substrate labeling.

Significance

The gut microbiota plays a critical role in the health of animals including humans, influencing metabolism, the immune system, and even behavior. Diet is one of the most significant factors in determining the function and composition of the gut microbiota, but our understanding of how specific dietary components directly impact individual microbes remains limited. We present the application of an approach that measures the carbon isotope “fingerprint” of proteins in biological samples. This fingerprint is similar to the fingerprint of the substrate used to make the proteins. We describe how we used this approach in mice to determine which dietary components specific intestinal microbes use as carbon sources to make their proteins. This approach can directly identify components of an animal’s diet that are consumed by gut microbes.
Deciphering enzymatic potential in metagenomic reads through DNA language model
Authors: Prabakaran R , Bromberg Y
Published: December 2024

Earth’s microbial world plays a fundamental role in shaping the biosphere, steering global processes, soil rejuvenation, and ecological fortification. An overwhelming majority of microbial entities, however, remain un(der)studied. Metagenomics stands to elucidate this microbial “dark matter” by directly sequencing the microbial community DNA from environmental samples. Yet, our ability to explore metagenomic sequences is mostly limited to establishing their similarity to curated datasets of organisms or genes/proteins. Aside from the difficulties in establishing such similarity, the reference-based approaches, by definition, forgo discovery of any entities sufficiently unlike the reference collection.

Presenting a paradigm shift, language model-based methods, offer promising avenues for reference-free analysis of metagenomic reads. Here, we introduce two language models, a pretrained foundation model REMME, aimed at understanding the DNA context of metagenomic reads, and the fine-tuned REBEAN model for predicting the enzymatic potential encoded within the read-corresponding genes. By emphasizing function recognition over gene identification, REBEAN is able to label molecular functions carried both by previously explored genes and by new (orphan) sequences. Inherently, REBEAN identifies the functionally relevant parts of a gene even though it is not explicitly trained to do so. It thus expands enzymatic annotation of unassembled metagenomic reads from extreme environments while maintaining consistency with available annotation methods. Here, our comprehensive analysis highlights our models’ potential for metagenomic read annotation and unearthing of novel enzymes, thus enriching our understanding of microbial communities.
Cells Prioritize the Regulation of Cell Mass Density
Authors: Fu Jinyu , Ni Qin , Wu Yufei , Gupta Anoushka , Ge Zhuoxu , Yang Hongru , Afrida Yasin , Barman Ishan , Sun Sean X.
Published: December 2024

A cell’s global physical state is characterized by its volume and dry mass. The ratio of cell mass to volume is the cell mass density (CMD), which is also a measure of macromolecular crowding and concentrations of all proteins. Using the Fluorescence eXclusion method (FXm) and Quantitative Phase Microscopy (QPM), we investigate CMD dynamics after exposure to sudden media osmolarity change. We find that while the cell volume and mass exhibit complex behavior after osmotic shock, CMD follows a straightforward monotonic recovery in 48 hours. The recovery is cell-cycle independent and relies on a coordinated adjustment of protein synthesis and volume growth rates. Surprisingly, we find that the protein synthesis rate decreases when CMD increases. This result is explained by CMD-dependent nucleoplasm-cytoplasm transport, which serves as negative regulatory feedback on CMD. The Na+/H+exchanger NHE plays a role in regulating CMD by affecting both protein synthesis and volume change. Taken together, we reveal that cells possess a robust control system that actively regulates CMD during environmental change.
Structure of theStaphylococcus aureusbacteriophage 80α neck shows the interactions between DNA, tail completion protein and tape measure protein
Authors: Kizziah James L. , Mukherjee Amarshi , Parker Laura K. , Dokland Terje
Published: December 2024

