bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammatory bowel disease and pulmonary embolism: a nationwide perspective
Authors: Aldiabat Mohammad , Alhuneafat Laith , Al Ta’ani Omar , Altarawneh Saba , Aleyadeh Wesam , Almuzamil Taimur , Butt Ali , Alahmad Majd , Madi Mahmoud Y , Alsabbagh Khaled , Ayoub Malek , Kilani Yassine , Alsakarneh Saqr , Jaber Fouad , Alhamdani Adee
Published: September 2024

Objective

To examine the characteristics and outcomes of patients with inflammatory bowel disease (IBD) hospitalized with pulmonary embolism (PE).

Methods

This cross-sectional observational study analyzed data from the 2016 to 2019 National Inpatient Sample to investigate hospitalizations for PE in the USA, stratified by the presence or absence of IBD. Adult patients were selected using the International Classification of Diseases, Tenth Revision codes for PE, Crohn’s disease, and ulcerative colitis. Data on patient demographics, comorbidities, and hospital characteristics were collected. Statistical analysis included univariable and multivariable logistic regression using Stata/BE 17.0, focusing on in-hospital mortality and complications in PE patients with and without IBD. Adjusted odds ratios (aOR) and their corresponding 95% confidence intervals (CI) were calculated when appropriate.

Results

PE/IBD group was younger (mean age 58.3 vs. 62.7 years; P < 0.001), had a higher proportion of white patients (81.2% vs. 70.9%; P < 0.001), and had a greater prevalence of chronic liver disease (7.54% vs. 6.02%; P = 0.002) when compared to PE/non-IBD patients. The PE/IBD group had lower prevalence rates of coronary artery disease, congestive heart failure, obesity, chronic obstructive pulmonary disease, hypertension, and diabetes. Regarding primary outcomes, there was no significant difference in in-hospital mortality between the two groups (aOR, 0.92; 95% CI, 0.77–1.09; P = 0.355). However, the IBD/PE group had a higher risk of acute kidney injury, sepsis, septic shock, cardiac arrhythmias, and deep vein thrombosis. As for secondary outcomes, PE/IBD patients had more extended hospital stays and higher healthcare costs compared with PE/non-IBD patients.

Conclusion

Hospitalized PE patients with IBD differ demographically and have a different comorbidity profile compared to those without IBD. PE/IBD patients demonstrate greater use of healthcare resources and elevated risk of hospitalization adverse events than PE/non-IBD patients, highlighting the necessity for individualized management approaches in this population.
Adolescents and Young Adults With Respiratory Failure in U.S. PICUs: A Pediatric Health Information System Database Study, 2011–2022
Authors: Gochenour Kevin S. , Ross Melissa H. , Flori Heidi R. , Kohne Joseph G.
Published: September 2024

Objectives:

To examine the clinical characteristics, outcomes, and resource use of adolescents and young adults (AYAs) admitted to PICUs in the United States with respiratory failure.

Design:

Retrospective cohort study.

Setting:

De-identified data from 48 U.S. children’s hospitals contributing to the Pediatric Health Information System (PHIS) database.

Patients:

All patients older than 30 days old with respiratory failure, defined as encounters with clinical transaction codes for noninvasive or invasive mechanical ventilation, admitted to PHIS database PICUs from January 2011 to December 2022. Patients were categorized into five cohorts (< 15, 15–18, 19–21, 22–25, and > 25 yr old).

Interventions:

None.

Measurements and Main Results:

A total of 430,238 patients were identified. AYA (≥ 15 yr old) accounted for 15% (65,740) of all PICU admissions with respiratory failure. Forty-nine percent (32,232/65,740) of AYA older than 25 years had medical technology dependence compared with 39% in those younger than 15 years (p < 0.001). Sixty-one percent of AYA older than 25 years had a cardiovascular comorbidity compared with 35% of those younger than 15 years (p < 0.001). Forty percent of AYA older than 25 years had a neurologic comorbidity, and 27% a gastrointestinal comorbidity, compared with 27% and 31%, respectively, in those younger than 15 years (all p < 0.001). Compared with those younger than 15 years, AYA median hospital crude mortality rate was higher at 7.7% compared with 5.2%, as were median hospital charges per encounter at $163K (interquartile range [IQR], $77K–$350K) vs. $121K (IQR, $53K–$278K; all p < 0.001). Median ventilator days and hospital length of stay in survivors were similar for all age cohorts.

Conclusions:

AYA represent a substantial proportion of patients admitted to the PICU with respiratory failure. These individuals have unique comorbidities and are at risk for increased mortality and resource utilization compared with younger patients during hospitalization. Medical complexity and sequelae of pediatric illness may delay the transition of AYA to adult care, necessitating collaboration between adult and pediatric critical care physicians to increase research across the age spectrum and develop and implement appropriate evidence-based guidelines.
Total versus Partial Pancreatectomy in Patients with Pancreatic Cancer Arising from Multifocal or Diffuse Intraductal Papillary Mucinous Neoplasia – A Multicenter Observational Study
Authors: Rompen Ingmar F. , Habib Joseph R. , Kinny-Köster Benedict , Campbell Brady A. , Stoop Thomas F. , Kümmerli Christoph , Andel Paul C.M. , Leseman Charlotte A. , Lesch Carolin , Daamen Lois A. , Javed Ammar A. , Lafaro Kelly J. , Nienhüser Henrik , Billeter Adrian T. , Molenaar I. Quintus , Müller-Stich Beat P. , Besselink Marc G. , He Jin , Loos Martin , Büchler Markus W. , Wolfgang Christopher L.
Published: September 2024

Aim:

To investigate the impact of total pancreatectomy (TP) on oncological outcomes for patients at high-risk of local recurrence or secondary progression in the remnant gland after partial pancreatectomy (PP) for IPMN-associated cancer.

