bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Mechanism for Subtype Selectivity of Endocannabinoids
Authors: Dutta Soumajit , Zhao Lawrence , Shukla Diwakar
Published: October 2024

Endocannabinoids are naturally occurring lipid-like molecules that bind to cannabinoid receptors (CB1and CB2) and regulate many of human bodily functions via the endocannabinoid system. There is a tremendous interest in developing selective drugs that target the CB receptors. However, the biophysical mechanisms responsible for the subtype selectivity for endocannbinoids have not been established. Recent experimental structures of CB receptors show that endocannbinoids potentially bind via membrane using the lipid access channel in the transmembrane region of the receptors. Furthermore, the N-terminus of the receptor could move in and out of the binding pocket thereby modulating both the pocket volume and its residue composition. On the basis of these observations, we propose two hypothesis to explain the selectivity of the endocannabinoid, anandamide for CB1receptor. First, the selectivity arises from distinct enthalpic ligand-protein interactions along the ligand binding pathway formed due to the movement of N-terminus and subsequent shifts in the binding pocket composition. Second, selectivity arises from the volumetric differences in the binding pocket allowing for differences in ligand conformational entropy. To quantitatively test these hypothesis, we perform extensive molecular dynamics simulations (∼0.9 milliseconds) along with Markov state modeling and deep learning-based VAMPnets to provide an interpretable characterization of the anandamide binding process to cannabinoid receptors and explain its selectivity for CB1. Our findings reveal that the distinct N-terminus positions along lipid access channels between TM1 and TM7 lead to different binding mechanisms and interactions between anandamide and the binding pocket residues. To validate the critical stabilizing interactions along the binding pathway, relative free energy calculations of anandamide analogs are used. Moreover, the larger CB2pocket volume increases the entropic effects of ligand binding by allowing higher ligand fluctuations but reduced stable interactions. Therefore, the opposing enthalpy and entropy effects between the receptors shape the endocannabinoid selectivity. Overall, the CB1selectivity of anandamide is explained by the dominant enthalpy contributions due to ligand-protein interactions in stable binding poses. This study shed lights on potential selectivity mechanisms for endocannabinoids that would aid in the discovery of CB selective drugs.
Characterizing the impacts of exotic species on the morphology of solitary threespine stickleback (Gasterosteus aculeatus) populations in southwestern British Columbia
Authors: Kienzle Hannah M. , Vamosi Steven M.
Published: October 2024

Exotic species are one of the greatest threats to native species, communities, and ecosystems. Introductions of multiple exotic species into an environment may have different effects on native populations compared to when exotic species are introduced individually. Threespine stickleback species pairs (Gasterosteus aculeatus) and neighbouring solitary populations in southwestern British Columbia, a textbook example of an adaptive radiation, are now under threat from multiple exotic species. We assessed whether variation in morphological characters and body shape among solitary threespine stickleback populations was associated with different combinations of introduced smallmouth bass (Micropterus dolomieu) and signal crayfish (Pacifastacus leniusculus). We also examined morphological changes over time spans of 18-43 years to determine whether contemporary characteristics have responded to the presence of exotic species. We found clear differences in stickleback traits and body shape among exotic species combinations. Stickleback coexisting with bass and crayfish were highly armoured, whereas bass-only lakes contained stickleback with reduced armour. Two stickleback populations that coexist with signal crayfish showed significant increases in size over time. These patterns suggest that smallmouth bass and signal crayfish may have significant and different impacts on stickleback morphology.
SpatialPPI 2.0: Enhancing Protein-Protein Interaction Prediction through Inter-Residue Analysis in Graph Attention Networks
Authors: Hu Wenxing , Ohue Masahito
Published: October 2024

Protein-protein interactions (PPIs) are fundamental to cellular functions, and accurate prediction of these interactions is crucial to understanding biological mechanisms and facilitating drug discovery. SpatialPPI 2.0 is an advanced graph neural network-based model that predicts PPIs by utilizing interresidue contact maps derived from both structural and sequence data. By leveraging the comprehensive PINDER dataset, which includes interaction data from the RCSB PDB and the AlphaFold database, SpatialPPI 2.0 improves the specificity and robustness of the prediction of PPI. Unlike the original SpatialPPI, the updated version employs interaction interface prediction as an intermediate step, allowing for a more effective assessment of interactions between isolated proteins. The model utilizes Graph Attention Networks (GAT) and Graph Convolutional Networks (GCN) to capture both local and global structural features. SpatialPPI 2.0 outperforms several state-of-the-art PPI and interface predictors, demonstrating superior accuracy and reliability. Furthermore, the model shows robustness when using structures predicted by AlphaFold, indicating its potential to predict interactions for proteins without experimentally determined structures. SpatialPPI 2.0 offers a promising solution for the accurate prediction of PPIs, providing insight into protein function and supporting advances in drug discovery and synthetic biology. SpatialPPI 2.0 is available athttps://github.com/ohuelab/SpatialPPI2.0
PET microplastics increase the risk of insulin resistance and pancreatitis
Authors: Mierzejewski Karol , Kurzyńska Aleksandra , Golubska Monika , Gałęcka Ismena , Całka Jarosław , Bogacka Iwona
Published: October 2024