Tailed bacteriophages with double-stranded DNA genomes (classCaudoviricetes) play an important role in the evolution of bacterial pathogenicity, both as carriers of genes encoding virulence factors and as the main means of horizontal transfer of mobile genetic elements (MGEs) in many bacteria, such asStaphylococcus aureus. TheS. aureuspathogenicity islands (SaPIs), including SaPI1, are a type of MGEs are that carry a variable complement of genes encoding virulence factors. SaPI1 is mobilized at high frequency by “helper” bacteriophages, such as 80α, leading to packaging of the SaPI1 genome into virions made from structural proteins supplied by the helper. 80α and SaPI1 virions consist of an icosahedral head (capsid) connected via a unique vertex to a long, non-contractile tail. At one end of the tail, proteins associated with the baseplate recognize and bind to the host. At the other end, a connector or “neck” forms the interface between the tail and the head. The neck consists of several specialized proteins with specific roles in DNA packaging, phage assembly, and DNA ejection. Using cryo-electron microscopy and three-dimensional reconstruction, we have determined the high-resolution structure of the neck section of SaPI1 virions made in the presence of phage 80α, including the dodecameric portal (80α gene product (gp) 42) and head-tail-connector (gp49) proteins, the hexameric head-tail joining (gp50) and tail terminator (gp52) proteins, and the major tail protein (gp53) itself. We were also able to resolve the DNA, the tail completion protein (gp51) and the tape measure protein (gp56) inside the tail. This is the first detailed structural description of these features in a bacteriophage, providing insights into the assembly and infection process in this important group of MGEs and their helper bacteriophages.
GRASP55 Safeguards Proper Lysosome Function by Controlling Sorting of Lysosomal Enzymes at the Golgi
Authors: Nüchel Julian , Omidi Maryam , Fernandes Stephanie A. , Tauber Marina , Pohl Sandra , Plomann Markus , Demetriades Constantinos
Published: December 2024

Lysosomes are multifunctional organelles that play important roles in cellular recycling, signaling, and homeostasis, relying on precise trafficking and activation of lysosomal enzymes. While the Golgi apparatus plays a central role in lysosomal enzyme sorting, the mechanisms linking Golgi function to lysosomal activity remain incompletely understood. Here, we identify the Golgi-resident protein GRASP55, but not its paralog GRASP65, as a key regulator of lysosome function. More specifically, we demonstrate that loss of GRASP55 expression leads to missorting and secretion of lysosomal enzymes, lysosomal dysfunction and bloating. GRASP55 deficiency also disrupts lysosomal mTORC1 signaling, reducing the phosphorylation of its lysosomal substrates, TFEB and TFE3, while sparing its non-lysosomal targets. Mechanistically, GRASP55 interacts with GNPTAB, a critical enzyme required for mannose 6-phosphate (M6P) tagging of lysosomal enzymes, and is necessary for its correct trafficking and stability. These findings reveal an essential role for GRASP55 in Golgi-lysosome communication and lysosomal enzyme trafficking, and suggest thatGRASP55/GORASP2may act as a susceptibility gene for lysosomal storage disorder (LSD)-like conditions. Overall, this work underscores the importance of Golgi-mediated protein sorting in lysosome function and lysosomal mTORC1 signaling, and provides insights into the molecular basis of LSD-related pathologies.
Intricacies of running a route without success in night-active bull ants (Myrmecia midas)
Authors: deeti sudhakar
Published: December 2024

How do ants resolve conflicts between different sets of navigational cues during navigation? When two cue sets point to diametrically opposite directions, theories predict that animals should pick one set of cues or the other. Here we tested how nocturnal bull ants Myrmecia midas adjust their paths along established routes if route following does not lead to their entry into their nest. During testing, foragers were repeatedly placed back along their homeward route up to nine times, a procedure called rewinding. This procedure produced an accumulating path integrator, or vector, in diametric opposition to the learned landmark views of the route. Repeated rewinding made some individuals head initially in the nest-to-feeder vector direction, but all ants ended up using the visual scene for homing, demonstrating the importance of view-based homing in this species. Repeated rewinding, however, led to path deteriorations, with increased path meander and scanning, results also found in desert ants. After nine rewinding trips, ants were displaced off their route in further manipulations, to a site near the nest, an unfamiliar site, or with the terrestrial surround entirely covered. The results show that a change in visual conditions diminished the weight accorded to path integration: the off-route ants no longer headed off in the vector direction as they did on the immediately preceding trial. They relied on celestial compass cues in other ways for homing. Experiment 2 showed the effects of rewinding in the unaltered natural habitat were not view-specific in these bull ants.
Estimates of epidemiological parameters for H5N1 influenza in humans: a rapid review
Authors: Ward Jack , Lambert Joshua W. , Russell Timothy W. , Azam James M. , Kucharski Adam J. , Funk Sebastian , Quilty Billy J. , Gressani Oswaldo , Hens Niel , Edmunds W. John
Published: December 2024

Background

The ongoing H5N1 panzootic in mammals has amplified zoonotic pathways to facilitate human infection. Characterising key epidemiological parameters for H5N1 is critical should this become widespread.