Summary Background Data:

Major risk factors for invasive progression in the remnant gland include multifocality, diffuse main duct dilation, and the presence of invasive cancer. In these high-risk patients, a TP may be oncologically beneficial. However, current guidelines discourage TP, especially in elderly patients.

Methods:

This international multicenter study compares TP versus PP in patients with adenocarcinoma arising from multifocal or diffuse IPMN (2002-2022). Log-rank test and multivariable Cox-analysis with interaction analysis was performed to assess overall survival (OS), disease-free survival (DFS), and local-DFS.

Results:

Of 359 included patients, 162 (45%) were treated with TP, whereas 197 (55%) underwent PP. Despite TP and PP having similar R0-rates (59% vs. 58%, P=0.866), patients undergoing a TP had significantly longer local-DFS compared to PP (P=0.039). However, no difference in OS was observed between the two surgical approaches (P=0.487). In a multivariable analysis, young age (optimal cut-off ≤63.6 yrs) was associated with an OS benefit derived from TP (HR:0.44, 95%CI:0.22-0.89), whereas no significant difference was observed in elderly patients (HR:1.24, 95%CI:0.92-1.67, Pinteraction=0.007).

Conclusion:

Since overall, patients with diffuse or multifocal IPMN with an invasive component do not benefit from TP in terms of OS, the indication for TP may be individualized to young patients who have sufficient life expectancy to benefit from the prevention of secondary progression or local recurrence.
Geography of the Underserved
Authors: Kaufman Elinore J. , Prentice Carter , Williams Devin , Song Jamie , Haddad Diane N. , Brown Joshua B. , Chen Xinwei , Colling Kristin , Chatterjee Paula
Published: September 2024

Objective:

To determine the proportion and characteristics of injured rural residents treated at urban trauma centers (TCs), urban non-trauma centers (NTCs), rural TCs, and rural NTCs.

Summary Background Data:

Timely treatment at a designated trauma center improves outcomes for patients with serious injuries, but rural residents have limited access to designated trauma centers. Rural non-trauma centers may constitute an underrecognized source of trauma care.

Methods:

We used the National Emergency Department Sample to conduct a retrospective, pooled cross-sectional study of ED visits among rural residents with injury severity score (ISS) ≥ 9 (indicating at least moderate injury). Hospitals were designated as a trauma (TC) or non-trauma center (NTC) and as rural or urban. We compared management, disposition, and outcomes among hospital types.

Results:

Of 748,587 injured rural residents from 2016-2020, 384,113 (51.3%) were treated in rural NTCs, 232,845 (31.1%) in urban TCs, 116,493 (15.6%) in urban NTCs, and 15,137 (2.0%) in rural TCs. Injuries treated at rural NTCs were moderate in severity (ISS 9-15) in 76.6% of visits, severe (ISS 16-25) in 15.7%, and very severe (ISS > 25) in 1.1%. Urban TCs saw the highest proportion of very severe injuries (17.3%). Rural NTCs managed 77.5% of visits definitively, discharging 72.8%. They transferred 21.9% of patients. Length of stay was longest and hospital charges highest for patients treated in urban TCs, which also performed the most procedures. Rural NTCs had the shortest length of stay and lowest mean charges.

Conclusions:

Rural non-trauma centers provided initial care for more than half of injured rural residents, including 2 in 5 of those with the most severe injuries, and managed more than 3 in 4 definitively. These hospitals may be an under-recognized component of the US trauma system.
Altered static brain activity and functional connectivity after heat stroke
Authors: Yang Ting , Hou Xinyu , Li Xu , Chen Xiaoxin , Qu Zhengwei , Zhang Wenzheng , Wang Maoyang , Li Jun
Published: September 2024

This study aimed to investigate the alteration of brain function based on resting-state functional MRI in patients after heat stroke. This study included 10 cases of patients after heat stroke and 10 cases of healthy controls. Abnormal brain function was calculated using amplitude of low-frequency fluctuations (ALFF) and degree centrality analysis, as well as functional connectivity analysis based on regions of interest (ROI). Correlation analyses were performed to evaluate the association between brain function changes and clinical scales. Combining ALFF and degree centrality results, the decreased brain regions included the left cuneus and the right angular gyrus, while the increased brain regions included the right cerebellar_Crus1. Using the left cuneus with significant differences in ALFF and degree centrality as ROI, the functional connectivity results revealed decreased brain regions including bilateral lingual gyrus, bilateral postcentral cingulate gyrus, and left precentral gyrus. The degree centrality value of the right cerebellar_Crus1 was positively correlated with glasgow coma scale (GCS) scores (r = 0.726, P = 0.027), and the functional connectivity value of the right posterior cingulate gyrus was positively correlated with GCS scores (r = 0.717, P = 0.030). Heat stroke patients exhibit abnormal activity in multiple brain regions, which has important clinical significance for evaluating the severity of the disease.
Care bundle for preventing intraventricular hemorrhage in premature infants: a best practice implementation project
Authors: Solaz García Álvaro , Ros Navarret Rosario , Aguar Carrascosa Marta , Valles Murcia Nerea , Llorens Roberto , Torrejón Rodríguez Laura , Pinilla González Alejandro , Albornos-Muñoz Laura , Escrig Fernández Raquel
Published: September 2024

Introduction:

Intraventricular hemorrhages remain a major problem in neonatology, because their complications affect neonatal morbidity, mortality, and long-term neurodevelopmental outcomes.