Microplastics and their effects on the body have recently been of great concern. Today it is clear that they are not indifferent to human health, but the full spectrum of their impact has not yet been fully described. Pancreatic diseases are becoming increasingly common worldwide, and their etiology is not well understood. Worryingly, these diseases have been increasingly diagnosed in children over the last 20 years, which was previously considered unusual. The aim of the study was therefore to determine the changes in the pancreas caused by PET microplastics in young organisms. For this purpose, the global metabolomic profile of the pancreas of piglets treated with a low (0.1 g/day) or high dose (1 g/day) of PET microplastics for 4 weeks was determined by UPLC-MS analysis. In addition, insulin levels and various biochemical parameters in the blood were analyzed. The study showed that PET microplastics affected the physiological processes in the pancreas at both low and high doses. We found that PET microplastics increased the tissue levels of important metabolites such as glucose, γ-aminobutyric acid, lysophosphatidylcholine or lysophosphatidylethanolamine. In addition, PET microplastics increased blood insulin concentrations and dose-dependently regulated lipase, cholesterol and calcium levels. These results suggest that PET microplastics increase the risk of insulin resistance and pancreatitis.
The Oscarella sponges genus: a hidden yet colorful diversity
Authors: Guiollot E. , Guillemain D. , Renard E. , Borchiellini C. , Schenkelaars Q.
Published: October 2024

The identification and ranking of new taxa are crucial for advancing our understanding of biodiversity. However, assigning samples to new taxa requires a cautious and rigorous approach. Historically, taxonomy has heavily relied on morphological traits, which can be subjective and may not always correspond to underlying genetic divergence. This challenge is especially pronounced in organisms with limited diagnostic morphological traits. A prime example is the poriferans of the genusOscarella(Homoscleromorpha), where species delimitation often depends on insufficient morphological features and genetic data. In this study, we addressed these challenges by integrating a comprehensive genetic dataset, including both mitochondrial and nuclear markers, with systematic photographic documentation of 192 specimens collected in Western Mediterranean Sea (Marseille Bay, France). This method allowed us to provide a more robust assessment ofOscarelladiversity, leading to the identification of four species new to science. In addition, our phylogenetic multigene analyses enabled us to propose a meaningful evolutionary scenario for color polymorphism. Additionally, our data showed the critical limitation in current methodologies forOscarellastudies, such as the low resolution of the widely usedcytochrome c oxidase subunit I(cox1/COI) gene, the lack of genetic data for many species, and the insufficient information regarding their geographical distribution. These findings underscore the need for more rigorous genetic frameworks and comprehensive datasets to enhance species delimitation and taxonomy.
TheArabidopsisamino acid transporter UmamiT20 confersBotrytis cinereasusceptibility
Authors: Prior Matthew J. , Weidauer Diana , Liao Jui-Yu , Kuwata Keiko , Locci Federica , Deng Chen , Ye Hong Bo , Cai Qiang , Bezrutczyk Margot , Zhao Chengsong , Chen Li-Qing , Jonikas Martin C. , Pilot Guillaume , Jin Hailing , Parker Jane , Frommer Wolf B. , Kim Ji-Yun
Published: October 2024

Induction of SWEET sugar transporters by bacterial pathogens via transcription activator-like (TAL) effectors is necessary for successful blight infection of rice, cassava and cotton, - likely providing sugars for bacterial propagation.

Here, we show that infection ofArabidopsisby the necrotrophic fungusBotrytis cinereacauses increased accumulation of amino acid transporter UmamiT20 mRNA in leaves. UmamiT20 protein accumulates in leaf veins surrounding the lesions after infection. Consistent with a role during infection,umamiT20 knock-outmutants were less susceptible toB. cinerea.

Functional assays demonstrate that UmamiT20 mediates amino acid transport of a wide range of amino acid substrates.

Pathogen-induced UmamiT20 mRNA and protein accumulation support the hypothesis that transporter-mediated pathogen susceptibility is not unique to SWEETs in bacterial blight of rice but also for a necrotrophic fungus and implicate nutrients other than sucrose, i.e., amino acids, in nutrition or nutrient signaling related to immunity. We hypothesize that stacking of mutations in different types of susceptibility-related nutrient carriers to interfere with access to several nutrients may enable engineering robust pathogen resistance in a wide range of plant-pathogen systems.

