bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increasing Systemic Immune-inflammation Index During Treatment in Patients With Advanced Pancreatic Cancer is Associated With Poor Survival
Authors: van ‘t Land Freek R. , Aziz Mohammad H. , Michiels Nynke , Mieog J. Sven D. , Bonsing Bert A. , Luelmo Saskia A.C. , Homs Marjolein Y.V. , Groot Koerkamp Bas , Papageorgiou Grigorios , van Eijck Casper H.J. 
Published: April 2023

Background and Objectives:
A high systemic immune-inflammation index (SIII) at diagnosis of various cancers, including pancreatic cancer, is associated with poor prognosis. The impact of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) chemotherapy or stereotactic body radiotherapy on this index is unknown. In addition, the prognostic value of changes in the SIII during treatment is unclear. In this retrospective analysis, we aimed to find answers regarding patients with advanced pancreatic cancer.

Methods:
Patients with advanced pancreatic cancer treated with FOLFIRINOX chemotherapy alone or with FOLFIRINOX chemotherapy followed by stereotactic body radiotherapy between 2015 and 2021 in 2 tertiary referral centers were included. Baseline characteristics, laboratory values at 3 time points during treatment, and survival outcomes were collected. The patient-specific evolutions of SIII and their association with mortality were assessed with joint models for longitudinal and time-to-event data.

Results:
Data of 141 patients were analyzed. At a median follow-up time of 23.0 months (95% CI: 14.6–31.3), 97 (69%) patients had died. Median overall survival was 13.2 months (95% CI: 11.0–15.5). During treatment with FOLFIRINOX, the log (SIII) was reduced by −0.588 (95% CI: −0.0978, −0.197; P = 0.003). One unit increase in log (SIII) increased the hazard ratio of dying by 1.604 (95% CI: 1.068–2.409; P = 0.023).

Conclusions:
In addition to carbohydrate antigen 19-9, the SIII is a reliable biomarker in patients with advanced pancreatic cancer.
A Noninvasive Technology Using Artificial Intelligence to Measure the Diameter of Esophageal Varices Under Endoscopy
Authors: Jin Jing , Dong Bill , Ye Chao , Zhang Qianqian , Wu Aijiu , Dong Lanfang , Kong Derun 
Published: April 2023

Background:
The diameter of esophageal varices (EVs) can not only predict variceal bleeding episodes but is also considered to be a significant factor in determining the endoscopic treatment of EVs. At present, visual observation is the most common method for estimating the diameter of EVs, the results of which may vary greatly between endoscopists.

Materials and Methods:
Herein, a noninvasive measurement technology, a virtual ruler (VR), was designed using artificial intelligence. The diameter and pressure of EVs in 7 patients were measured using VR and an esophageal varix manometer (EVM). Statistical methods, including the Bland-Altman Plot and Pearson correlation coefficient analysis, were used to compare the aforementioned 2 methods.

Results:
The results showed that the diameter of EVs measured using the aforementioned 2 methods did not differ. In addition, the time taken to measure the diameter of EVs using VR was 31 seconds (range, 25 to 44 s), significantly shorter compared with 159 seconds (range, 95 to 201 s) taken using an EVM (P< 0.01). Furthermore, the diameter of EVs measured using an EVM exhibited a high linear correlation with pressure.

Conclusions:
The current study demonstrated that VR was more accurate in measuring the diameter of EVs compared with EVMs while reducing unnecessary early intervention and the risk of complications. In terms of clinical risk and economic cost, this technology is hardly a burden. Overall, VR could be a useful software for the endoscopic detection and treatment of EVs in patients with liver cirrhosis.
Alternative Substrates in the Critically Ill Subject (ASICS): Safety, Feasibility, Tolerability and Metabolic Profiling of a Novel Ketogenic Feed
Authors: McNelly Angela , Langan Anne , Bear Danielle E. , Page Alexandria , Martin Tim , Seidu Fatima , Santos Filipa , Rooney Kieron , Liang Kaifeng , Baldwin Tomas , Heales Simon J , Alldritt Isabelle , Crossland Hannah , Atherton Philip J. , Wilkinson Daniel , Montgomery Hugh , Prowle John , Pearse Rupert , Eaton Simon , Puthucheary Zudin A. 
Published: April 2023

AbstractBioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone bodies may form an alternative substrate source, but the feasibility and safety of inducing a ketogenic state in physiologically unstable patients is not known.Twenty-nine mechanically ventilated adults with multi-organ failure were randomised into a two-centre safety and feasibility trial of ketogenic versus standard enteral feeding. Ketogenic feeding was feasible, safe, well tolerated and resulted in ketosis. Patients receiving ketogenic feeding had fewer hypoglycaemic events (0% vs. 1.58%), required less exogenous insulin (0.0 IU (IQR 0-16) vs.78 IU (IQR 0-412) but had slightly more daily episodes of diarrhoea (53.5% vs. 42.9%) over the trial period. Untargeted metabophenotyping revealed altered Cahill cycle flux and bioenergetic states, suggesting an advantageous metabolic profile. Ketogenic feeding is feasible and may be a novel intervention for addressing bioenergetic failure in critically ill patients.Clinical Trials.govregistration:NCT04101071; 19.09.2019.Take-home MessageCritical illness leads to altered metabolic states and bioenergetic failure caused by impaired utilisation of glucose, fatty acids and amino acids. This contributes to organ dysfunction across multiple tissues. Ketones may provide a safe and acceptable alternative metabolic fuel enabling energy production and maintaining tissue homeostasis.TweetKetogenic enteral feeding in early critical illness is feasible, safe and may decrease insulin requirements.
A Graph Embedding Approach for Deciphering the Longitudinal Associations of Global Mobility and COVID-19 Cases
Authors: Awasthi Raghav , Modi Meet , Dudeja Hardik , Bajaj Tanav , Rastogi Shruti , Sethi Tavpritesh 
Published: April 2023

AbstractThe COVID-19 pandemic has highlighted the importance of monitoring mobility patterns and their impact on disease spread. This paper presents a methodology for developing effective pandemic surveillance systems by extracting scalable graph features from mobility networks. We utilized Meta’s “Travel Patterns” dataset to capture the daily number of individuals traveling between countries from March 2020 to April 2022. We have used an optimized node2vec algorithm to extract scalable features from the mobility networks. Our analysis revealed that movement embeddings accurately represented the movement patterns of countries, with geographically proximate countries exhibiting similar movement patterns. The temporal association dynamics between Global mobility and COVID-19 cases highlighted the significance of high-page rank centrality countries in mobility networks as a key intervention target in controlling infection spread. Our proposed methodology provides a useful approach for tracking the trajectory of infectious diseases and developing evidence-based interventions.
CORE CONSERVED TRANSCRIPTIONAL REGULATORY NETWORKS DEFINE THE INVASIVE TROPHOBLAST CELL LINEAGE
Authors: Vu Ha T.H. , Scott Regan L. , Iqbal Khursheed , Soares Michael J. , Tuteja Geetu 
Published: April 2023

ABSTRACTThe invasive trophoblast cell lineage in rat and human share crucial responsibilities in establishing the uterine-placental interface of the hemochorial placenta. These observations have led to the rat becoming an especially useful animal model to study hemochorial placentation. However, our understanding of similarities or differences between regulatory mechanisms governing rat and human invasive trophoblast cell populations is limited. In this study, we generated single-nucleus (sn) ATAC-seq data from gestation day (gd) 15.5 and 19.5 rat uterine-placental interface tissues and integrated the data with single-cell RNA-seq data generated at the same stages. We determined the chromatin accessibility profiles of invasive trophoblast, natural killer, macrophage, endothelial, and smooth muscle cells, and compared invasive trophoblast chromatin accessibility to extravillous trophoblast (EVT) cell accessibility. In comparing chromatin accessibility profiles between species, we found similarities in patterns of gene regulation and groups of motifs enriched in accessible regions. Finally, we identified a conserved gene regulatory network in invasive trophoblast cells. Our data, findings and analysis will facilitate future studies investigating regulatory mechanisms essential for the invasive trophoblast cell lineage.
Ongoing introgression of a secondary sexual plumage trait in a stable avian hybrid zone
Authors: Long Kira M. , Rivera-Colón Angel G. , Bennett Kevin F. P. , Catchen Julian M. , Braun Michael J. , Brawn Jeffrey D. 
Published: April 2023