Aim:

The aim of this project was to prevent intraventricular hemorrhage in premature infants during their first days of life in a neonatal intensive care unit (NICU).

Methods:

This pre- and post-implementation clinical audit project used the JBI Evidence Implementation Framework and was conducted in a tertiary-level Spanish NICU with a consecutive sample. A baseline audit was conducted using 13 audit criteria derived from JBI summaries of the best available evidence. This was followed by the implementation of an action plan, which included a care bundle and health care professionals’ education. These improvement strategies were then evaluated using a follow-up audit.

Results:

The baseline and follow-up audits evaluated 54 and 56 infants, respectively. The follow-up audit showed 100% improvement for Criteria 2, 3, 6, and 7, which covered sleep safety and noise. Criteria 12 and 13, which covered cord clamping and positioning the infant, improved by 25.99%. Criterion 9, on antenatal corticosteroids, showed a slight improvement of 5.56%.

Conclusions:

This study increased compliance with an evidence-based, family-centered care approach to preventing intraventricular hemorrhage in premature infants. This was achieved by conducting a baseline and follow-up audit, implementing a training program, and keeping more comprehensive nursing records. Further studies could assess the long-term effectiveness of interventions and/or the incidence of intraventricular hemorrhage and neurodevelopmental disorders in premature infants.

Spanish abstract:

http://links.lww.com/IJEBH/A262
Tautology explains evolution without variation and selection. A Comment on: ‘An evolutionary process without variation and selection’ (2021), by Gabora
et al.
Authors: Zachar István , Máté Jakab , Számadó Szabolcs
Published: September 2024

Gabora and Steel (Gabora L, Steel M. 2021 An evolutionary process without variation and selection.
J. R. Soc. Interface
18, 20210334. [doi:10.1098/rsif.2021.0334]) claim that cumulative adaptive evolution is possible without natural selection, that is, without variation and competition. To support this claim, the authors modelled a theoretical process called self–other reorganization (SOR) that envisages a population of reflexively autocatalytic sets that can accumulate beneficial changes without any form of birth, death or selection, that is without population dynamics. The authors claim that despite being non-Darwinian, adaptive evolution happens in SOR, deeming it relevant to the origin of life and to cultural evolution. We analysed SOR and the claim that it implements evolution without variation and selection. We found that the authors, by design, ignore the growth and/or degradation of autocatalytic sets or their components, assuming all effects are beneficial and all entities in SOR are identical and immutable. We prove that due to these assumptions, SOR is a trivial model of horizontal percolation of beneficial effects over a static population. We implemented an extended model of SOR including more realistic assumptions to prove that accounting for any of the ignored processes inevitably leads to conventional Darwinian dynamics. Our analysis directly challenges the authors’ claims, revealing evidence of an overly fragile foundation. While the best-case scenario the authors incorrectly generalize from may be mathematically valid, stripping away their unrealistic assumptions reveals that SOR does not represent real entities (e.g. protocells) but rather models the triviality that fast horizontal diffusion of effects can effectively equalize a population. Adaptation in SOR is solely because the authors only consider beneficial effects. The omission of death/growth dynamics and maladaptive effects renders SOR unrealistic and its relevance to evolution, cultural or biological, questionable.
Density functional theory-based study on the structural, electronic and spectral properties of gas-phase PbMg

n
−

(
n
= 2–12) clusters
Authors: Jiang Zai-Fu , Zhang Ding-Mei , Kong Pan-Long , Wang Jing-Jing , Dai Wei , Zhu Ben-Chao
Published: September 2024

Gas-phase PbMg

n
−

(
n
= 2–12) cluster structures were globally searched on their potential energy surfaces by means of the CALYPSO prediction software. Structural optimization and calculations of properties such as relative energy and electronic structure were then carried out by density functional theory for each size of low energy isomer. The structural, relative stability, natural charge population, natural electronic configuration and distribution of the strongest peaks of the infrared and Raman spectra of the low energy isomers of PbMg

n
−

(
n
= 2–12) clusters were systematically investigated in the present work. It was shown that the PbMg

7
−

cluster ground state isomer exhibits the highest stability, for which special electronic excitation and chemical bonding analyses were performed. It is reasonable to believe that this work enriches the structural, spectroscopic and other data of magnesium-based clusters and provides some theoretical basis for possible future experimental syntheses.
Intravital imaging of pulmonary lymphatics in inflammation and metastatic cancer
Authors: Cleary Simon J. , Qiu Longhui , Seo Yurim , Baluk Peter , Liu Dan , Serwas Nina K. , Cyster Jason G. , McDonald Donald M. , Krummel Matthew F. , Looney Mark R.
Published: September 2024

