bluuebunny/crossref_metadata_2025 huggingface dataset:
Do emergency Medicaid programs improve post-discharge health care access for trauma patients? A statewide mixed-methods study
Authors: Knowlton Lisa Marie , Arnow Katherine , Cosby Zaria , Davis Kristen , Hendricks Wesley D. , Gibson Alexander B. , Chen Peiqi , Morris Arden M. , Wagner Todd H.
Published: December 2024

BACKGROUND

Hospital presumptive eligibility (HPE) emergency Medicaid programs offset patient bills at hospitalization and can provide long-term Medicaid coverage. We characterized postdischarge outpatient health care utilization among HPE Medicaid trauma patients and identified patient access facilitators and barriers once newly insured. We hypothesized utilization would be increased among HPE trauma patients compared with other HPE patients, but that challenges in access to care would remain.

METHODS

We performed a convergent mixed methods study of California HPE beneficiaries using a 2016 to 2021 customized statewide longitudinal claims dataset from the Department of Health Care Services. We compared adults 18 years and older with a diagnosis to other HPE patients. Patients were tracked for 2 months postdischarge to evaluate health care utilization: outpatient specialist visits, emergency room (ER) visits, readmissions, and mental health. Thematic analysis of semistructured interviews with HPE Medicaid patients aimed to understand facilitators and barriers to access to care (n = 20).

RESULTS

Among 199,885 HPE patients, 39,677 (19.8%) had a primary diagnosis of trauma. In the 2 months postdischarge, 40.8% of trauma vs. 36.6% of nontrauma accessed outpatient specialist services; 18.6% vs. 17.2% returned to ED, 8.4% vs. 10.2% were readmitted; and 1.4% vs. 1.8% accessed mental health services. In adjusted analyses, trauma HPE patients had 1.18 increased odds of accessing outpatient specialist services (p < 0.01). Patients cited HPE facilitators to accessing care: rapid insurance acquisition, outpatient follow-up, hospital staff support, as well as ongoing barriers to access (HPE program information recall, lack of hospital staff follow up postdischarge, and difficulty navigating a complex health care system).

CONCLUSION

Hospital presumptive eligibility Medicaid is associated with higher rates of outpatient specialist visits and fewer readmissions following injury, suggesting improved trauma patient access. Opportunities to improve appropriateness of health care utilization include more robust and longitudinal education and engagement with HPE Medicaid patients to help them navigate newfound access to services.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level III.
Dynamic Preservation of Donation After Circulatory Death Liver Grafts From Donors Aged 60 y and Older
Authors: Blondeel Joris , van Leeuwen Otto B. , Schurink Ivo J. , Lantinga Veerle A. , Gilbo Nicholas , de Goeij Femke H.C. , Pirenne Jacques , Huurman Volkert A.L. , de Meijer Vincent E. , de Jonge Jeroen , Porte Robert J. , Monbaliu Diethard
Published: December 2024

Background.

Donor livers from older donation after circulatory death (DCD) donors are frequently discarded for transplantation because of the high risk of graft failure. It is unknown whether DCD livers from older donors benefit from dynamic preservation.

Methods.

In a multicenter study, we retrospectively compared graft and patient outcomes after transplantation of livers from DCD donors older than 60 y, preserved with either static cold storage (SCS), ex situ sequential dual hypothermic perfusion, controlled oxygenated rewarming, and normothermic perfusion (DHOPE-COR-NMP), or in situ abdominal normothermic regional perfusion (aNRP).

Results.

Fifty-six liver transplants were included in the SCS cohort, 33 in the DHOPE-COR-NMP cohort, and 27 in the aNRP cohort. Donor warm ischemia time was significantly shorter in the SCS group than in DHOPE-COR-NMP (P < 0.001) and aNRP (P < 0.001) groups. Cold ischemia times were similar. One-year incidence of nonanastomotic biliary strictures was lower after DHOPE-COR-NMP (3%, P = 0.03) or aNRP (7%, P = 0.13), compared with SCS alone (21%). Anastomotic strictures were less frequent in aNRP (19%) compared with DHOPE-COR-NMP (52%; P = 0.015). One-year graft and patient survival were similar.

Conclusions.

Dynamic preservation allows safe transplantation of livers from DCD donors aged 60 y or older. The risk of nonanastomotic strictures was significantly lower after DHOPE-COR-NMP than after SCS, despite longer donor warm ischemia times.
Comparison of the virulence of community and hospital isolated Acinetobacter baumannii in HeLa cell line and insect model, Galleria mellonella
Authors: Muzahid Nazmul Hasan , Ramesh Aarthi , Siew Tan Hock , Hasan Md Zobaer , Narayanan Kumaran , Rahman Sadequr
Published: December 2024