AbstractHybrid zones are dynamic systems where natural selection, sexual selection, and other evolutionary forces can act on reshuffled combinations of distinct genomes. The movement of hybrid zones, individual traits, or both are of particular interest for understanding the interplay between selective processes. In a hybrid zone involving two lek-breeding birds, secondary sexual plumage traits ofManacus vitellinus, including bright yellow collar and olive belly color, have introgressed asymmetrically ∼50 km across the genomic center of the zone into populations more genetically similar toManacus candei. Males with yellow collars are preferred by females and are more aggressive than parentalM. candei, suggesting that sexual selection was responsible for the introgression of male traits. We assessed the spatial and temporal dynamics of this hybrid zone using historical (1989 - 1994) and contemporary (2017 - 2020) transect samples to survey both morphological and genetic variation. Genome-wide SNP data and several male phenotypic traits show that the genomic center of the zone has remained spatially stable, whereas the olive belly color of maleM. vitellinushas continued to introgress over this time period. Our data suggest that sexual selection can continue to shape phenotypes dynamically, independent of a stable genomic transition between species.
Improved detection of aberrant splicing using the Intron Jaccard Index
Authors: Scheller Ines F. , Lutz Karoline , Mertes Christian , Yépez Vicente A. , Gagneur Julien 
Published: April 2023

ABSTRACTDetection of aberrantly spliced genes is an important step in RNA-seq-based rare disease diagnostics. We recently developed FRASER, a denoising autoencoder-based method for aberrant splicing detection that outperformed alternative approaches. However, as FRASER’s three splice metrics are partially redundant and tend to be sensitive to sequencing depth, we introduce here a more robust intron excision metric, the Intron Jaccard Index, that combines alternative donor, alternative acceptor, and intron retention signal into a single value. Moreover, we optimized model parameters and filter cutoffs using candidate rare splice-disrupting variants as independent evidence. On 16,213 GTEx samples, our improved algorithm called typically 10 times fewer splicing outliers while increasing the proportion of candidate rare splice-disrupting variants by 10 fold and substantially decreasing the effect of sequencing depth on the number of reported outliers. Application on 303 rare disease samples confirmed the reduction fold-change of the number of outlier calls for a slight loss of sensitivity (only 2 out of 22 previously identified pathogenic splicing cases not recovered). Altogether, these methodological improvements contribute to more effective RNA-seq-based rare diagnostics by a drastic reduction of the amount of splicing outlier calls per sample at minimal loss of sensitivity.
Pharmaceutical and Non-Pharmaceutical Interventions for Controlling the COVID-19 Pandemic
Authors: Molla Jeta , Farhang-Sardroodi Suzan , Moyles Iain R , Heffernan Jane M 
Published: April 2023

AbstractDisease spread can be affected by pharmaceutical (such as vaccination) and non-pharmaceutical interventions (such as physical distancing, mask-wearing, and contact tracing). Understanding the relationship between disease dynamics and human behavior is a significant factor to controlling infections. In this work, we propose a compartmental epidemiological model for studying how the infection dynamics of COVID-19 evolves for people with different levels of social distancing, natural immunity, and vaccine-induced immunity. Our model recreates the transmission dynamics of COVID-19 in Ontario up to December 2021. Our results indicate that people change their behaviour based on the disease dynamics and mitigation measures. Specifically, they adapt more protective behaviour when the number of infections is high and social distancing measures are in effect, and they recommence their activities when vaccination coverage is high and relaxation measures are introduced. We demonstrate that waning of infection and vaccine-induced immunity are important for reproducing disease transmission in Fall 2021.
Clinical Phenotype Prediction From Single-cell RNA-seq Data using Attention-Based Neural Networks
Authors: Mao Yuzhen , Lin Yen-Yi , Wong Nelson K.Y. , Volik Stanislav , Sar Funda , Collins Colin , Ester Martin 
Published: April 2023