Intravital microscopy has enabled the study of immune dynamics in the pulmonary microvasculature, but many key events remain unseen because they occur in deeper lung regions. We therefore developed a technique for stabilized intravital imaging of bronchovascular cuffs and collecting lymphatics surrounding pulmonary veins in mice. Intravital imaging of pulmonary lymphatics revealed ventilation-dependence of steady-state lung lymph flow and ventilation-independent lymph flow during inflammation. We imaged the rapid exodus of migratory dendritic cells through lung lymphatics following inflammation and measured effects of pharmacologic and genetic interventions targeting chemokine signaling. Intravital imaging also captured lymphatic immune surveillance of lung-metastatic cancers and lymphatic metastasis of cancer cells. To our knowledge, this is the first imaging of lymph flow and leukocyte migration through intact pulmonary lymphatics. This approach will enable studies of protective and maladaptive processes unfolding within the lungs and in other previously inaccessible locations.

Graphical abstract
Implementation of Ribo-BiFC method to plant systems using a split mVenus approach
Authors: Raabe Karel , Náprstková Alena , Pieters Janto , Torutaeva Elnura , Jirásková Veronika , Kahrizi Zahra , Michailidis Christos , Honys David
Published: September 2024

Translation is a fundamental process for every living organism. In plants, the rate of translation is tightly modulated during development and in response to environmental cues. However, it is difficult to measure the actual translation state of the tissuesin vivo. Here, we report the implementation of anin vivotranslation marker based on bimolecular fluorescence complementation, the Ribo-BiFC. We combined method originally developed for fruit-fly with an improved low background split-mVenus BiFC system previously described in plants. We labelledArabidopsis thalianasmall subunit ribosomal protein (RPS) and large subunit ribosomal protein (RPL) with fragments of the mVenus fluorescent protein. Upon the assembly of the 80S ribosome, the mVenus fragments complemented and were detected by fluorescent microscopy. We show that these recombinant proteins are in close proximity in the tobacco epidermal cells, although the signal is reduced when compared to BiFC signal from known interactors. This Ribo-BiFC method system can be used in stable transgenic lines to enable visualisation of translational rate in plant tissues and could be used to study translation dynamics and its changes during plant development, under abiotic stress or in different genetic backgrounds.
Conserved Evolutionary Response to Whole Genome Duplication in Angiosperms Revealed Using High Resolution Gene Expression Profiling
Authors: Leal J. Luis , Hodková Eva , Billhardt Anja , Eklund D. Magnus , Granath Gustaf , Egoavil Pilar Herrera , Chen Jun , Milesi Pascal , Salojärvi Jarkko , Lascoux Martin
Published: September 2024

Autopolyploidy, the result of genome duplication within a single species, is widespread among plant lineages and believed to have played a major role in angiosperm evolution and diversification. Whole genome duplication often triggers significant morphological and ecological changes in autopolyploids vis-a-vis their diploid progenitors, which are induced by subtle changes in gene expression patterns, often of a stochastic nature. Recent results have nonetheless identified specific changes in meiotic, metabolic, and defense response pathways that seem to be commonly shared among autopolyploid species, hinting at convergent evolution. Notably, a set of 12 core meiotic genes, including several genes involved in meiotic crossover formation, has been found to undergo strong selective pressure in the aftermath of autopolyploidization. For the most part these findings have been based on the study ofArabidopsis arenosaandA. lyrataautotetraploids and the question has remained as to whether the evolutionary forces shaping the establishment and evolution of autopolyploidy in the Arabidopsis model system extend more broadly across angiosperms, an area where our knowledge is still limited. In order to address these questions, we conducted a comparative transcriptome analysis ofBetula pubescens, a highly introgressed autotetraploid, and its diploid sister species,B. pendula, two birch species belonging to the Fagales order that diverged from Brassicales 120-140 Mya. Our results reveal significant changes in the expression patterns ofB. pubescensin genes involved in secondary metabolic processes and the regulation of stress response to pathogens, in agreement with results obtained in other autopolyploid plant complexes. Allele-specific expression analysis identified 16 meiotic genes inB. pubescenswith constrained expression patterns, strongly favoring alleles introgressed fromB. humilisorB. nana, a set that includes 8 meiotic genes −ASY1,ASY3,PDS5B,PRD3,SYN1,SMC3, SHOC1andSCC4− previously found to be under selection in Arabidopsis autopolyploids. These results provide support to the hypothesis that whole genome duplication triggers similar genomic responses across flowering plants, and that the evolutionary path available to autopolyploids for regaining meiotic stability is highly conserved and dependent on a small group of core meiotic genes.
Precision Repair of Zone-Specific Meniscal Injuries Using a Tunable Extracellular Matrix-Based Hydrogel System
Authors: Lee Se-Hwan , Li Zizhao , Zhang Ellen Y. , Kim Dong Hwa , Huang Ziqi , Lee Sang Jin , Kang Hyun-Wook , Burdick Jason A. , Mauck Robert L. , Heo Su Chin
Published: September 2024