Acinetobacter baumannii is an important nosocomial pathogen causing high infections and morbidity among affected individuals and most studies focus on nosocomial strains. However, A. baumannii can also be isolated from community healthy individuals. This study compared the pathogenicity of hospital and community A. baumannii isolates using Galleria mellonella and human cell cultures. The insect model, G. mellonella and in vitro HeLa cell line were used with ten A. baumannii isolates (six community and four hospital isolates from Segamat, Malaysia). G. mellonella killing assays and HeLa cell adherence, invasion, and cytotoxicity assays were performed to investigate the virulence and invasion potential of the isolates. Out of the ten isolates investigated, three community and two hospital isolates were found to be highly virulent in G. mellonella infection model, killing 100 % larvae within 96 hours. These strains were also found to be invasive and have significant cytotoxicity in HeLa cells. Our study revealed that community and hospital isolated A. baumannii could be equally virulent judged by both model systems. Undoubtedly, besides hospital settings, the presence of highly virulent A. baumannii in community reservoirs poses a significant public health risk and requires additional investigation.
Selection of Bone-Targeting Peptides for Therapeutic Intervention: An In Vivo Evaluation and Comparison Study
Authors: Stellpflug Austin , Joshi Amit , Wang Shue , Wang Bo
Published: December 2024

Hydroxyapatite (HA)-binding peptides are emerging as promising candidates for bone-targeted therapies due to their strong affinity for mineralized tissues and biocompatibility. However, most studies to date have focused onin vitrocharacterization, providing limited insight into theirin vivoperformance. This study bridges that gap by evaluating thein vivobehavior of HA-binding peptides D8, E8, YD8, and YE8 using fluorescence imaging to assess their biodistribution in healthy and pathological bone environments. In healthy animal models, D8 demonstrated the strongest binding across mineralized tissues, including the skull, femur, and tibia, while YD8 showed moderate binding. In contrast, E8 and YE8 exhibited limited localization influenced by peptide dosage and binding kinetics. Pathological models, including defective tibia and osteogenesis imperfecta (OIM) mice, revealed preferential accumulation of D8 and YD8 in structurally compromised regions, underscoring their potential for targeting diseased bone microenvironments. Fluorescence imaging, enhanced by spectral unmixing algorithms, proved effective for assessing peptide localization and distribution. These findings highlight the utility of HA-binding peptides for bone-targeted therapies and emphasize the importance ofin vivostudies in advancing their therapeutic and diagnostic applications. This work provides a foundation for optimizing peptide designs to improve specificity and efficacy in bone repair and regeneration.
Dopaminergic responses to identity prediction errors depend differently on the orbitofrontal cortex and hippocampus
Authors: Takahashi Yuji K. , Zhang Zhewei , Kahnt Thorsten , Schoenbaum Geoffrey
Published: December 2024

Adaptive behavior depends on the ability to predict specific events, particularly those related to rewards. Armed with such associative information, we can infer the current value of predicted rewards based on changing circumstances and desires. To support this ability, neural systems must represent both the value and identity of predicted rewards, and these representations must be updated when they change. Here we tested whether prediction error signaling of dopamine neurons depends on two areas known to represent the specifics of rewarding events, the HC and OFC. We monitored the spiking activity of dopamine neurons in rat VTA during changes in the number or flavor of expected rewards designed to induce errors in the prediction of reward value or reward identity, respectively. In control animals, dopamine neurons registered both error types, transiently increasing firing to additional drops of reward or changes in reward flavor. These canonical firing signatures of value and identity prediction errors were significantly disrupted in rats with ipsilateral neurotoxic lesions of either HC or OFC. Specifically, HC lesions caused a failure to register either type of prediction error, whereas OFC lesions caused persistent signaling of identity prediction errors and much more subtle effects on signaling of value errors. These results demonstrate that HC and OFC contribute distinct types of information to the computation of prediction errors signaled by dopaminergic neurons.
AmpliPiper: A versatile amplicon-seq analysis tool for multilocus DNA barcoding
Authors: Bertelli Astra , Steindl Sonja , Kirchner Sandra , Schwahofer Paula , Haring Elisabeth , Szucsich Nikolaus , Kruckenhauser Luise , Kapun Martin
Published: December 2024

The advent of third generation sequencing technology has revolutionized parallelized sequencing of DNA fragments of varying lengths, such as PCR amplicons, which provides unprecedented new opportunities for large-scale and diverse DNA barcoding projects that, for example, aim to quantify the accelerating biodiversity crisis. However, the broad-scale application of these new technologies for biodiversity research is often hindered by the demand for advanced bioinformatics skills to carry out quantitative analyses. To facilitate the application of multilocus amplicon sequencing (amplicon-seq) data for biodiversity and integrative taxonomic research questions, we present AmpliPiper, an automated and user-friendly software pipeline which carries out bioinformatics analyses of multilocus amplicon-seq data generated with Oxford Nanopore (ONT) sequencing. AmpliPiper combines analysis methods for DNA barcoding data that include demultiplexing of pooled amplicon-seq data, haplotype-specific consensus sequence reconstruction, species identification based on comparison to the BOLD and GenBank databases, phylogenetic analyses and species delimitation. We demonstrate the applicability and workflow of our approach based on a newly generated dataset of 14 hoverfly (Syrphidae) samples that were amplified and sequenced at four marker genes. We further benchmark our approach with Sanger sequencing and simulated amplicon-seq data which show that DNA barcoding with ONT is both accurate and sensitive to detect even subtle genetic variation.
AI-first structural identification of pathogenic protein targets
Authors: Saluri Mihkel , Landreh Michael , Bryant Patrick
Published: December 2024