Lay Abstract

Pathogens infect plants to gain access to their nutrient resources, enabling the pathogens to cause disease and reproduce efficiently. Here we find that an amino acid transporter constitutes a susceptibility factor for the fungal pathogenB. cinerea.
Antarctic biosecurity policy effectively manages the rates of alien introductions
Authors: Leihy Rachel I. , McGeoch Melodie A. , Clarke David A. , Peake Lou , Buba Yehezkel , Belmaker Jonathan , Chown Steven L.
Published: October 2024

Reducing the rates and impacts of biological invasions is a major policy goal of international biodiversity agreements. Yet the extent to which this goal is being achieved and the agreements hence successful in this respect remains unclear. Here we use a comprehensive record of alien species introduction in the terrestrial Antarctic, including its surrounding Southern Ocean Islands, spanning 115 years (1900–2015), to quantify the impact of biosecurity policy on alien species introduction rates in the region, where invasive alien species are a primary environmental conservation threat and management priority. We show that although many parts of the Antarctic have been colonised by non-indigenous taxa, recent rates of introduction appear to be slowing or static in most parts, compared with increases in the past. Our results vindicate the regional Antarctic focus on biosecurity measures, but also demonstrate the need for stricter enforcement due to rapid socio-environmental changes.

Three key points

Biological invasions present a large and growing threat to Antarctic ecosystems under climate change and expanding human activity

Over the 20thcentury, there was no trend in alien species introduction rate in five Antarctic regions and a significantly increasing trend in the remaining five regions

Despite this variation, in most regions, the number of introductions remains low, indicating that Antarctic biosecurity has been effective at slowing the rate of introduction
Same-day discharge versus overnight stay after pulmonary vein isolation: an assessment on clinical outcomes and healthcare utilization
Authors: Slingerland SR (Stacey) , Van den Broek JLPM (Maarten) , Schulz DN (Daniela) , van Steenbergen GJ (Gijs) , Dekker LRC (Lukas) , Ouss AJ (Alexandre) , van Veghel D (Dennis)
Published: October 2024

Background

Atrial fibrillation is increasingly prevalent and constitutes a severe economic and clinical burden. Pulmonary vein isolation (PVI) is an effective treatment. Evidence on the safety of same-day discharge (SDD) after PVI, instead of overnight stay (ONS), is limited.

Methods & results

This retrospective study uses data from PVI’s performed between June 2018 and December 2020 in the Netherlands. Baseline characteristics, clinical outcome data and health care utilization, extracted from two national databases, were compared between the implementation of an SDD protocol in a single centre and a national benchmark where majority is an ONS strategy. Descriptive and bivariate analyses were performed. We included data from 11,812 PVI’s; 1,360 in the SDD group and 10,452 for the ONS benchmark. The SDD protocol group performed 57.7% of PVI’s in SDD, the benchmark 5.3% (p<.001). The SDD protocol group performed more cryoballoon PVI (90.8% vs. 39.2%, p<.001). There were no differences in bleeding (p=.830), thromboembolic (p=.893) or vascular complications (p=.720), or cardiac tamponade (p=.634). Peri-procedural hospital stay was significantly shorter in the SDD protocol group (0.50 day vs. 1.52 days, p<.001), without a reallocation of healthcare to outpatient clinic (p=.230), emergency department (p=.132) or higher rate of readmission (p=.092).

Conclusion

The SDD protocol group with 57.7% SDD has similar complication rates and lower health care utilization, compared to the national ONS benchmark with 5.3% SDD, indicating that SDD is a safe and effective alternative for ONS in patients undergoing PVI. The 5.3% ONS in the benchmark suggests a potential reduction of nationwide healthcare utilization.
Integer programming framework for pangenome-based genome inference
Authors: Chandra Ghanshyam , Hossen Md Helal , Scholz Stephan , Dilthey Alexander T , Gibney Daniel , Jain Chirag
Published: October 2024

Affordable genotyping methods are essential in genomics. Commonly used genotyping methods primarily support single nucleotide variants and short indels but neglect structural variants. Additionally, accuracy of read alignments to a reference genome is unreliable in highly polymorphic and repetitive regions, further impacting genotyping performance. Recent works highlight the advantage of haplotype-resolved pangenome graphs in addressing these challenges. Building on these developments, we propose a rigorous alignment-free genotyping framework. Our formulation seeks a path through the pangenome graph that maximizes the matches between the path and substrings of sequencing reads (e.g.,k-mers) while minimizing recombination events (haplotype switches) along the path. We prove that this problem is NP-Hard and develop efficient integer-programming solutions. We benchmarked the algorithm using downsampled short-read datasets from homozygous human cell lines with coverage ranging from 0.1× to 10×. Our algorithm accurately estimates complete major histocompatibility complex (MHC) haplotype sequences with small edit distances from the ground-truth sequences, providing a significant advantage over existing methods on low-coverage inputs. Although our algorithm is designed for haploid samples, we discuss future extensions to diploid samples.