AbstractMotivationA patient’s disease phenotype can be driven and determined by specific groups of cells whose marker genes are either unknown, or can only be detected at late-stage using conventional bulk assays such as RNA-Seq technology. Recent advances in single-cell RNA sequencing (scRNA-seq) enable gene expression profiling in cell-level resolution, and therefore have the potential to identify those cells driving the disease phenotype even while the number of these cells is small. However, most existing methods rely heavily on accurate cell type detection, and the number of available annotated samples is usually too small for training deep learning predictive models.ResultsHere we propose the method ScRAT for clinical phenotype prediction using scRNA-seq data. To train ScRAT with a limited number of samples of different phenotypes, such as COVID and non-COVID, ScRAT first applies a mixup module to increase the number of training samples. A multi-head attention mechanism is employed to learn the most informative cells for each phenotype without relying on a given cell type annotation. Using three public COVID datasets, we show that ScRAT outperforms other phenotype prediction methods. The performance edge of ScRAT over its competitors increases as the number of training samples decreases, indicating the efficacy of our sample mixup. Critical cell types detected based on high-attention cells also support novel findings in the original papers and the recent literature. This suggests that ScRAT overcomes the challenge of missing marker genes and limited sample number with great potential revealing novel molecular mechanisms and/or therapies.
When cheating turns into a stabilizing mechanism of mutualistic networks
Authors: Duchenne François , Aubert Stéphane , Barreto Elisa , Brenes Emanuel , Maglianesi María A. , Santander Tatiana , Guevara Esteban A. , Graham Catherine H. 
Published: April 2023

AbstractMutualistic interactions, such as plant-mycorrhizal or plant-pollinator interactions, are widespread in ecological communities and frequently exploited by cheaters, species that profit from interactions without providing benefits in return. Cheating usually negatively affects the fitness of the individuals that are cheated on, but the effects of cheating at the community level remains poorly understood. Here we describe two different kinds of cheating in mutualistic networks and use a generalized Lotka-Volterra model to show that they have very different consequences for the persistence of the community. Conservative cheating, where a species cheats on its mutualistic partners to escape the cost of mutualistic interactions, negatively affects community persistence. In contrast, innovative cheating occurs with species with whom legitimate interactions are not possible, because of a physiological or morphological barrier. Innovative cheating can enhance community persistence under some conditions: when cheaters have few mutualistic partners, cheat at low or intermediate frequency and the cost associated with mutualism is not too high. In this case, the negative effects of cheating on partner persistence are over-compensated at the community level by the positive feedback loops that arise in mutualistic networks. Using an empirical dataset of plant-bird interactions, we found that observed cheating patterns are highly consistent with theoretical cheating patterns found to increase community persistence. This result suggests that the cheating patterns observed in nature could contribute to promote species coexistence in mutualistic communities, instead of necessarily destabilizing them.
ATP13A4 upregulation drives the elevated polyamine transport system in the breast cancer cell line MCF7
Authors: van Veen Sarah , Kourti Antria , Ausloos Elke , Van Asselberghs Joris , Van den Haute Chris , Baekelandt Veerle , Eggermont Jan , Vangheluwe Peter 
Published: April 2023

AbstractPolyamine homeostasis is disturbed in several human diseases, including cancer, which is hallmarked by increased intracellular polyamine levels and an upregulated polyamine transport system (PTS). So far, the polyamine transporters contributing to the elevated levels of polyamines in cancer cells have not yet been described, despite the fact that polyamine transport inhibitors are considered for cancer therapy. Here, we tested whether upregulation of candidate polyamine transporters of the P5B- transport ATPase family is responsible for the increased PTS in the well-studied breast cancer cell line MCF7 compared to the non-tumorigenic epithelial breast cell line MCF10A. We found that MCF7 cells present elevated expression of a previously uncharacterized P5B-ATPase ATP13A4, which is responsible for the elevated polyamine uptake activity. Furthermore, MCF7 cells are more sensitive to polyamine cytotoxicity, as demonstrated by cell viability, cell death and clonogenic assays. Importantly, overexpression of ATP13A4 WT in MCF10A cells induces a MCF7 polyamine phenotype, with significantly higher uptake of BODIPY-labelled polyamines and increased sensitivity to polyamine toxicity. In conclusion, we establish ATP13A4 as a new polyamine transporter in the human PTS and show that ATP13A4 may play a major role in the increased polyamine uptake of breast cancer cells. ATP13A4 therefore emerges as a candidate therapeutic target for anticancer drugs that block the PTS.
Single-cell phenomics reveals behavioural and mechanical heterogeneities underpinning collective migration during mouse anterior patterning
Authors: Stower Matthew , Zhou Felix , Hathrell Holly , Yeung Jason , Thowfeequ Shifaan , Godwin Jonathan , Schneider Falk , Lagerholm Christoffer , Fritzsche Marco , Thiyagalingam Jeyan , Lu Xin , Rittscher Jens , Srinivas Shankar 
Published: April 2023