The likelihood for pandemics is increasing as the world population grows and becomes more interconnected. Obtaining structural knowledge of protein-protein interactions between a pathogen and its host can inform pathogenic mechanisms and treatment or vaccine design. Currently, there are 52 nonredundant human-pathogen interactions with known structure in the PDB, although there are 21’064 with experimental support in the HPIDB, meaning that only 0.2% of known interactions have known structure. Recent improvements in structure prediction of protein complexes based on AlphaFold have made it possible to model heterodimeric complexes with very high accuracy. However, it is not known how this translates to host-pathogen interactions which share a different evolutionary relationship. Here, we analyse the structural protein-protein interaction network between ten different pathogens and their human host. We predict the structure of 9452 human-pathogen interactions of which only 10 have known structure. We find that we can model 30 interactions with an expected TM-score of ≥0.9, expanding the structural knowledge in these networks three-fold. We select the highly-scoringFrancisella tularensisdihydroprolyl dehydrogenase (IPD) complex with human immunoglobulinKappaconstant (IGKC) for detailed analysis with homology modeling and native mass spectrometry. Our results confirm the predicted 1:2:1 heterotetrameric complex with potential implications for bacterial immune response evasion. We are entering a new era where structure prediction can be used to guide vaccine and drug development towards new pathogenic targets in very short time frames.
Persistent genomic erosion in whooping cranes despite demographic recovery
Authors: Fontsere Claudia , Speak Samuel A. , Caven Andrew J. , Rodríguez Juan Antonio , Wang Xuejing , Pacheco Carolina , Cassatt-Johnstone Molly , Femerling Georgette , Maloney Brigid , Balacco Jennifer , Collins Joanna , Sims Ying , Abueg Linelle , Fedrigo Olivier , Jarvis Erich D. , Hartup Barry K. , Shapiro Beth , Gilbert M. Thomas P. , van Oosterhout Cock , Morales Hernán E.
Published: December 2024

Integratingin-situ(wild) andex-situ(captive) conservation efforts can mitigate genetic diversity loss and help prevent extinction of endangered wild populations. The whooping crane (Grus americana) experienced severe population declines in the 18th century, culminating into a collapse to 16 individuals in 1941. Legal protections and conservation actions have since increased the population to approximately 840 individuals, yet the impact on genomic diversity remains unclear. We analysed the temporal dynamics of genomic erosion by sequencing a high-quality genome reference, and re-sequencing 16 historical and 37 modern genomes, including wild individuals and four generations of captive-bred individuals. Genomic demographic reconstructions reveal a steady decline, accelerating over the past 300 years with the European settlement of North America. Temporal genomic analyses show that despite demographic recovery, the species has lost 70% of its genetic diversity and has increased their inbreeding. Although the modern population bottleneck reduced the ancestral genetic load, modern populations possess more realized load than masked load, possibly resulting in a chronic loss of fitness. Integrating pedigree and genomic data, we underscore the role of breeding management in reducing recent inbreeding. Yet ongoing heterozygosity loss, load accumulation, and background inbreeding argues against the species’ downlisting from their current Endangered status on the IUCN Red List and the Endangered Species Act. The presence of private genetic variation in wild and captive populations suggests that wild-captive crosses could enhance genetic diversity and reduce the realized load. Our findings emphasize the role of genomics in informing conservation management and policy.
The Blueprint for Survival: The Blue Dasher Dragonfly as a Model for Urban Adaptation
Authors: Tolman Ethan R. , Gamett Ellie , Beatty Christopher D. , Goodman Aaron , Hahn Brittney , Benischek Christian , Castillo Gracie , Derderian Ethan , Fernandez-Juarez Santiago , Gallafent Ben , Jenson James , Jordan Dick , Schneider Magnolia , Salazar Roberto , Tamano Towako , Wei Maleah , Idec Jacob , Guralnick Rob , Ware Jessica L. , Kohli Manpreet K.
Published: December 2024

Human alteration of natural environments and habitats is a major driver of species decline. However, a handful of species thrive in human altered environments. The biology, distribution, population structure and molecular adaptations enabling certain species to thrive in human-altered habitats are not well understood. Here, we evaluate the population and functional genomics, niche space and geometric morphometrics of the blue dasher (Pachidiplax longipennis), one of the most ubiquitously observed insects in human altered habitats. We identify a number of genes involved with the success of the blue dasher in human altered habitats. We specifically identify genes contributing to immune function and response to oxidative stress that could be key to the success ofP. longipennisin degraded habitats.

Intriguingly, some genes related to these functions are found in regions of high genomic conservation between populations ofP. longipennis, while others are in regions of the genome that are highly structured. Using one of the most robust locality datasets for any species to date, we also generate habitat suitability predictions which show thatP. longipennishas spread with urbanization, as humans have created more suitable habitat for this species. Our work demonstrates thatP. longipenniscould serve as a useful indicator for identifying modified habitats where generalists are pushing out regional specialists. Furthermore, the genes we have putatively identified as associated with the success ofP. longipennisin urban habitats are an important starting point for predicting which species will fare well in the Anthropocene.
Longitudinal Measurement Properties of the Participation Questionnaire for Preschoolers: Reliability, Responsiveness, and Interpretability
Authors: Nakamura Takuto , Koshio Iku , Maruyama Sho , Ikeda Kohei , Nagayama Hirofumi , Sasada Satoshi
Published: December 2024

Purpose

This study aimed to evaluate the test−retest reliability, responsiveness, and interpretability of the Preschool Questionnaire for Participation (PQP), a tool for assessing participation in preschool children with autism spectrum disorder (ASD).