Implementation

https://github.com/at-cg/PHI
VizCNV: An integrated platform for concurrent phased BAF and CNV analysis with trio genome sequencing data
Authors: Du Haowei , Lun Ming Yin , Gagarina Lidiia , Mehaffey Michele G , Hwang James Paul , Jhangiani Shalini N. , Bhamidipati Sravya V. , Muzny Donna M. , Poli M Cecilia , Ochoa Sebastian , Chinn Ivan K. , Linstrand Anna , Posey Jennifer E. , Gibbs Richard A , Lupski James R. , Carvalho Claudia M. B.
Published: October 2024

Background

Copy number variation (CNV) is a class of genomic Structural Variation (SV) that underlie genomic disorders and can have profound implications for health. Short-read genome sequencing (sr-GS) enables CNV calling for genomic intervals of variable size and across multiple phenotypes. However, unresolved challenges include an overwhelming number of false-positive calls due to systematic biases from non-uniform read coverage and collapsed calls resulting from the abundance of paralogous segments and repetitive elements in the human genome.

Methods

To address these interpretative challenges, we developed VizCNV. The VizCNV computational tool for inspecting CNV calls uses various data signal sources from sr-GS data, including read depth, phased B-allele frequency, as well as benchmarking signals from other SV calling methods. The interactive features and view modes are adept for analyzing both chromosomal abnormalities [e.g., aneuploidy, segmental aneusomy, and chromosome translocations], gene exonic CNV and non-coding gene regulatory regions. In addition, VizCNV includes a built-in filter schema for trio genomes, prioritizing the detection of impactful germline CNVs, such asde novoCNVs. Upon computational optimization by fine-tuning parameters to maximize sensitivity and specificity, VizCNV demonstrated approximately 83.8% recall and 77.2% precision on the 1000 Genome Project data with an average coverage read depth of 30x.

Results

We applied VizCNV to 39 families with primary immunodeficiency disease without a molecular diagnosis. With implemented build-in filter, we identified twode novoCNVs and 90 inherited CNVs >10 kb per trio. Genotype-phenotype analyses revealed that a compound heterozygous combination of a paternal 12.8 kb deletion of exon 5 and a maternal missense variant allele ofDOCK8are likely the molecular cause of one proband.

Conclusions

VizCNV provides a robust platform for genome-wide relevant CNV discovery and visualization of such CNV using sr-GS data.
Aluminium induces suberin biosynthesis in barley roots via ABA
Authors: Meng Hongjun , Zhang Qihui , Kreszies Tino , Acosta Ivan F. , Schreiber Lukas
Published: October 2024

Aluminum (Al) toxicity is a major factor limiting plant growth in acidic soils. The beneficial element silicon (Si) can mitigate some effects of Al. However, the impact of Al on suberized apoplastic barriers in roots are largely unknown while the effects of Si on suberin remains controversial.

This study employed physiological, histochemical, and analytical methods, along with Laser Capture Microdissection (LCM) RNA-sequencing, to explore the effects of Al and Si on suberin development in barley (Hordeum vulgareL.), a species sensitive to Al stress.

Exposure of barley seedlings to Al resulted in increased suberin deposition, which could be restored with the addition of Si, particularly in the root endodermis. Gene expression analyses using LCM RNA-seq across different root tissues demonstrated that Al-induced suberin biosynthesis is mainly regulated by the abscisic acid (ABA) pathway. In addition, the application of fluridone, an inhibitor of ABA synthesis and a suberin mutant, further supported the pivotal role of ABA in the Al response and the role of suberin in influencing Al uptake.

Our findings underscore the complex interplay between Al stress and suberin biosynthesis in barley, providing insights into potential strategies for enhancing crop resilience to Al toxicity.
Selective breeding for determinacy and photoperiod sensitivity in common bean (Phaseolus vulgarisL.)
Authors: Denning-James Kate E , Chater Caspar , Cortés Andrés J , Blair Matthew W , Peláez Diana , Hall Anthony , De Vega Jose J
Published: October 2024

Common bean (Phaseolus vulgarisL.) is a legume pulse crop that provides significant dietary and ecosystem benefits globally. We investigated two key traits, determinacy and photoperiod sensitivity, that are integral to its management and crop production, and that were early selected during the domestication of both Mesoamerican and Andean gene pools. Still, significant variation exists among common bean landraces for these traits. Since landraces form the basis for trait introgression in pre-breeding, understanding these traits’ genetic underpinnings and relation with population structure is vital for guiding breeding and genetic studies.

We explored genetic admixture, principal component, and phylogenetic analyses to define subpopulations and gene pools, and genome-wide association mapping (GWAS) to identify marker-trait associations in a diversity panel of common bean landraces. We observed a clear correlation between these traits, gene pool and subpopulation structure. We found extensive admixture between the Andean and Mesoamerican gene pools in some regions. We identified 13 QTLs for determinacy and 10 QTLs for photoperiod sensitivity, and underlying causative genes. Most QTLs appear to be firstly described. Our study identified known and novel causative genes and a high proportion of pleiotropic effects for these traits in common bean, and likely translatable to other legume species.