Aim

To identify and estimate critical epidemiological parameters for H5N1 from past and current outbreaks, and to compare their characteristics with human influenza subtypes.

Methods

We searched PubMed, Embase, and Cochrane Library for systematic reviews reporting parameter estimates from primary data or meta-analyses. To address gaps, we searched Google Scholar for studies of any design providing relevant estimates. We estimated the basic reproduction number for the outbreak in the US and estimated the serial interval using data from previous household clusters in Indonesia. We also applied a branching process model to simulate transmission chain size and duration to assess if simulated transmission patterns align with observed dynamics.

Results

From 32 studies, we identified H5N1’s epidemiological profile as having lower transmissibility (R0 < 0.2) but higher severity compared to human subtypes. Evidence suggests H5N1 has longer incubation (∼4 days vs ∼2 days) and serial intervals (∼6 days vs ∼3 days) than human subtypes, impacting transmission dynamics. Key gaps remain regarding latent and infectious periods.

Conclusions

We characterised critical epidemiological parameters for H5N1 infection. The current U.S. outbreak shows lower pathogenicity but similar transmissibility compared to prior outbreaks. Longer incubation and serial intervals may enhance contact tracing feasibility. These estimates offer a baseline for monitoring changes in H5N1 epidemiology.
Metagenomics disentangles epidemiological and microbial ecological associations between community antibiotic use and antibiotic resistance indicators measured in sewage
Authors: Brown Connor L. , Rumi Monjura Afrin , McDaniel Lauren , Maile-Moskowitz Ayella , Sein Justin , Nguyen Loc , Choi Minyoung , Hindi Fadi , Mullet James , Emon Muhit , Moumi Nazifa Ahmad , Blair Matthew F. , Davis Benjamin C. , Rao Jayashmina , Baffoe-Bonnie Anthony , Vikesland Peter , Pruden Amy , Zhang Liqing
Published: December 2024

Wastewater-based surveillance (WBS) is proving to be a valuable source of information regarding pathogens circulating in the community, but complex microbial ecological processes that underlie antibiotic resistance (AR) complicate the prospect of extending WBS for AR monitoring. The epidemiological significance of observed relative abundances of antibiotic resistance genes (ARGs) in sewage is unclear, in part due to multiple sources and in-sewer processes that shape the ARG signal at the entry to the wastewater treatment plant (WWTP). Differentiating between human-derived signals of resistance and those associated with downstream physical and ecological processes could help amplify public health value of WBS of AR by removing noise. In particular, autochthonous sewage microbiota, i.e., microbes stably associated with sewage collection networks independent of human/fecal input, could influence profiles of antibiotic resistance via seasonality, temperature, or other factors that alter human community-level AR signals at a given time point. Here we address this fundamental challenge by differentiating distinct associations between sewage-borne antibiotic resistant bacteria and outpatient antibiotic use in the community served by the sewershed. This was made possible using a unique dataset of outpatient antibiotic prescription rates encompassing the majority of antibiotic use over a 5-year period. Leveraging a yearlong 2x weekly sampling of a conventional WWTP with deep metagenomic sequencing (average 29 Gbp/sample) and extensive bioinformatics analysis, we identify striking associations between sewage-borne ARGs and antibiotic usage depending on the putative bacterial host and the presumed environmental stability of the antibiotic. It was found that a subset of ARGs, predominantly associated with Enterobacteriaceae, displayed a direct correlation with antibiotic usage, while ARGs predominantly associated with Pseudomonadaceae displayed a lagged relationship with antibiotic usage (between 1-3 months). Nested statistical modeling was applied to model the relationship between Pseudomonas metagenome assembled genomes and lagged sulfamethoxazole/trimethoprim use while jointly considering sewage characteristics and seasonality. This effort demonstrates the utility of WBS for understanding epidemiological dimensions of AR and provides a framework for accomplishing this purpose by considering microbial ecological factors that contribute to the corresponding signals in sewage.
Multidimensional dietary patterns and their joint associations with intersecting sociodemographic characteristics among adults in Canada: a cross-sectional study
Authors: Hutchinson Joy M , Spicker Dylan , Lamarche Benoît , Wallace Michael , Côté Mélina , Torres Espín Abel , Kirkpatrick Sharon I
Published: December 2024