Methods

A cohort study was conducted with data collected at four time points over six months from children with ASD aged 51–75 months. Test−retest reliability was examined using intraclass correlation coefficients (ICCs) for 275 participants who completed the study. Responsiveness was examined by analyzing correlations between changes in PQP scores and changes in multiple scales based on four predefined hypotheses. To assess interpretability, the Global Rating of Change (GRC) Scale was used as an anchor to analyze receiver operating characteristic curves and estimate the minimal important change (MIC).

Results

ICCs ranged from 0.80 to 0.92 for individual factors and reached 0.93 for the total score. Three of the four hypotheses for responsiveness were supported within the expected range. However, the correlation between the GRC Scale and changes in PQP scores was below 0.3, preventing MIC calculation.

Conclusion

While the MIC could not be calculated, the PQP demonstrated test−retest reliability equivalent to or better than existing participation measures. Given the limited verification of responsiveness for other tools, the PQP’s strong longitudinal reliability and validity provide a foundation for future research.
An integrative analysis of consortium-based multi-omics QTL and genome-wide association study data uncovers new biomarkers for lung cancer
Authors: Wang Yanru , Wang Aoxuan , Xie Ning , Xu Xiaowen , Wang Xiang , Zhao Mengshen , Wang Xuan , Zhou Jiacheng , Zhao Yang , Hu Zhibin , Shen Hongbing , Hung Rayjean J. , Amos Christopher I. , Li Yi , Christiani David C. , Chen Feng , Wei Yongyue , Zhang Ruyang
Published: December 2024

The role of molecular traits (e.g., gene expression and protein abundance) in the occurrence, development, and prognosis of lung cancer has been extensively studied. However, biomarkers in other molecular layers and connections among various molecular traits that influence lung cancer risk remain largely underexplored. We conducted the first comprehensive assessment of the associations between molecular biomarkers (i.e., DNA methylation, gene expression, protein and metabolite) and lung cancer risk through epigenome-wide association study (EWAS), transcriptome-wide association study (TWAS), proteome-wide association study (PWAS) and metabolome-wide association study (MWAS), and then we synthesized all omics layers to reveal potential regulatory mechanisms across layers. Our analysis identified 61 CpG sites, 62 genes, 6 proteins, and 5 metabolites, yielding 123 novel biomarkers. These biomarkers highlighted 90 relevant genes for lung cancer, 83 among them were first established in our study. Multi-omics integrative analysis revealed 12 of these genes overlapped across omics layers, suggesting cross-omics interactions. Moreover, we identified 106 potential cross-layer regulatory pathways, indicating that cell proliferation, differentiation, immunity, and protein-catalyzed metabolite reaction interact to influence lung cancer risk. Further subgroup analyses revealed that biomarker distributions differ across patient subgroups. To share all signals in different omics layers with community, we released a free online platform, LungCancer-xWAS, which can be accessed athttp://bigdata.njmu.edu.cn/LungCancer-xWAS/. Our findings underscore the importance of xWAS which integrating various types of molecular quantitative trait loci (xQTL) data with genome-wide association study (GWAS) data to deepen understanding of lung cancer pathophysiology, which may provide valuable insights into potential therapeutic targets for the disease.
Fast FEM-based Electric Field Calculations for Transcranial Magnetic Stimulation
Authors: Cao Fang , Madsen Kristoffer Hougaard , Worbs Torge , Puonti Oula , Siebner Hartwig Roman , Schmitgen Arno , Kunz Patrik , Thielscher Axel
Published: December 2024

Objective

To provide a Finite-Element Method (FEM) for rapid, repeated evaluations of the electric field induced by transcranial magnetic stimulation (TMS) in the brain for changing coil positions.

Approach

Previously, we introduced a first-order tetrahedral FEM enhanced by super- convergent patch recovery (SPR), striking a good balance between computational efficiency and accuracy (Saturninoet al2019J. Neural Eng.16066032). In this study, we refined the method to accommodate repeated simulations with varying TMS coil position. Starting from a fast direct solver, streamlining the pre- and SPR-based post-calculation steps using weight matrices computed during initialization strongly improved the computational efficiency. Additional speedups were achieved through efficient multi-core and GPU acceleration, alongside the optimization of the volume conductor model of the head for TMS.

Main Results

For an anatomically detailed head model with ∼4.4 million tetrahedra, the optimized implementation achieves update rates above 1 Hz for electric field calculations in bilateral gray matter, resulting in a 60-fold speedup over the previous method with identical accuracy. An optimized model without neck and with adaptive spatial resolution scaled in dependence to the distance to brain grey matter, resulting in ∼1.9 million tetrahedra, increased update rates up to 10 Hz, with ∼3% numerical error and ∼4% deviation from the standard model. Region-of-interest (ROI) optimized models focused on the left motor, premotor and dorsolateral prefrontal cortices reached update rates over 20 Hz, maintaining a difference of <4% from standard results. Our approach allows efficient switching between coil types and ROI during runtime which greatly enhances the flexibility.

Significance

The optimized FEM enhances speed, accuracy and flexibility and benefits various applications. This includes the planning and optimization of coil positions, pre-calculation and training procedures for real-time electric field simulations based on surrogate models as well as targeting and dose control during neuronavigated TMS.
Functional traits of ectomycorrhizal trees influence their effects on surrounding soil organic matter properties
Authors: Edwards Joseph D. , Dalling James W. , Fraterrigo Jennifer M. , Eddy William C. , Yang Wendy H
Published: December 2024

Ectomycorrhizal (EM) effects on forest ecosystem carbon (C) and nitrogen (N) cycling are highly variable, which may be due to underappreciated functional differences among EM-associating trees. We hypothesize that differences in functional traits among EM tree genera will correspond to differences in soil organic matter (SOM) dynamics.