Highlight

We identified and explored QTLs for the domestication-related determinacy and photoperiod sensitivity traits, which are traits critically associated with population structure and management and crop production.
Endogenous EWSR1-FLI1 degron alleles enable control of fusion oncoprotein expression in tumor cell lines and xenografts
Authors: McGinnis James H. , Enriquez Alberto Bremauntz , Vandiver Florentina , Bai Xin , Kim Jiwoong , Kilgore Jessica , Saha Purbita , O’Hara Ryan , Xie Yang , Banaszynski Laura A. , Williams Noelle , McFadden David G.
Published: October 2024

Pediatric malignancies frequently harbor chromosomal translocations that induce expression of fusion oncoproteins. The EWSR1-FLI1 fusion oncoprotein acts as a neomorphic transcription factor and is the dominant genetic driver of Ewing’s sarcoma. Interrogation of the mechanisms by which EWSR1-FLI1 drives tumorigenesis has been limited by a lack of model systems to precisely and selectively control its expression in patient-derived cell lines and xenografts. Here, we report the generation of a panel of patient-derived EWS cell lines in which inducible protein degrons were engineered into the endogenous EWSR1-FLI1 locus. These alleles enabled rapid and efficient depletion of EWSR1-FLI1. Complete suppression of EWSR1-FLI1 induced a reversible cell cycle arrest at the G1-S checkpoint, and we identified a core set of transcripts downstream of EWSR1-FLI1 across multiple cell lines and degron systems. Additionally, depletion of EWSR1-FLI1 potently suppressed tumor growth in xenograft models validating efforts to directly target EWSR1-FLI1 in Ewing’s sarcoma.
Multidimensional Epigenetic Clocks Demonstrate Accelerated Aging Across Physiological Systems in Schizophrenia: A Meta-Analysis
Authors: Harvanek Zachary M. , Sehgal Raghav , Borrus Daniel , Kasamoto Jessica , Priyanka Ahana , Corley Michael J. , Vinkers Christiaan H. , Boks Marco P. , Smith Ryan , Dwaraka Varun B. , Lasky-Su Jessica , Higgins-Chen Albert T.
Published: October 2024

Importance: Schizophrenia is associated with increased age-related morbidity, mortality, and frailty, which are not entirely explained by behavioral factors. Prior studies using epigenetic clocks have suggested that schizophrenia is associated with accelerated aging, however these studies have primarily used unidimensional clocks that summarize aging as a single “biological age” score.

Objective: This meta-analysis uses multidimensional epigenetic clocks that split aging into multiple scores to analyze biological aging in schizophrenia. These novel clocks may provide more granular insights into the mechanistic relationships between schizophrenia, epigenetic aging, and premature morbidity and mortality.

Study selection: Selected studies included patients with schizophrenia-spectrum disorders and non- psychiatric controls with available DNA methylation data. Seven cross-sectional datasets were available for this study, with a total sample size of 1,891 patients with schizophrenia and 1,881 controls.

Data extraction and synthesis: Studies were selected by consensus Meta-analyses were performed using fixed-effect models.

Main outcomes and measures: We analyzed multidimensional epigenetic clocks, including causality- enriched CausAge clocks, physiological system-specific SystemsAge clocks, RetroelementAge, DNAmEMRAge, and multi omics-informed OMICmAge. Meta-analyses examined clock associations with schizophrenia disease status and clozapine use, after accounting for age and sex.

Results: Overall SystemsAge, CausAge, DNAmEMRAge, and OMICmAge scores demonstrated increased epigenetic aging in patients with schizophrenia after strict multiple-comparison testing. Ten of the eleven SystemsAge sub-clocks corresponding to different physiological systems demonstrated increased aging, with strongest effects for Heart and Lung followed by Metabolic and Brain systems. The causality- enriched clocks indicated increases in both damaging and adaptive aging, though these effects were weaker compared to SystemsAge scores. OMICmAge indicated changes in multiple clinical biomarkers, including hematologic and hepatic markers that support system-specific aging, as well as novel proteins and metabolites not previously linked to schizophrenia. Most clocks demonstrated age acceleration at the first psychotic episode. Notably, clozapine use was associated with increased Heart and Inflammation aging, which may partially be driven by smoking. Most results survived strict Bonferroni multiple testing correction.

Conclusions and relevance: These are the first analyses of novel multidimensional clocks in patients with schizophrenia and provide a nuanced view of aging that identifies multiple organ systems at high risk for disease in schizophrenia-related disorders.
Barriers and Facilitators to Heart Failure Guideline-Directed Medical Therapy in an Integrated Health System and Federally-Qualified Health Centers: A Thematic Qualitative Analysis
Authors: Philbin Sarah E. , Gleason Lacey P. , Persell Stephen D. , Walter Eve , Petito Lucia C. , Tibrewala Anjan , Yancy Clyde W. , Beidas Rinad S. , Wilcox Jane E. , Mutharasan R. Kannan , Lloyd-Jones Donald , O’Brien Matthew J , Kho Abel N. , McHugh Megan C. , Smith Justin D. , Ahmad Faraz S.
Published: October 2024

Background

Clinical guidelines recommend medications from four drug classes, collectively referred to as quadruple therapy, to improve outcomes for patients with heart failure with reduced ejection fraction (HFrEF). Wide gaps in uptake of these therapies persist across a range of settings. In this qualitative study, we identified determinants (i.e., barriers and facilitators of quadruple therapy intensification, defined as prescribing a new class or increasing the dose of a currently prescribed medication.