Meniscus injuries present significant therapeutic challenges due to their limited self-healing capacity and diverse biological and mechanical properties across meniscal tissue. Conventional repair strategies neglect to replicate the complex zonal characteristics within the meniscus, resulting in suboptimal outcomes. In this study, we introduce an innovative, age- and stiffness-tunable meniscus decellularized extracellular matrix (DEM)-based hydrogel system designed for precision repair of heterogeneous, zonal-dependent meniscus injuries. By synthesizing age-dependent DEM hydrogels, we identified distinct cellular responses: fetal bovine meniscus-derived DEM promoted chondrogenic differentiation, while adult meniscus-derived DEM supported fibrochondrogenic phenotypes. The incorporation of methacrylate hyaluronic acid (MeHA) further refined the mechanical properties and injectability of the DEM-based hydrogels. The combination of age-dependent DEM with MeHA allowed for precise stiffness tuning, influencing cell differentiation and closely mimicking native tissue environments.In vivotests confirmed the biocompatibility of hydrogels and their integration with native meniscus tissues. Furthermore, advanced 3D bioprinting techniques enabled the fabrication of hybrid hydrogels with biomaterial and mechanical gradients, effectively emulating the zonal properties of meniscus tissue and enhancing cell integration. This study represents a significant advancement in meniscus tissue engineering, providing a promising platform for customized regenerative therapies across a range of heterogeneous fibrous connective tissues.
Local adaptation to climate facilitates a global invasion
Authors: Gamba Diana , Vahsen Megan L. , Maxwell Toby M. , Pirtel Nikki , Romero Seth , Van Ee Justin J. , Penn Amanda , Das Aayudh , Ben-Zeev Rotem , Baughman Owen , Blaney C. Sean , Bodkins Randy , Budha-Magar Shanta , Copeland Stella M. , Davis-Foust Shannon L. , Diamond Alvin , Donnelly Ryan C. , Dunwiddie Peter W. , Ensing David J. , Everest Thomas A. , Hoitink Holly , Holdrege Martin C. , Hufbauer Ruth A. , Juzėnas Sigitas , Kalwij Jesse M. , Kashirina Ekaterina , Kim Sangtae , Klisz Marcin , Klyueva Alina , Langeveld Michel , Lutfy Samuel , Martin Daniel , Merkord Christopher L. , Morgan John W. , Nagy Dávid U. , Ott Jacqueline P. , Puchalka Radoslaw , Pyle Lysandra A. , Rasran Leonid , Rector Brian G. , Rosche Christoph , Sadykova Marina , Shriver Robert K. , Stanislavschi Alexandr , Starzomski Brian M. , Stone Rachel L. , Turner Kathryn G. , Urza Alexandra K. , VanWallendael Acer , Wegenschimmel Carl-Adam , Zweck Justin , Brown Cynthia S. , Leger Elizabeth A. , Blumenthal Dana M. , Germino Matthew J. , Porensky Lauren M. , Hooten Mevin B. , Adler Peter B. , Lasky Jesse R.
Published: September 2024

Local adaptation may facilitate range expansion during invasions, but the mechanisms promoting destructive invasions remain unclear. Cheatgrass (Bromus tectorum), native to Eurasia and Africa, has invaded globally, with particularly severe impacts in western North America. We sequenced 307 genotypes and conducted controlled experiments. We found that diverse lineages invaded North America, where long-distance gene flow is common. Ancestry and phenotypic clines in the native range predicted those in the invaded range, indicating pre-adapted genotypes colonized different regions. Common gardens showed directional selection on flowering time that reversed between warm and cold sites, potentially maintaining clines. In the Great Basin, genomic predictions of strong local adaptation identified sites where cheatgrass is most dominant. Preventing new introductions that may fuel adaptation is critical for managing ongoing invasions.
Machine-learning convergent melanocytic morphology despite noisy archival slides
Authors: Tada M , Gaskins G , Ghandian S , Mew N , Keiser MJ , Keiser ES
Published: September 2024

Melanocytic atypia, ranging from benign to malignant, often leads to diagnostic discordance, complicating its prediction by machine learning models. To overcome this, we paired H&E-stained histology images with contiguous or serial sections immunohistochemically (IHC) stained for melanocytic cells via antibodies for MelanA, MelPro, or SOX10. We developed a deep-learning pipeline to identify melanocytic atypia by digitizing a real-world archival dataset of 122 paired whole slide images from 61 confirmed melanoma in situ (MIS) cases at two institutions. Only 37.7% of the cases contained tissue pairs that matched well enough for deep learning. Nonetheless, the MelanA+MelPro models achieved an average area under the receiver-operating characteristic (AUROC) of 0.948 and an average area under the precision-recall curve (AUPRC) of 0.611, while the SOX10 models had an average of 0.867 AUROC and 0.433 AUPRC. Despite learning from biologically different IHC stains, the convolutional neural network (CNN) models independently exhibited an intuitive convergent rationale by explainable AI saliency calculations. Different antibodies, with nuclear versus cytoplasmic staining, provided complementary yet consistent information, which the CNNs integrated effectively. The resulting multi-antibody virtual stains identified morphologic cytologic and small-scale architectural features directly from H&E-stained histology images, which can assist pathologists in assessing cutaneous MIS.
CRAK-Velo: Chromatin Accessibility Kinetics integration improves RNA Velocity estimation
Authors: El Kazwini Nour , Gao Mingze , Boudjelthia Idris Kouadri , Cai Fangxin , Huang Yuanhua , Sanguinetti Guido
Published: September 2024