SUMMARYDistal Visceral Endoderm (DVE) cells show a stereotypic unidirectional migration essential for correct orientation of the anterior-posterior axis. They migrate within a simple epithelium, the Visceral Endoderm (VE). It is unknown how DVE cells negotiate their way amongst the surrounding VE cells, what determines the bounds of DVE migration within the VE, and the relative contributions of different cell behaviours to this migration. To address these questions, we used lightsheet microscopy to generate a multi-embryo, singlecell resolution, longitudinal dataset of cell behaviour and morphology. We developed a machine learning based pipeline to segment cells and a data-informed systematic computational framework to extract and compare select morphological, behavioural and molecular parameters of all VE cells in a unified coordinate space. Unbiased clustering of this single-cell ‘phenomic’ dataset reveals considerable patterned phenotypic heterogeneity within the VE and a previously unknown sub-grouping within the DVE. While migrating, DVE cells retain regular morphology, do not exchange neighbours and are crowded, all hallmarks of the jammed state. In contrast, VE cells immediately ahead of them deform and undergo neighbour exchange. We show that DVE cells are characterised by higher levels of apical F-actin and elevated tension relative to the VE cells immediately ahead of them through which they migrate, but stop migrating upon reaching a region of the VE with matching elevated tension.Lefty1mutants, known to show abnormal over-migration of DVE cells, show disruption to this patterned tension in the VE. Our findings provide novel insights into the control of cell behaviour during the remodelling of curved epithelia, indicating that the collective migration of sub-sets of cells can be circumscribed by modulating the mechanical properties of surrounding cells and that migrating cells in this context remain as a jammed solid flock, with surrounding cells facilitating their movement by becoming unjammed.Graphical Abstract
Epigenetic mechanisms to propagate histone acetylation by p300/CBP
Authors: Kikuchi Masaki , Morita Satoshi , Wakamori Masatoshi , Sato Shin , Uchikubo-Kamo Tomomi , Shirouzu Mikako , Umehara Takashi 
Published: April 2023

AbstractHistone acetylation is important for the activation of gene transcription but little is known about its direct ‘read/write’ mechanisms. Here, we report cryo-electron microscopy structures in which a p300/CBP multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTacviathe bromodomain pocket responsible for ‘reading’, but also interacted with the DNA minor groovesviathe outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 ‘writes’ by ‘reading’ H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP ‘replicates’ histone NT acetylation within the H3-H4 tetramer to inherit epigenetic storage, and ‘transcribes’ it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.
The unreasonable effectiveness of equilibrium gene regulation through the cell cycle
Authors: Vilar Jose M. G. , Saiz Leonor 
Published: April 2023

AbstractSystems like the prototypicallacoperon can reliably hold the repression of transcription upon DNA replication across cell cycles with just ten repressor molecules per cell and, in addition, behave as if they were at equilibrium. The origin of this type of phenomena is still an unresolved question of major implications. Here, we develop a general theory to analyze strong perturbations in quasi-equilibrium systems and use it to quantify the effects of DNA replication in gene regulation. We find a scaling law that connects actual transcription with its predicted equilibrium values in terms of a single kinetic parameter. We show that even the simplest, exceptionally reliable natural system functions beyond the physical limits of naïve regulation through compensatory mechanisms that suppress nonequilibrium effects. We validate the approach with bothin vivocell-population and single-cell characterization of thelacoperon. Analyses of synthetic systems without adjuvant activators, such as the cAMP receptor protein (CRP), do not show this reliability. Our results provide a rationale for the function of CRP, beyond just being a tunable activator, as a mitigator of cell cycle perturbations.