Background: Dietary patterns consist of multiple interrelated components, while individuals have numerous characteristics that may jointly influence dietary patterns. Studies to assess associations between sociodemographic characteristics and dietary patterns typically do not consider this complexity. Objective: The objective of this study was to examine joint relationships between dietary patterns and sociodemographic characteristics among adults in Canada. Methods: 24-hour dietary recall data for adults ≥18 years were drawn from the 2015 Canadian Community Health Survey Nutrition (n=14 097). Three mixed graphical models were developed to explore networks of sociodemographic characteristics, dietary components, and sociodemographic characteristics and dietary components together. Networks included 30 log-transformed food groups (grams), sex, age, household food security status, income, employment status, education, geographic region, and smoking status. Results are expressed as (edge weight; [95% CI]). Results: The strongest pairwise relationships were observed among dietary components and among sociodemographic characteristics. Positive linear relationships were observed among vegetable groupings; for example, between green and orange vegetables (0.12; [0,08, 0.16]). Negative relationships were observed among subgroups of each of animal foods, beverages, and grains; for example, between refined and whole grains (-0.30; [-0.33, -0.26]). In the model including dietary components and sociodemographic characteristics, age was associated with grains (other) (-0.12; [-0.16, -0.09]), coffee/tea (0.21; 95% CI [0.17, 0.24]), and whole grains (0.12; [0.08, 0.15]). Sex was associated with sweet beverages (0.11; [0.06, 0.17]), alcohol (0.18; [0.13, 0.24]), cured meat (0.20; [0.15, 0.26]), and red meat (0.16; [0.11, 0.21]). Conclusions: In some cases, pairwise relationships between dietary components suggest displacement, for example, of whole grains by refined grains. Age and sex were the characteristics most strongly connected to dietary components. Statement of significance: Exploring joint relationships between intersecting sociodemographic characteristics and multidimensional dietary patterns can assist with better understanding dietary heterogeneity to inform policies and programs that support healthy eating.
Interplay of PD-L1, FOXP3, and CD8 in the Immune Microenvironment of Penile Squamous Cell Carcinoma: Expression Profiles and Correlations
Authors: Canete-Portillo Sofia , Cubilla Antonio L. , Netto George J. , Chaux Alcides
Published: December 2024

Background

Penile squamous cell carcinoma (PSCC) presents significant challenges in diagnosis and treatment. Understanding the complex immunological landscape, particularly the interaction between PD-L1, FOXP3, and CD8, is crucial for developing effective therapeutic strategies.

Methods

We analyzed 108 PSCC cases through 528 tissue microarray samples. Immunohistochemical staining was performed using standardized protocols to detect PD-L1, FOXP3, and CD8 expression. Expression patterns were evaluated in both tumor and stromal compartments, with assessment of membranous staining for PD-L1 and quantification of FOXP3+ and CD8+ lymphocytes.

Results

PD-L1 expression in tumor cells showed a moderate positive correlation (r=0.477, P<0.001) with CD8+ T-cell infiltration in the tumor compartment, suggesting an adaptive immune resistance mechanism. PD-L1 expression in tumor cells demonstrated a weak positive correlation (r=0.289, P=0.002) with FOXP3 expression in tumor-associated lymphocytes. The strongest correlation observed (r=0.717, P<0.001) was between FOXP3 expression in stromal lymphocytes and CD8+ T-cell presence in stromal areas. PD-L1 expression in lymphocytes showed a significant correlation (r=0.354, P<0.001) with FOXP3 expression in stromal lymphocytes.

Conclusions

Our findings reveal complex interactions between PD-L1, FOXP3, and CD8 within the tumor microenvironment of PSCC. The strong correlation between stromal FOXP3+ and CD8+ cells points to a crucial immune regulatory axis that could influence treatment outcomes. These results provide insights for developing targeted therapeutic strategies and improving patient care in PSCC.
Development and Evaluation of Machine Learning Models for the Detection of Emergency Department Patients with Opioid Misuse from Clinical Notes
Authors: Shahid Usman , Parde Natalie , Smith Dale L. , Dickinson Grayson , Bianco Joseph , Thorpe Dillon , Hota Madhav , Afshar Majid , Karnik Niranjan S. , Chhabra Neeraj
Published: December 2024

Objectives

The accurate identification of Emergency Department (ED) encounters involving opioid misuse is critical for health services, research, and surveillance. We sought to develop natural language processing (NLP)-based models for the detection of ED encounters involving opioid misuse.