We explored how differences among three genera of angiosperm EM trees (Quercus, Carya,andTilia) in functional traits associated with leaf litter quality, resource use and allocation patterns, and microbiome assembly related to overall soil biogeochemical properties.

In support of our hypothesis, we found consistent differences among EM tree genera in function traits.Quercustrees had lower litter quality, lower δ13C in SOM, higher δ15N in leaf tissues, greater oxidative extracellular enzyme activities, and higher EM fungal diversity thanTiliatrees, whileCaryatrees were often intermediary. These functional traits corresponded to overall SOM C and N dynamics and soil fungal and bacterial community composition.

Our findings suggest that trait variation among EM-associating tree species should be an important consideration in assessing plant-soil relationships such that EM trees cannot be categorized as a unified functional guild.
RasGRP1 Signalling Programs Developing γδ-Thymocytes towards the γδT17 Lineage Through Control of c-Maf Expression
Authors: Joannou K. , Golec D.P. , Henao-Caviedes L.M. , May J.F. , Kelly R.G. , Baldwin T.A.
Published: December 2024

The γδ TCR instructively directs both lineage specification and effector programming of developing γδ T cells. However, the manner in which different TCR signal strengths and other auxiliary signals coordinate downstream of the γδ TCR to regulate γδ T cell development remains unclear. In this study we characterized the role of Ras guanyl-releasing protein 1 (RasGRP1) in the development and effector programming of γδ T cells. While RasGRP1 was not necessary for bulk γδ T cell generation, we found it required for efficient generation of Vγ4+thymocytes, and lineage-committed CD73+γδ T cells in the thymus and periphery. Despite a decrease in immature CD73+γδ thymocytes, we report an expansion of the perinatal wave of CD8+IFNγ+γδ T cell population in the absence of RasGRP1. IL-17 producing γδ T cells were significantly reduced in RasGRP1 KO mice, with a specific loss of Vγ2+γδ T cells that corresponds to a loss of c-Maf expression as early as the DN1d thymocyte stage. Critically, these adult-programmed γδT17s could express c-Maf in response to CCR9 stimulation, with RasGRP1 being required for CCR9-induced c-Maf expression. Thus, RasGRP1 activation serves as an important signalling hub in the effector programming of γδ T cells, which integrates signals from both non-TCR and TCR inputs to direct differentiation.
A novel isoform of Tensin1 promotes actin filament assembly for efficient erythroblast enucleation
Authors: Ghosh Arit , Coffin Megan , Diaz Dimitri M. , Barndt Sarah , Schulz Vincent , Gallagher Patrick , Lo Su Hao , Fowler Velia M.
Published: December 2024

Mammalian red blood cells are generated via a terminal erythroid differentiation pathway culminating in cell polarization and enucleation. Actin filament polymerization is critical for enucleation, but the molecular regulatory mechanisms remain poorly understood. We utilized publicly available RNA-seq and proteomics datasets to mine for actin-binding proteins and actin- nucleation factors differentially expressed during human erythroid differentiation and discovered that a focal adhesion protein—Tensin-1—dramatically increases in expression late in differentiation. Remarkably, we found that differentiating human CD34+ cells express a novel truncated form of Tensin-1 (eTNS1; Mr ∼125 kDa) missing the N-terminal half of the protein, due to an internal mRNA translation start site resulting in a unique exon 1. eTNS1 localized to the cytoplasm during terminal erythroid differentiation, with no apparent membrane association or focal adhesion formation. Knocking out eTNS1 had no effect on assembly of the spectrin membrane skeleton but led to impaired enucleation and absent or mis-localized actin filament foci in enucleating erythroblasts. We conclude that eTNS1 is a novel regulator of actin filament assembly during human erythroid terminal differentiation required for efficient enucleation.
Macroevolutionary changes in gene expression response to an immune stimulus across the diversity of fishes
Authors: Flanagan Ben A. , Fuess Lauren E. , Vrtílek Milan , Roth-Monzón Andrea , Bolnick Daniel I.
Published: December 2024

Our understanding of the vertebrate immune system is dominated by a few model organisms such as mice. This use of a few model systems is reasonable if major features of the immune systems evolve slowly and are conserved across most vertebrates, but may be problematic if there is substantial macroevolutionary change in immune responses. Here, we present a test of the macroevolutionary stability, across 15 species of jawed fishes, of the transcriptomic response to a standardized immune challenge. Intraperitoneal injection of an immune adjuvant (alum) induces a fibrosis response in nearly all jawed fishes, which in some species contributes to anti-helminth resistance. Despite this conserved phenotypic response, the underlying transcriptomic response is highly inconsistent across species. Although many gene orthogroups exhibit differential expression between saline versus alum-injected fish in at least one species, few orthogroups exhibit consistent differential expression across species. This result suggests that although the phenotypic response to alum (fibrosis) is highly conserved, the underlying gene regulatory architecture is very flexible and cannot readily be extrapolated from any one species to fishes (or vertebrates) more broadly. The vertebrate immune response is remarkably changeable over macroevolutionary time, requiring a diversity of model organisms to describe effectively.
EpiPAMPAS: Rapid detection of intra-protein epistasis via parsimonious ancestral state reconstruction and counting mutations
Authors: Dabbaghie Fawaz , Thedinga Kristina , Bazykin Georgii A , Marschall Tobias , Kalinina Olga
Published: December 2024

Motivation

An epistatic interaction is a non-linear combination of effects of individual mutations on fitness. This type of interaction is a known driver for evolution, as they alter the organism’s fitness and adaptability. In this work we introduce EpiPAMPAS, a statistical method that is based on multiple sequence alignments (MSA) and detecting mutations in the same direction on a dendrogram instead of a phylogenetic tree using the Sankoff algorithm.