Methods

We conducted interviews with physicians, nurse practitioners, physician assistants, and pharmacists working in primary care or cardiology settings in an integrated health system or Federally Qualified Health Centers (FQHCs). We report results with a conceptual model integrating two frameworks: 1) the Theory of Planned Behavior (TPB), which explains how personal attitudes, perception of others’ attitudes, and perceived behavioral control influence intentions and behaviors; and 2) The Consolidated Framework for Implementation Research (CFIR) 2.0 to understand how multi-level factors influence attitudes toward and intention to use quadruple therapy.

Results

Thirty-one clinicians, including thirteen eighteen (58%) primary care and (42%) cardiology clinicians, participated in the interviews. Eight (26%) participants were from FQHCs. A common facilitator in both settings was the belief in the importance of quadruple therapy. Common barriers included challenges presented by patient frailty, clinical inertia, and time constraints. In FQHCs, primary care comfort and ownership enhanced the intensification of quadruple therapy while limited access to and communication with cardiology specialists presented a barrier. Results are presented using a combined TPB-CFIR framework to help illustrate the potential impact of contextual factors on individual-level behaviors.

Conclusions

Determinants of quadruple therapy intensification vary by clinician specialty and care setting. Future research should explore implementation strategies that address these determinants by specialty and setting to promote health equity.
A Novel Early Onset Spinocerebellar Ataxia 13 BAC Mouse Model with Cerebellar Hypoplasia, Tremor, and Ataxic Gait
Authors: Yin Junxiang , Nick Jerelyn A. , Khare Swati , Kloefkorn Heidi E. , Gao Ming , Wu Michael , White Jennifer , Resnick James L. , Allen Kyle D. , Nick Harry S. , Waters Michael F.
Published: October 2024

Spinocerebellar ataxia 13 (SCA13) is an autosomal dominant neurological disorder caused by mutations inKCNC3. Our previous studies revealed thatKCNC3mutation R423H results in an early-onset form of SCA13. Previous biological models of SCA13 include zebrafish and Drosophila but no mammalian systems. More recently, mouse models withKCNC3mutations presented behavioral abnormalities but without obvious pathological changes in the cerebellum, a hallmark of patients with SCA13. Here, we present a novel transgenic mouse model by bacterial artificial chromosome (BAC) recombineering to express the full-length mouse Kcnc3 expressing the R424H mutation. This BAC-R424H mice exhibited behavioral and pathological changes mimicking the clinical phenotype of the disease. The BAC-R424H mice (homologous to R423H in human) developed early onset clinical symptoms with aberrant gait, tremor, and cerebellar hypoplasia/atrophy. Histopathological analysis of the cerebellum in BAC-R424H mice showed progressive Purkinje cell loss and thinning of the molecular cell layer. Additionally, Purkinje cells of BAC-R424H mice showed significantly lower spontaneous firing frequency with a corresponding increase in inter-spike interval compared to that of wild-type mice. Our SCA13 transgenic mice recapitulate both neuropathological and behavioral changes manifested in human SCA13 R423H patients and provide an advantageous approach to understanding the role of voltage-gated potassium channel in cerebellar morphogenesis and function. This mammalianin vivomodel will lead to further understanding of the R423H allelic form of SCA13 from the molecular to the behavioral level and serve as a platform for testing potential therapeutic compounds.
Craving Connections: Exploring the Relationship Between Pregnancy Cravings, Maternal Health, and Child Preferences in Indian Families
Authors: Kruthi M Nithya , Duraimani Shanthi Lakshmi , Fathima Sarah , Ghori Junaid Ahmed Khan , Saikia Katherine , KM Annervaz , AR Balamurali , Ranganathan Rahul , Thummala Sabitha
Published: October 2024

Although Pregnancy cravings are a common phenomenon, their implications on maternal health, family dietary habits, and child food preferences remain underexplored, particularly in the Indian context. This study aimed to investigate the prevalence and nature of pregnancy cravings among Indian women and their potential impact on maternal health outcomes and family dietary patterns. A cross-sectional survey was conducted with 119 women who had experienced pregnancy, collecting data on craving patterns, maternal health indicators, and perceived influences on family diet. Results revealed that most women craved sugary snacks, predominantly in the second trimester. Notably, 61.9% of participants’ cravings did not align with their spouse’s food preferences, suggesting potential shifts in family dietary habits. The study also found associations between cravings, mood swings, and morning sickness, highlighting the complex interplay of physiological and psychological factors during pregnancy. These findings underscore the need for culturally sensitive, personalised prenatal care that address both the nutritional and emotional aspects of pregnancy cravings, influencing long-term family health outcomes.
LIMPACAT : Multi-Omics Attention Transformer for Immune Prediction in Liver Cancer Using Whole-Slide Imaging
Authors: Chiu Yen-Jung
Published: October 2024