Methods

A sample of ED encounters enriched for opioid misuse was manually annotated and clinical notes extracted. We evaluated classic machine learning (ML) methods, fine-tuning of publicly available pretrained language models, and a previously developed convolutional neural network opioid classifier for use on hospitalized patients (SMART-AI). Performance was compared to ICD-10-CM codes. Both raw text and text transformed to the United Medical Language System were evaluated. Face validity was evaluated by term feature importance.

Results

There were 1123 encounters used for training, validation, and testing. Of the classic ML methods, XGBoost had the highest AU_PRC (0.936), accuracy (0.887), and F1 score (0.863) which outperformed ICD-10-CM codes [accuracy 0.870; F1 0.830]. Logistic regression, support vector machine, and XGBoost models had higher AU_PRC using transformed text, while decision trees performed better using raw text. Excluding XGBoost, fine-tuned pre-trained language models outperformed classic ML methods. The best performing model was the fine-tuned SMART-AI based model with domain adaptation [AU_PRC 0.948; accuracy 0.882; F1 0.851]. Explainability analyses showed the most predictive terms were ‘heroin’, ‘opioids’, ‘alcoholic intoxication, chronic’, ‘cocaine’, ‘opiates’, and ‘suboxone’.

Conclusions

NLP-based models outperform entry of ICD-10-CM diagnosis codes for the detection of ED encounters with opioid misuse. Fine tuning with domain adaptation for pre-trained language models resulted in improved performance.
Protective role of dietary antioxidant intake on long-term effects of extreme PM2.5exposure on respiratory health
Authors: Govindaraju Thara , Smith Catherine L , Ikin Jillian , Owen Alice J , Carroll Matthew , Borg Brigitte M. , Gao Caroline X , Brown David , Poland David , Allgood Shantelle , Abramson Michael J , Walker-Bone Karen , McCaffrey Tracy A , Lane Tyler J
Published: December 2024

Objective

Evidence for the protective effects of dietary antioxidants on respiratory health following exposure to smoke from landscape fires is scarce. This study assessed whether the long-term respiratory effects of fine particulate matter (PM2.5) from the 2014 Hazelwood coal mine fire were moderated by dietary antioxidants, 8.5 years later.

Methods

We conducted a cross-sectional analysis of data collected 8.5 years after the mine fire from 282 residents of Morwell (a highly exposed town adjacent to the mine) and 166 residents from the nearby unexposed town of Sale. Coal mine fire-related PM2.5was the primary exposure and meeting recommended dietary intake for antioxidants including vitamins (A, E and C), minerals (zinc, magnesium and selenium) and omega-3 fatty acids assessed through the Australian Eating Survey (AES) was the moderator. Respiratory symptoms were the primary outcome. Analyses used logistic regression models, adjusting for potential confounders.

Results

Vitamins A and E, magnesium, and zinc attenuated the association between fire-related PM2.5and prevalence of chronic cough; three of the four (except magnesium) attenuated the association between fire-related PM2.5and chronic phlegm. Omega-3 fatty acids attenuated the association between PM2.5and COPD.

Conclusion

Meeting recommended intakes of vitamins, A and E, magnesium and zinc may provide protection against the long-term adverse effects of exposure to particulate matter from other medium duration but extreme exposure events. Advocating incorporation of fruits and vegetables in daily diet could offer more than the conventional health benefits due to their high antioxidant content.

Highlights

➢ A coal mine fire exposed a regional Victorian community to extreme levels of PM2.5.

➢ We examined if dietary antioxidants mitigated PM2.5effects on respiratory health.

➢ Vitamins A and E and Zinc reduced PM2.5effects on chronic cough and chronic phlegm.
Sex Differences in Non-Acute Myocardial Infarction Cardiogenic Shock: Insights from the Northwell-Shock Registry
Authors: Li Shuojohn , Adi Abduljabar , Miller Marcy , Sakr Fouad , Jnani Jack , Rodriguez Emily A. , Tan Samuel , Mokhtari Moein Bayat , Ramsis Ramsis , Smoller Rebecca , Stevens Gerin R. , Hernandez-Montfort Jaime , Griffin Matthew , Pierce Matthew , Villela Miguel Alvarez
Published: December 2024

2.