Results

We tested EpiPAMPAS on both simulated and real sequencing data. On the simulated data, our method was able to detect the simulated epistatic pairs with very low p-value. In a real-world application, we tested the influenza proteins N1, N2, H1, H3 and HIV-1 envelope protein subtypes A, B and C. We observe that EpiPAMPAS detects fewer interacting pairs than comparable statistical approaches, although the overlap between detected positions is good. Moreover, some of the amino acids from the detected pairs are known to be deleterious for viral fitness.

Availability

EpiPAMPAS is available under MIT license athttps://github.com/kalininalab/EpiPAMPAS
Comparative mapping of single-cell transcriptomic landscapes in neurodegenerative diseases
Authors: Shwab E. Keats , Man Zhaohui , Gingerich Daniel C. , Gamache Julia , Garrett Melanie E. , Serrano Geidy E. , Beach Thomas G. , Crawford Gregory E. , Ashley-Koch Allison E. , Chiba-Falek Ornit
Published: December 2024

INTRODUCTION

Alzheimer’s disease (AD), Dementia with Lewy bodies (DLB), and Parkinson’s disease (PD) represent a spectrum of neurodegenerative disorders (NDDs). Here, we performed the first direct comparison of their transcriptomic landscapes.

METHODS

We profiled the whole transcriptomes of NDD cortical tissue by snRNA-seq. We used computational analyses to identify common and distinct differentially expressed genes (DEGs), biological pathways, vulnerable and disease-driver cell subtypes, and alteration in cell-to-cell interactions.

RESULTS

The same vulnerable inhibitory neuron subtype was depleted in both AD and DLB. Potentially disease-driving neuronal cell subtypes were present in both PD and DLB. Cell-cell communication was predicted to be increased in AD but decreased in DLB and PD. DEGs were most commonly shared across NDDs within inhibitory neuron subtypes. Overall, we observed the greatest transcriptomic divergence between AD and PD, while DLB exhibited an intermediate transcriptomic signature.

DISCUSSION

These results help explain the clinicopathological spectrum of this group of NDDs and provide unique insights into the shared and distinct molecular mechanisms underlying the pathogenesis of NDDs.
Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers Apolipoprotein B Containing Lipoproteins in Mice
Authors: Helsley Robert N. , Zelows Mikala M. , Noffsinger Victoria P. , Anspach Garrett B. , Dharanipragada Nikitha , Mead Anna E. , Cobo Isidoro , Carter Abigail , Wu Qinglin , Shalaurova Irina , Saito Kai , Morganti Josh M. , Gordon Scott M. , Graf Gregory A.
Published: December 2024

Genome- and epigenome-wide association studies have associated variants and methylation status of carnitine palmitoyltransferase 1a (CPT1a) to reductions in very low-density lipoprotein (VLDL) cholesterol and triglyceride levels. We report significant associations between the presence ofCPT1aSNPs and reductions in plasma cholesterol, as well as positive associations between hepatic Cpt1a expression and plasma cholesterol levels across inbred mouse strains. Mechanistic studies show that both wild type and human apolipoprotein B100 (apoB)-transgenic mice with liver-specific deletion ofCpt1a(LKO) display lower circulating apoB levels consistent with reduced LDL-cholesterol (LDL-C) and LDL particle number. Despite a reduction in steady-state plasma lipids, VLDL-triglyceride (VLDL-TG) and cholesterol (VLDL-C) secretion rates are increased, suggesting accelerated clearance of apoB-containing lipoproteins (apoB-LPs) in LKO mice. Mechanistic approaches show greater peroxisome proliferator activated receptor α (PPARα) signaling which favors enhanced lipoprotein lipase-mediated metabolism of apoB-LPs, including increases in ApoCII and ApoAIV and reductions in ApoCIII & Angptl3. These studies provide mechanistic insight linking genetic variants and methylation status ofCPT1ato reductions in circulating apoB-LPs in humans.