RNA velocity has recently emerged as a key tool in the analysis of single-cell transcriptomic data, yet connecting RNA velocity analyses to underlying regulatory processes has proved challenging. Here we propose CRAK-Velo, a semi-mechanistic model which integrates chromatin accessibility data in the estimation of RNA velocities. CRAK-Velo provides biologically consistent estimates of developmental flows and enables accurate cell-type deconvolution, while additionally shining light on regulatory processes at the level of interactions between genes and chromatin regions.
The Precise Basecalling of Short-Read Nanopore Sequencing
Authors: Wang Ziyuan , Tu Mei-Juan , Song Chengcheng , Liu Ziyang , Wang Katherine K. , Chen Shuibing , Yu Ai-Ming , Ding Hongxu
Published: September 2024

The nanopore sequencing of short sequences, whose lengths are typically less than 0.3kb therefore comparable with Illumina sequencing techniques, has recently gained wide attention. Here, we design a scheme for training nanopore basecallers that are specialized for short biomolecules. With bioengineered RNA (BioRNA) molecules as examples, we demonstrate the superior accuracy of basecallers trained by our scheme.
Identification of SPP1-positive macrophages by single-cell spatial analysis in human lung tissues with mycobacterial infection
Authors: Katano Harutaka , Hebisawa Akira , Sato Yuko , Hoshino Yoshihiko
Published: September 2024

Tuberculosis and non-tuberculous mycobacterial (NTM) diseases are infections caused byMycobacterium tuberculosisand non-tuberculous mycobacteria such as theMycobacterium aviumcomplex, leading to the formation of granulomatous lesions with caseous necrosis in the lungs. Although granulomatous tissues are infiltrated by numerous inflammatory cells, including macrophages, lymphocytes, and neutrophils, the mechanisms underlying granuloma formation caused by mycobacteria remain unclear. In this study, we performed single-cell spatial analysis on lung tissue samples from patients with tuberculosis and NTM diseases to investigate the infiltrating cell populations. We analyzed seven lung lesions and identified individual cell types infiltrating the granulomatous tissue. Based on gene expression profiles, at least four macrophage subtypes were identified. Notably, SPP1-positive macrophages predominantly found infiltrating the granulomatous tissue. Langhans giant cells expressed SPP1, and numerous SPP1-positive macrophages without giant cell morphology were also observed around the granulomas. RNA-seq analysis revealed elevated SPP1 expression in mycobacterium-infected tissues. The SPP1-CD44 signaling pathway was active in SPP1-positive macrophages and their neighboring cells in mycobacterium-infected tissues. SPP1-positive macrophages were also observed around granulomas in other granulomatous diseases, such as granulomatosis with polyangiitis and sarcoidosis. These findings suggest that SPP1-CD44 signaling in SPP1-positive macrophages may play a role in the pathology of granulomatous diseases, including mycobacterial infections.

Brief summary

SPP1-CD44 signaling in SPP1-positive macrophages may play a role in granuloma formation in mycobacterial and other granulomatous diseases.
The ‘very moment’ when UDG recognizes a flipped-out uracil base in dsDNA
Authors: Saravanan Vinnarasi , Raouraoua Nessim , Brysbaert Guillaume , Giordano Stefano , Lensink Marc F. , Cleri Fabrizio , Blossey Ralf
Published: September 2024

Uracil-DNA glycosylase (UDG) is the first enzyme in the base-excision repair (BER) pathway, acting on uracil bases in DNA. How UDG finds its targets has not been conclusively resolved yet. Based on available structural and other experimental evidence, two possible pathways are under discussion. In one, the action of UDG on the DNA bases is believed to follow a ‘pinch-push-pull’ model, in which UDG generates the base-flip in an active manner. A second scenario is based on the exploitation of bases flipping out thermally from the DNA. Recent molecular dynamics (MD) studies of DNA in trinucleosome arrays have shown that base-flipping can be readily induced by the action of mechanical forces on DNA alone. This alternative mechanism could possibly enhance the probability for the second scnenario of UDG-uracil interaction via the formation of a recognition complex of UDG with flipped-out base. In this work we describe DNA structures with flipped-out uracil bases generated by MD simulations which we then subject to docking simulations with the UDG enzyme. Our results for the UDG-uracil recognition complex support the view that base-flipping induced by DNA mechanics can be a relevant mechanism of uracil base recognition by the UDG glycosylase in chromatin.
Characterization of nuclear mitochondrial insertions in canine genome assemblies
Authors: Schall Peter Z. , Meadows Jennifer R.S. , Ramos-Almodovar Fabian , Kidd Jeffrey M.
Published: September 2024

Background

The presence of mitochondrial sequences in the nuclear genome (Numts) confounds analyses of mitochondrial sequence variation and is a potential source of false positives in disease studies. To improve the analysis of mitochondrial variation in canines, we completed a systematic assessment of Numt content across genome assemblies, canine populations and the carnivore lineage.

Results

Centering our analysis on the UU_Cfam_GSD_1.0/canFam4/Mischka assembly, a commonly used reference in dog genetic variation studies, we find a total of 321 Numts, located throughout the nuclear genome and encompassing the entire sequence of the mitochondria. Comparison to 14 canine genome assemblies identified 63 Numts with presence-absence dimorphism among dogs, wolves, and a coyote. Further, a subset of Numts were maintained across carnivore evolutionary time (arctic fox, polar bear, cat), with 8 sequences likely more than 10 million years old, and shared with the domestic cat. On a population level, using structural variant data from the Dog10K Consortium for 1,879 dogs and wolves, we identified 11 Numts that are absent in at least one sample as well as 53 Numts that are absent from the Mischka assembly.