Background

Previous studies had explored the role of patients’ sex in defining clinical presentation, management, and outcomes among patients with acute myocardial infarction (AMI) related cardiogenic shock (CS). However, the effect of sex among patients with non-acute myocardial infarction related CS (nonAMI-CS) is less well defined.

Method

Adult patients treated for CS (International Classification of Diseases, Tenth Revision, [ICD-10] code R57.0) between 2016 and 2022 across eleven hospitals within our health system, all utilizing a shared electronic medical record, were included. CS etiologies were defined as AMI, nonAMI and others. For nonAMI-CS patients, stratification by sex was performed to compare the incidence of specific etiologies, baseline characteristics, management and outcomes between men and women. Comparisons were conducted using t-tests, Wilcoxon rank-sum tests or chi-square tests. Logistic regression models were developed to examine the effect of sex on in-hospital mortality, management strategies, and mortality predictors.

Result

2,256 patients admitted for nonAMI-CS were identified. Women comprised 36% of the study cohort and were older and had more medical comorbidities. There was no significant difference in presenting CS severity as measured by Society for Cardiovascular Angiography and Interventions (SCAI) stages, APACHE scores or in-hospital mortality. There were significant differences in the specific etiologies of nonAMI-CS, where women had more valvular cardiogenic shock. Women received fewer invasive interventions including pulmonary artery catheter (PAC) and intra-aortic balloon pump (IABP) when compared to men but similar rates of Impella and venoarterial extracorporeal membrane oxygenation (VA-ECMO). Lastly, women were more likely to be discharged to skilled nursing facilities while men more likely to home.

Conclusion

Significant sex-specific differences exist in nonAMI-CS including specific etiologies, management strategies, and factors associated with mortality. Despite older age, more comorbidities and lower rates of invasive management procedures, women had similar survival to men but higher need for skilled facilities upon discharge.
Uncertainty in blacklisting potential Pacific plant invaders using species distribution models
Authors: Holle Valén , Rönnfeldt Anna , Schifferle Katrin , Cabral Juliano Sarmento , Craven Dylan , Knight Tiffany , Seebens Hanno , Weigelt Patrick , Zurell Damaris
Published: December 2024

Invasive alien species pose a growing threat to global biodiversity, necessitating evidence-based prevention measures. Species distribution models (SDMs) are a useful tool for quantifying the potential distribution of alien species in non-native areas and deriving blacklists based on establishment risk. Yet, uncertainties due to different modelling decisions may affect predictive accuracy and the robustness of such blacklists. We thus aim to assess the relevance of three distinct sources of uncertainty in SDM-based blacklists: species data, environmental data and SDM algorithms.

Focusing on 82 of the most invasive plant species on the Hawaiian Islands, we built SDMs to quantify their establishment potential in the Pacific region. We considered two different species datasets (native vs. global occurrences), two environmental predictor sets (climatic vs. edapho-climatic), and four different SDM algorithms. Based on SDM predictions, we derived blacklists using three distinct blacklisting definitions and quantified the variance in blacklist rankings associated with each source of uncertainty.

On average, SDMs showed fair predictive performance. SDM algorithm choice resulted in the largest variation in blacklist ranks while the relevance of species and environmental data was lower and varied across blacklist definitions. Nevertheless, using only native occurrences led to a clear underestimation of the establishment potential for certain species and to lower predictive performance, including high-ranking species on blacklists.

SDMs can serve as a robust decision support tool to plan preventive management strategies. To establish robust model-aided blacklists, we recommend ensemble models using multiple SDM algorithms that rely on global rather than native occurrences only. The relevance of environmental predictors additional to climate should be carefully considered and weighed against spatial coverage of those data to ensure sufficiently large sample sizes and predictive accuracy. We advocate for explicit assessment of uncertainty to increase confidence in blacklists and allow more reliable decision-making.
Two strains of Toscana virus show different virulence and replication capacity in mice and cell culture models
Authors: Roy Marlène , Lacôte Sandra , Desloire Sophie , Thiesson Adrien , Pulido Coralie , Aurine Noémie , Mathieu Cyrille , Pain Bertrand , Marianneau Philippe , Arnaud Frédérick , Ratinier Maxime
Published: December 2024