HIGHLIGHTS

Loss-of-function SNPs inCPT1aassociate with reductions in plasma cholesterol in humans

Hepatic Cpt1a expression positively associates with plasma cholesterol levels across inbred strains of mice

Liver-specific Cpt1a deficiency lowers circulating apoB, plasma cholesterol, LDL-C, and LDL particle number

Cpt1a ablation activates PPARα and favors clearance of apoB-containing lipoproteins
Headwaters to Valley: Water quality in rivers transitioning from forest to agricultural bottomland
Authors: Neufeld Doug Graber , Alderfer Isaac , Bauman Zachary , Buckwalter Micah
Published: December 2024

Many waterways flow out of forestlands, which tend to maintain higher water quality, into agricultural lands, which tend to degrade water quality. The roles of these two types of land cover in impacting key water quality parameters (phosphorus as orthophosphate, nitrogen as nitrate, total suspended sediment (TSS), and indicator bacteria) were investigated for the watershed of the North and South Fork of the Shenandoah River, Virginia. This area has a particularly sharp boundary between heavily forested and heavily agricultural regions. Two datasets were analyzed: 1) a large number of datapoints spanning a 20-year range in the Water Quality Portal (WQP) database, and 2) transects along three representative rivers systems over the span of a 4-year period. Overall nutrient levels were significantly better in forested regions than agricultural regions; while TSS and indicator bacteria showed some trends, but less consistently, of higher water quality in forested regions. All parameters had significant variation in both forested and agricultural areas. Transects showed that waterways flowing out of forestland maintained higher water quality for approximately the first 8 km in agricultural land. Both transect and WQP data indicated higher water quality when the percent of forested land cover in a drainage basin was about 70-80%. Thus, forestland does mitigate the impacts of agriculture on water quality to some degree, but this effect rapidly diminishes as forest cover of the watershed lessens. Furthermore, forests themselves have degraded water quality at certain times and places; for instance, nutrients level were in the medium to high stress level for aquatic life in approximately 15% of samples. This study illustrates general trends of land cover effects on water quality, while also highlighting both site-specific variability, and the dynamics of water quality as water flows out of forested areas into agricultural areas.
Restoring Oscillatory Dynamics in Alzheimer’s Disease: A Laminar Whole-Brain Model of Serotonergic Psychedelic Effects
Authors: Gendra Jan C. , Lopez-Sola Edmundo , Castaldo Francesca , Lleal-Custey Èlia , Sanchez-Todo Roser , Vohryzek Jakub , Salvador Ricardo , Andrzejak Ralph G. , Ruffini Giulio ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2024

Classical serotonergic psychedelics show promise in addressing neurodegenerative disorders such as Alzheimer’s disease by modulating pathological brain dynamics. However, the precise neurobiological mechanisms underlying their effects remain elusive. This study introduces a personalized whole-brain model built upon a laminar neural mass framework to elucidate these effects. Using multimodal neuroimaging data from thirty subjects diagnosed with Alzheimer’s disease, we simulate the impact of serotonin 2A receptor activation, characteristic of psychedelics, on cortical dynamics. By modulating the excitability of layer 5 pyramidal neurons, our models reproduce hallmark changes in EEG power spectra observed under psychedelics, including alpha power suppression and gamma power enhancement. These spectral shifts are shown to correlate strongly with the regional distribution of serotonin 2A receptors. Furthermore, simulated EEG reveals increased complexity and entropy, suggesting restored network function. These findings underscore the potential of serotonergic psychedelics to reestablish healthy oscillatory dynamics in the prodromal and early phases of Alzheimer’s disease and offer mechanistic insights into their potential therapeutic effects in neurodegenerative disorders.
Evaluating Enhanced LLMs for Precise Mental Health Diagnosis from Clinical Notes
Authors: Boggavarapu Lokesh , Srivastava Vineet , Varanasi Amit Maheswar , Lu Yingda , Bhaumik Runa
Published: December 2024

Anxiety, depression, and other mental health conditions are affecting millions of people worldwide each year. However, limited access to mental health professionals and the stigma surrounding mental illness often deter individuals from seeking help. Many areas, especially rural and underserved communities, face a significant shortage of mental health professionals, making it difficult for individuals to access timely support and treatment. Traditional therapy can be expensive, time-consuming, and intimidating, discouraging individuals from seeking care and delaying essential treatment. The goal of this project is to harness the power of large language models

In the medical domain, large language models (LLMs) have the potential to significantly enhance clinical practice by assisting with tasks such as diagnostic support, therapeutic interventions, and summarization. However, these models often generate inaccurate responses, or “hallucinations,” when faced with queries they cannot effectively handle, raising concerns in the medical community. To address the limitations of LLMs, Retrieval-Augmented Generation (RAG) was leveraged to enhance their performance. By integrating external knowledge sources such as ICD-10-CM guidelines and psychiatric diagnostic manuals, RAG enables LLMs to retrieve relevant information in real time to support their predictions. This study examines whether LLMs can understand and accurately predict mental health-related medical codes from clinical notes. These codes are crucial for clinical documentation and treatment planning. We tested several LLMs (e.g., GPT, LLaMA, Gemini-Pro) enhanced with reliable resources like ICD-10-CM guidelines to evaluate their ability to identify and understand mental health terms and ICD-10-CM codes in psychiatric clinical notes. Our findings reveal that current models lack a robust understanding of the meaning and nuances of these codes, limiting their reliability for mental health applications. This underscores the need for improved strategies to represent and integrate these complex alphanumeric codes within LLMs. Enhancing their capability to accurately process mental health terminologies would make LLMs more reliable and trustworthy tools for mental health professionals, ultimately supporting better care and outcomes for patients.
An atypical phenotype is a risk factor for higher mortality in Alzheimer’s disease
Authors: Bader Ilse , Groot Colin , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Ossenkoppele Rik
Published: December 2024

Background

Survival estimates for individuals with Alzheimer’s disease (AD) are informative to understand the full disease trajectory, but precise estimates for atypical AD variants are scarce. Atypical AD variants are characterized by non-amnestic phenotypes, an early-onset and lower prevalence ofAPOEε4-carriership, which are all possible modulators of clinical trajectories. We aimed to provide survival estimates for posterior cortical atrophy (PCA; “visual-AD”), logopenic variant primary progressive aphasia (lvPPA; “language-AD”) and behavioral-AD (bvAD), and to evaluate the effect of phenotypical atypicality beyond known mortality-determinants.