Conclusions

We highlight scenarios where the presence of Numts is a potentially confounding factor and provide an annotation of these sequences in canine genome assemblies. This resource will aid the identification and interpretation of polymorphisms in both somatic and germline mitochondrial studies in canines.
MPXV Infects Human PBMCs in a Type I Interferon-Sensitive Manner
Authors: Bosquillon de Jarcy Laure , Postmus Dylan , Jansen Jenny , Melchert Julia , Hoffmann Donata , Corman Victor M. , Goffinet Christine
Published: September 2024

MPOX virus (MPXV), formerly known as monkeypox virus, led to a rapidly evolving pandemic starting May 2022, with over 90,000 cases reported beyond the African continent. This pandemic outbreak was driven by the MPXV variant Clade IIb. In addition, Clade I viruses circulating in the Democratic Republic of Congo (DRC) are drawing increased attention as cases constantly rise and Clade Ib, first identified in 2023, is now co-circulating with Clade Ia and seems to exhibit enhanced human-to-human transmissibility. While most infected individuals display a self-limiting disease with singular pox-like lesions, some endure systemic viral spread leading to whole-body rash with risks for necrosis, organ loss, and death. Intra-host dissemination and cellular tropism of MPXV are largely unexplored in humans. To establish a potential susceptibility of circulating immune cells to MPXV, we exposed human PBMCs from healthy donorsex vivoto a currently circulating MPXV clade IIb virus isolate in absence and presence of IFN-α2a. qPCR of DNA extracted from cell lysates, but less from supernatants, revealed increasing MPXV DNA quantities that peaked at five to six days post-exposure, suggesting susceptibility of PBMCs to infection. IFN-α2a pretreatment markedly reduced the quantity of MPXV DNA, suggesting that infection is sensitive to type I IFNs. Plaque assays from supernatants showed that infection gave rise tode novoproduction of infectious MPXV. In virus-inclusive scRNA-sequencing, monocytes, cycling NK cells and regulatory CD4+T-cells scored positive for viral RNA, suggesting that these are the MPXV-susceptible cell types within the human PBMC population. Analysis of differentially expressed genes displayed a pronounced downregulation of expression pathways driving innate immunity in MPXV-infected cells, a well-established feature of poxviral infection. Pretreatment of PBMCs with current antivirals Cidofovir and Tecovirimat resulted in reduced amounts of viral antigen production and of released infectivity, suggesting suitability of the human PBMC infection model as a platform for evaluation of current and future antivirals and justifying trials to investigate Cidofovir and Tecovirimat as drugs reducing intra-patient viral spread. Together, our data suggest that human PBMCs are productively infected by MPXV which is accompanied by significant modulation of the cellular milieu. Our results have the potential to illuminate aspects of intra-host propagation of MPXV that may involve a lymphohematogenous route for replication and/or intra-host dissemination.
The Primate Major Histocompatibility Complex: An Illustrative Example of Gene Family Evolution
Authors: Fortier Alyssa Lyn , Pritchard Jonathan K.
Published: September 2024

Gene families are groups of evolutionarily-related genes. One large gene family that has experienced rapid evolution is the Major Histocompatibility Complex (MHC), whose proteins serve critical roles in innate and adaptive immunity. Across the ∼60 million year history of the primates, some MHC genes have turned over completely, some have changed function, some have converged in function, and others have remained essentially unchanged. Past work has typically focused on identifying MHC alleles within particular species or comparing gene content, but more work is needed to understand the overall evolution of the gene family across species. Thus, despite the immunologic importance of the MHC and its peculiar evolutionary history, we lack a complete picture of MHC evolution in the primates. We readdress this question using sequences from dozens of MHC genes and pseudogenes spanning the entire primate order, building a comprehensive set of gene and allele trees with modern methods. Overall, we find that the Class I gene subfamily is evolving much more quickly than the Class II gene subfamily, with the exception of the Class II MHC-DRB genes. We also pay special attention to the often-ignored pseudogenes, which we use to reconstruct different events in the evolution of the Class I region. We find that despite the shared function of the MHC across species, different species employ different genes, haplotypes, and patterns of variation to achieve a successful immune response. Our trees and extensive literature review represent the most comprehensive look into MHC evolution to date.
A regulatory module driving the recurrent evolution of irreducible molecular complexes.
Authors: Tikanova Polina , Ross James Julian , Hagmueller Andreas , Puehringer Florian , Pliota Pinelopi , Krogull Daniel , Stefania Valeria , Hunold Manuel , Koreshova Alevtina , Koller Anja , Ostapchuk Ivanna , Okweri Jacqueline , Gokcezade Joseph , Duchek Peter , Dong Gang , Ben-David Eyal , Burga Alejandro
Published: September 2024