Toscana virus (TOSV), belonging toPhenuiviridaefamily, is circulating in most Mediterranean countries and is transmitted to humans by infected female sand flies. While most infections are asymptomatic, TOSV is considered as a leading cause of meningitis and encephalitis in humans during summer. Three TOSV genotypes (named A, B, and C) have been identified, although no virus strain belonging to lineage C has been isolated so far. To date, the relationship between TOSV genetic diversity and viral pathogenicity or replication capacity remains unknown. This study aimed to compare two TOSV strains from either lineage A (TOSV-A) or B (TOSV-B) in several cell culture and two mouse models. We showed that TOSV-A replicated more efficiently in BSR and A549 cells while TOSV-B had a replication advantage in human induced pluripotent stem cells differentiated in neural cells and LL-5 sand fly cells.In vivo, we were unable to detect any virus in the brains of immunocompetent C57BL/6JRj mice infected with either strain of TOSV. On the contrary, we showed that TOSV-A disseminated to the central nervous system of 129/Svifnar-/-mice unlike TOSV-B, despite higher viremia of TOSV-B and a greater dissemination of this strain in other organs. The reasons for these differences are not yet known, although we showed that the presence of TOSV neutralizing antibodies in serum was slightly delayed in TOSV-A-infected mice. Altogether, the data presented in this study provide new avenues to study TOSV-induced pathogenesis and ultimately unveil molecular viral determinants modulating TOSV replication capacity.

Author Summary

Toscana virus is a sand fly-borne phlebovirus with tropism for the human central nervous system (CNS) and the causal agent of aseptic meningitis and encephalitis during summer in countries surrounding the Mediterranean Sea. The pathogenesis induced by TOSV is still poorly understood as well as the correlation between TOSV genetic diversity and viral pathogenicity or replication capacity. In this study, we characterised two TOSV strains belonging to two different genetic lineages (named A and B) in severalin vitro,ex vivoandin vivomodels of infection. We showed that the biological properties of these two strains is strikingly different and, importantly, we identified 129/Svifnar-/-mice as a suitable model to study the mechanism of TOSV invasion of the CNS and viral pathogenesis. Our comparative study also highlights the importance of strengthening our efforts to identify molecular viral determinants modulating TOSV-induced pathogenesis and vector transmission, in order to better characterise the epidemiological risk posed by circulating strains.
Both tobacco TA29 and sesame GN13 promoters provide anther-specific GUS expression in transgenic sesame (Sesamum indicumL.)
Authors: Debnath Anirban Jyoti , Basu Debabrata , Sikdar Samir Ranjan
Published: December 2024

Yield improvement is one of the most concerning areas of the “Queen of Oilseed” sesame (Sesamum indicumL.) for its successful commercialisation. Heterosis breeding is an alternate approach for improving sesame compared to the time- and labour-consuming conventional breeding. However, tedious hand emasculation and pollination processes restrict the implementation of commercial heterosis on sesame. The unavailability of male sterile, restorer, and maintainer lines further complicates the problem. Biotechnological gene manipulation can silence anther-specific vital gene(s) leading to male sterility. Anther-specific gene study is therefore crucial to reach such a goal. In this study, we have cloned two established anther-specific promoters: sesame SiBGproplus (hereafter GN13, NCBI accession no.KT246471) and tobacco TA29 (NCBI accession no.X52283) in the plant expression vector pCAMBIA2301 producing respective GN13::GUS and TA29::GUS chimeric vectors. We recovered putatively transgenic T0 sesame lines using conventionalAgrobacterium-mediated transformation with 1.76% and 1.71% frequencies, respectively. The T0 lines were segregated at the 3:1 Mendelian segregation ratio for kanamycin resistance and generated T1 transgenic lines by self-fertilisation. Most of the T1 transgenics had a single copy of transgene integration. The histological assay revealed the tapetum-specific GUS expression in the T1 transgenic lines; GUS expression was undetected in other tested plant parts. The results depict successful anther/tapetum-specific expression of two promoters in transgenic sesame lines. In further research, these promoters could be used for anther-specific cytotoxic gene expression, RNAi, or CRISPR-mediated mutational approaches to destroy androecium selectively and exhibit male sterility in sesame, resulting in heterosis-mediated improvement.
Cold stress involves CBF dependent regulatory pathway to remodel wood formation inEucalyptus gunniihybrids
Authors: Bachir Ines Hadj , Ployet Raphael , San Clemente Hélène , Aguilar Marielle , Dupas Annabelle , Ladouce Nathalie , Martinez Yves , Grima-Pettenati Jacqueline , Teulières Chantal , Cassan-Wang Hua , Mounet Fabien
Published: December 2024