Methods

This observational study included 2081 amyloid-positive patients (age 65±8 years) from the Amsterdam Dementia Cohort classified as typical AD (n=1801) or atypical AD (n=280; PCA [n=112], lvPPA [n=86], and bvAD [n=82]). Survival estimates from first-visit (∼time-of-diagnosis) to death/censoring (Central Public Administration) were determined (Kaplan-Meier analysis) and compared (Log-Rank tests) across diagnostic groups. To assess effects of atypical AD on mortality, cox proportional-hazard models were performed including age, sex, education, MMSE-score andAPOEε4-carriership (model-1), followed by adding the atypical AD group (model-2) or atypical AD variants individually (model-3), while using typical AD as reference. A likelihood ratio test was performed between model-1 and 2 to assess whether atypical AD improved the model-fit.

Results

The estimated median survival time for atypical AD of 6.3 years (95%CI: [5.8-6.9]) was shorter than for typical AD (7.2[7.0-7.5], p=0.02). Median survival times across the atypical AD variants were consistently shorter (PCA: 6.3[5.5-7.3], p=0.055); lvPPA: 6.6[5.7-7.7], p=0.110; bvAD: 6.3[5.0-9.1], p=0.121, 48% deceased). In cox proportional-hazards model-1, male sex (HR=1.46[1.30-1.64], p<0.001), age (HR=1.02[1.01-1.03], p<0.001), and MMSE (HR=0.94[0.93-0.96], p<0.001) were associated with increased mortality risk.APOEε4heterozygosity was associated with reduced mortality risk compared to non-carriers (HR=0.85[0.74-0.97], p=0.015). In model-2, atypical AD improved the model fit (model 2; χ²=8.88, p=0.003) and was associated with 31% increased mortality risk compared to typical AD (HR=1.31[1.10-1.56], p=0.002). In model-3, contributions of the variants were: HRPCA=1.35[1.05-1.73], p=0.019; HRlvPPA=1.27[0.94-1.69], p=0.114; HRbvAD=1.31[0.94-1.83], p=0.105].

Conclusions

Survival in atypical AD was shorter compared to typical AD. Atypicality appears an important risk factor for mortality beyond age, sex, education,APOEε4-carriership and disease severity.

Trial registration information

NA.
Parkinson’s Disease Pathogenic Variants: Cross-Ancestry Analysis and Microarray Data Validation
Authors: Hong Samantha , Koretsky Mathew J. , Lichtenberg Jens , Leonard Hampton , Pitz Vanessa ,   the Global Parkinson’s Genetics Program (GP2)
Published: December 2024

Background

Known pathogenic variants in Parkinson’s disease (PD) contribute to disease development but have yet to be fully explored by arrays at scale.

Objectives

This study evaluated genotyping success of the NeuroBooster array (NBA) and determined the frequencies of pathogenic variants across ancestries.

Method

We analyzed the presence and allele frequency of 34 pathogenic variants in 28,710 PD cases, 9,614 other neurodegenerative disorder cases, and 15,821 controls across 11 ancestries within the Global Parkinson’s Genetics Program dataset. Of these, 25 were genotyped on NBA and cluster plots were used to assess their quality.

Results

Genes previously predicted to have high or very high confidence of causing PD tend to have more pathogenic variants and are present across ancestry groups. Twenty-five of the 34 pathogenic variants were typed by the NBA array and classified “good” (n=12), “medium” (n=4), and “bad” (n=9) variants.

Conclusion

Our results confirm the likelihood that established PD genes are pathogenic and highlight the importance of ancestrally diverse research in PD. We also show the usefulness of the NBA as a reliable tool for genotyping of rare variants for PD.
Representation learning based on proteomic profiles uncovers key cell types and biological processes contributing to the plasma proteome
Authors: Zhuang Jiali , Smith Erin N. , Diogo Dorothée
Published: December 2024

The plasma proteome is a potential source of information on health status and physiological condition and holds great potential as candidate biomarkers for diagnosis, prognosis, intervention response monitoring, and patient stratification. As proteins in the plasma can be derived from numerous cellular and tissue sources, and their levels influenced by diverse mechanisms, a comprehensive assessment of patterns of protein variation could provide insight into mechanisms driving health and disease. By applying neural network-based representation learning and unsupervised clustering to the plasma proteomic profiles of 51,180 participants in the UK biobank, we identified 36 protein modules representing major cell types and biological processes present in the plasma proteome. We discovered that the overall abundances of proteins belonging to certain modules are associated with disease status and genetic variants. Those associations reflect complex and multi-faceted mechanisms that regulate protein abundances in circulation. An investigation into the protein modules associated with disease variants uncovered both known disease biology and novel findings that may translate into testable hypotheses. Our approach generates biologically relevant groupings of plasma proteins that can be deployed to inform the design of more predictive biomarker panels and shed new light on the effects of disease-associated genetic variants.