To sustain life, molecular complexes require the concerted action of multiple proteins, each relying on one another to perform intricate tasks. However, how such interdependent protein interactions evolve in the first place is poorly understood. To address this, we investigated the origins of a group of fast-evolving genetic parasites, toxin-antidote elements, which boil down this dilemma to a simple question: what came first, the toxin or the antidote? By integrating quantitative genetics, biochemistry, and evolutionary genomics, we discovered that toxins and antidotes can arise simultaneously through the duplication of a regulatory module comprising an F-box protein in linkage to its substrate. Our findings provide one solution to the recurrent emergence of mutual dependence in protein complexes and illustrate in detail how complexity can swiftly arise from simplicity.
Precision-dependent modulation of social attention
Authors: Gao Wenhui , Zhu Changbo , Si Bailu , Zhou Liqin , Zhou Ke
Published: September 2024

Social attention, guided by cues like gaze direction, is crucial for effective social interactions. However, how dynamic environmental context modulates this process remains unclear. Integrating a hierarchical Bayesian model with fMRI, this study investigated how individuals adjusted attention based on the predictions about cue validity (CV). Thirty-three participants performed a modified Posner location-cueing task with varying CV. Behaviorally, individuals’ allocation of social attention was finely tuned to the precision (inverse variance) of CV predictions, with the predictions being updated by precision-weighted prediction errors (PEs) about the occurrence of target locations. Neuroimaging results revealed that the interaction between allocation of social attention and CV influenced activity in regions involved in spatial attention and/or social perception, such as the temporoparietal junction (TPJ), frontal eye field (FEF), superior temporal sulcus (STS), and inferior parietal sulcus (IPS). Precision-weighted PEs about target locations specifically modulated activity in the TPJ, STS, and primary visual cortex (V1), underscoring their roles in refining attentional predictions. Dynamic causal modeling (DCM) further demonstrated that enhanced absolute precision-weighted PEs about target locations strengthened the effective connectivity from V1 and STS to TPJ, emphasizing their roles in conveying residual error signals from low-level sensory areas to high-level critical attention areas. These findings elucidated how the precision of contextual predictions dynamically modulated social attention, offering insights into the computational and neurocognitive mechanisms of context-dependent social attention.
Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network
Authors: Boutelle Anthony M. , Mabene Aicha R. , Yao David , Xu Haiqing , Wang Mengxiong , Tang Yuning J. , Lopez Steven S. , Sinha Sauradeep , Demeter Janos , Cheng Ran , Benard Brooks A. , Valente Liz J. , Drainas Alexandros P. , Fischer Martin , Majeti Ravindra , Petrov Dmitri A. , Jackson Peter K. , Yang Fan , Winslow Monte M. , Bassik Michael C. , Attardi Laura D.
Published: September 2024

TP53, the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible geneZmat3as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seqUltrasomatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorialin vivoCRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We establishedZmat3as a core component of p53-mediated tumor suppression and identifiedCdkn1aas the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combinedZmat3-Cdkn1ainactivation dramatically enhanced cell proliferation and migration compared to controls, akin top53inactivation. Together, our findings placeZMAT3andCDKN1Aas hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.
Reversible excision of thewzylocus inSalmonellaTyphimurium may aid recovery following phage predation
Authors: Charity Oliver JD , Thilliez Gaetan , Al-Khanaq Haider , Acton Luke , Kolenda Rafał , Bawn Matt , Petrovska Liljana , Kingsley Robert A
Published: September 2024

Bacteriophage (phage) are promising novel antimicrobials but a key challenge to their effective implementation is the rapid emergence of phage resistance. An improved understanding of phage-host interactions is therefore needed. The Anderson phage typing scheme differentiates closely related strains ofSalmonella entericaserovar Typhimurium (S. Typhimurium) based on sensitivity to a panel of phage preparations. Switches in phage type are indicative of changes in phage sensitivity and inform on the dynamics of phage interaction with their host bacteria. We investigated the molecular basis of switches between the relatively phage sensitiveS. Typhimurium DT8 and phage resistant DT30 strains that are present in the same phylogenetic clade. DT30 strains emerged from DT8 strains predominantly by deletion of a genomic region affecting thewzylocus encoding an O-antigen polymerase. The deletion site was flanked by two perfect direct repeats designated attL and attR. During broth culture in the presence of a typing phage that used O-antigen as primary receptor the Δwzygenotype increased in frequency compared with culture in the absence of phage and removal of attL prevented deletion of thewzylocus. Co-culture ofS. Typhimurium DT8 with a strain lackingwzyresulted in reversion of the latter to wild type. We propose a model in which reversible deletion of thewzylocus enables recovery ofS. Typhimurium DT8 following predation by phage that use O-antigen as their primary receptor. This was consistent with ancestral state reconstruction of DT8 and DT30 phylogeny that supported a model of reversible transition from DT8 to DT30 in natural populations.

Importance

S. Typhimurium is a major pathogen of livestock that adversely affects productivity and animal welfare and poses a risk of foodborne disease in the human population. Antibiotics are used to controlSalmonellainfections in livestock that contributes to the antimicrobial resistance global emergency. Viruses of bacteria (phage) are one alternative to antibiotics to controlSalmonellain the food chain but their successful implementation as antimicrobials is restricted by the rapid emergence of resistance to phage. A better understanding of the outcome of phage-bacteria interactions is needed to optimise the design and implementation of phage-based antimicrobials. This study identifies a genetic mechanism that confers resistance to phage that use O-antigen as a receptor on the surface ofSalmonella. The mechanism is likely to impart a fitness cost on the bacterium but importantly the mechanism has the potential to be revert to a fully fit state once phage predation ceases. A model for how the mechanism may contribute to survival and recovery following phage predation is proposed.