While being the most planted tree worldwide, mostEucalyptusspecies are sensitive to frost. Long-term exposure to cold temperatures, among other abiotic cues, triggers modification of secondary xylem differentiation inEucalyptus, but the molecular mechanisms behind it remain unknown. Overexpression of key players of cold signalling pathway, the CRT-repeat binding factors (CBF), not only causes the expected increase in freezing tolerance but also remodels wood in a similar trend to cold acclimation, making it a good candidate for wood functional adaptation to cold stress. To gain insight in CBF role in cold-induced secondary cell wall (SCW) remodelling, we used both targeted and untargeted methodologies to show that chilling and freezing temperatures induced the deposition of a thick SCW with alterations in lignin and polysaccharides composition as well as modifications of wood anatomy in aEucalyptuscold-tolerant hybrid. Using co-expression network approaches, we identified CBF transcription factors (TFs) as a regulatory hub in xylem cold response. Direct targets of the CBF TFs were identified by DAPseq and unravelled promising candidates involved in SCW deposition and hormonal signalling pathways. Our results shed new light on the interplay between cold response and wood formation, bringing new evidence for the role of the cell wall in trees tolerance to abiotic stresses.
Frequency-specific theta states in the hippocampus modulate population activity with respect to behavioural context
Authors: Masaracchia Laura , Fredes Felipe , Vidaurre Diego
Published: December 2024

Neural activity reflects both external stimuli and the brain's internal state, which shapes how information is processed and perceived. An example of modulation of neural responses by network states is phase-precession in the hippocampus, where the phase of theta oscillations affects the firing of single neurons (place cells) and its relation to the external world. Here, we examine a different form of oscillation-to-neuron modulation, where frequency and power of the oscillation, instead of phase, modulate neural firing patterns at the population level. We refer to this as ensemble pattern modulation. To study this effect, we use electrophysiological recordings of rats performing an odour-memory (non-spatial) task. Using a data-driven model, we identified two distinct theta states: low-power-lower-theta (LPLT) and high-power-higher-theta (HPHT). Through decoding analyses, we found that these states differentially modulate hippocampal neural ensemble activity, in this case reflective of the trial outcome. This suggests that amplitude and frequency variations within theta oscillations may reconfigure neural firing at the network level to support distinct cognitive functions.
Single-cell multi-omic analysis of fibrolamellar carcinoma reveals rewired cell-to-cell communication patterns and unique vulnerabilities
Authors: Farghli Alaa R. , Chan Marina , Sherman Marc S. , Dickerson Lindsay K. , Shui Bo , Nukaya Manabu , Stephanou Andreas , Ma Rosanna K. , Pepe-Mooney Brian J. , Smith Colton J. , Long Donald , Munn Paul R. , McNairn Adrian , Grenier Jennifer K. , Karski Michael , Ronnekleiv-Kelly Sean M. , Pillarisetty Venu G. , Goessling Wolfram , Gujral Taranjit S. , Vakili Khashayar , Sethupathy Praveen
Published: December 2024

Fibrolamellar carcinoma (FLC) is a rare malignancy disproportionately affecting adolescents and young adults with no standard of care. FLC is characterized by thick stroma, which has long suggested an important role of the tumor microenvironment. Over the past decade, several studies have revealed aberrant markers and pathways in FLC. However, a significant drawback of these efforts is that they were conducted on bulk tumor samples. Consequently, identities and roles of distinct cell types within the tumor milieu, and the patterns of intercellular communication, have yet to be explored. In this study we unveil cell-type specific gene signatures, transcription factor networks, and super-enhancers in FLC using a multi-omics strategy that leverages both single-nucleus ATAC-seq and single-nucleus RNA-seq. We also infer completely rewired cell-to-cell communication patterns in FLC including signaling mediated by SPP1-CD44, MIF-ACKR3, GDF15-TGFBR2, and FGF7-FGFR. Finally, we validate findings with loss-of-function studies in several models including patient tissue slices, identifying vulnerabilities that merit further investigation as candidate therapeutic targets in FLC.