This study introduces LIMPACAT (Liver Immune Microenvironment Prediction and Classification Attention Transformer), a framework that leverages whole-slide images (WSIs) to predict immune cell levels associated with prognosis in liver cancer. Since direct immune cell composition data is unavailable in the TCGA-LIHC dataset, we inferred immune cell levels using liver-specific single-cell RNA sequencing (scRNA-seq) data to simulate bulk RNA-seq profiles, allowing estimation of immune compositions within the tumor microenvironment. To ensure consistency, we tested three normalization methods—log normalization, canonical correlation analysis (CCA), and SCTransform—for scRNA-seq data integration and preprocessing, which facilitated reliable predictions of immune cell distributions in bulk RNA-seq.

By applying this scRNA-seq-informed cell composition deconvolution model to real bulk RNA-seq data from liver cancer samples, we confirmed alignment in immune cell composition estimates between bulk RNA-seq and scRNA-seq. Using a multiple instance learning (MIL) framework with an attention transformer, LIMPACAT achieved approximately 80% accuracy in classifying immune cell levels relevant to patient prognosis. These findings highlight the feasibility of integrating WSIs and multi-omics data to enhance immune profiling and prognostic predictions in liver cancer research.
Identifying Modulators of Cellular Responses by Heterogeneity-sequencing
Authors: Berg Kevin , Sakellaridi Lygeri , Rummel Teresa , Hennig Thomas , Whisnant Adam , Lodha Manivel , Krammer Tobias , Prusty Bhupesh K , Dölken Lars , Saliba Antoine-Emmanuel , Erhard Florian
Published: October 2024

The destructive nature of single-cell transcriptomics has hindered predicting and interpreting heterogeneous outcomes of molecular challenges. By exploiting information on the pre-perturbation state and fate of thousands of individual cells using droplet-based single cell RNA-seq with metabolic RNA labeling, we developed Heterogeneity-seq for predicting causal factors that impact on molecular outcomes. Heterogeneity-seq uncovered genes with an effect on drug treatment and novel proand antiviral host factors of cytomegalovirus infection.
Adaptive Gaze and Hand Coordination while Manipulating and Monitoring the Environment in Parallel
Authors: Fooken Jolande , Johansson Roland S. , Flanagan J. Randall
Published: October 2024

Research on eye-hand coordination has focused on action tasks performed in isolation. However, real world action tasks are often performed concurrently with perception tasks that compete for gaze. Here we examine how participants adapt their eye and hand movements when performing an object manipulation task—in which they repeatedly grasped a ball and inserted it into a slot—while simultaneously monitoring a text display to detect probabilistically occurring letter changes. We varied the visuomotor demands of the action task by having participants use either their fingertips or tweezers. We found that fixations allocated to the action task were exclusively directed to the ball and slot, and were more prevalent when using tweezers. The timing of ball and slot fixations were coupled in time with ball grasp and slot entry. On average, gaze shifted away from the landmarks ∼400 ms before contact when using fingertips—allowing the use of peripheral vision to direct the hand—and around the contact time when using tweezers—further allowing central vision to guide the hand as it approached the ball or slot. We found that participants controlled the timing of their hand movements, as well as the timing and patterns (sequence of fixations) of their eye movements, to exploit the temporal regularities of the perception task, thereby lowering the probability that a letter change would occur during action task fixations. Our results illustrate that eye-hand coordination can be flexibly and intelligently adapted when simultaneously acting on and perceiving the environment.
Hijacking and recording intracellular RNAs in human cells using eukaryotic reprogrammed tracrRNAs
Authors: Lee Seok-Hoon , Park Junho , Jung Chanju , Bae Sangsu
Published: October 2024

Recording intracellular RNA expression events is critical for understanding cell states and biological processes, but no method without responsive promoters is available in mammalian cells. Here, we determined the sequence formula of eukaryotic reprogrammed tracrRNA, named euRptr, which can hijack intracellular RNAs to make a complex with CRISPR-associated tools. By leveraging the programmability of euRptr, we devised the system “CHEETAH” to directly capture and record intracellular RNAs in human cells. We validated that CHEETAH induces self-editing by hijacking endogenous mRNAs, that CHEETAH selectively records different viral RNA fragments on a DNA reporter using base editors with a shared-euRptr, and that CHEETAH enables multiplexed, time-resolved recording of viral RNAs on a DNA Tape using prime editors, providing a new avenue for investigating intracellular RNA in eukaryotes.
Exploring N6-Methyladenosine and long transcripts in glioma cells and extracellular vesicles
Authors: Batool Syeda Maheen , Escobedo Ana K. , Lee Hanna , Khanna Prerna , Haas Kase D. , Hsia Tiffaney , Carter Bob S. , Balaj Leonora
Published: October 2024

Glioma represents the most common primary central nervous system (CNS) neoplasm in adults. Previous studies have identified m6A as a key player in glioma pathogenesis, promoting cell stemness and tumor cell proliferation. However, there is also evidence of a potential anti-cancer role of m6A. Here, we present a comprehensive overview of the m6A landscape in a glioma cell line model using Nanopore direct RNA sequencing platform. The study investigates functional and biological impact of targeted knockdown (KD) of key m6A regulators (reader: IGF2BP2, writer: METTL3, eraser: ALKBH5). Transcriptome wide mapping of m6A demonstrated enrichment in CDS and 3’UTR regions. Differential patterns of non-DRACH motifs were observed across the KD conditions. Our analysis identified 716 common m6A sites across all conditions and clusters of KD specific modifications enriched for distinct functional pathways. IGF2BP2 KD was associated with pathways involving protein metabolism and apoptosis regulation. METTL3 KD was linked to cell cycle and stress response regulation and ALKBH5 KD impacted ribosome biogenesis and protein synthesis. Here, for the first time we also report detection of full-length RNA transcripts in extracellular vesicles (EVs) derived RNA from knockdown and control conditions. These findings underscore the unique contributions of each m6A regulator to glioma cell transcriptomics and suggest potential pathways for elucidating the overall role of m6A machinery in glioma pathogenesis. Important clinical applications include identification of novel diagnostic, prognostic, and therapeutic m6A RNA biomarkers.
Genomic Analysis of Progenitors in Viral Infection Implicates Glucocorticoids as Suppressors of Plasmacytoid Dendritic Cell Generation
Authors: Jo Yeara , Greene Trever T. , Zhang Kai , Chiale Carolina , Fang Ziyan , Dallari Simone , Marooki Nuha , Wang Wei , Zuniga Elina I.
Published: October 2024

Plasmacytoid Dendritic cells (pDCs) are the most potent producers of interferons, which are critical antiviral cytokines. pDC development is, however, compromised following a viral infection, and this phenomenon, as well as its relationship to conventional (c)DC development is still incompletely understood. By using lymphocytic choriomeningitis virus (LCMV) infection in mice as a model system, we observed that DC progenitors skewed away from pDC and towards cDC development duringin vivoviral infection. Subsequent characterization of the transcriptional and epigenetic landscape of fms-like tyrosine kinase 3+(Flt3+) DC progenitors and follow-up studies revealed increased apoptosis and reduced proliferation in different individual DC-progenitors as well as a profound IFN-I-dependent ablation of pre-pDCs, but not pre-DC precursor, after both acute and chronic LCMV infections. In addition, integrated genomic analysis identified altered activity of 34 transcription factors in Flt3+DC progenitors from infected mice, including two regulators of Glucocorticoid (GC) responses. Subsequent studies demonstrated that addition of GCs to DC progenitors led to downregulated pDC-primed-genes while upregulating cDC-primed-genes, and that endogenous GCs selectively decreased pDC, but not cDC, numbers uponin-vivoLCMV infection. These findings demonstrate a significant ablation of pre-pDCs in infected mice and identify GCs as suppressors of pDC generation from early progenitors. This provides an explanation for the impaired pDC development following viral infection and links pDC generation to the hypothalamic-pituitary-adrenal axis.

Significance Statement

Plasmacytoid dendritic cells (pDCs) play critical roles in antiviral responses. However, adaptations of DC progenitors lead to compromised pDC generation after viral infection. Here, we characterized the transcriptional and epigenetic landscapes of DC progenitors after infection. We observed widespread changes in gene expression and chromatin accessibility, reflecting shifts in proliferation, apoptosis, and differentiation potential into various DC subsets. Notably, we identified alterations in the predicted activity of 34 transcription factors, including two regulators of glucocorticoid responses. Our data demonstrate that glucocorticoids inhibit pDC generation by reprogramming DC progenitors. These findings establish a molecular framework for understanding how DC progenitors adapt to infection and highlight the role of glucocorticoid signaling in this process.
Immune cell death on silicone surfaces drives biofilm formation
Authors: Jagirdar Sameer Kumar , Jhunjhunwala Siddharth
Published: October 2024

Silicone venous catheters are one of the most used healthcare devices worldwide. Nevertheless, they are associated with a high risk of infections, largely due to biofilm formation on catheter surfaces. Silicone is not inherently prone to bacterial adhesion; therefore, it is unclear as to what drives catheter infection and consequent biofilm formation. Previously it has been shown that circulating immune cells, including neutrophils and monocytes may adhere onto and die by apoptosis on silicone surfaces. This study investigates how immune cell death on silicone surfaces contributes to bacterial biofilm formation. The results show that neutrophil apoptosis on silicone surfaces significantly increases biofilm formation. Also, components of dead neutrophils were sufficient to cause increased biofilm formation. Further, silicone surfaces modified with a hyaluronic acid/polyarginine (HA/PA) coating reduce immune cell attachment and consequently biofilm formation. These findings suggest that to prevent catheter infection and biofilm formation, in addition to preventing bacterial attachment, it is necessary to minimize immune cell death on the catheter surface.
Integrating Multidimensional Data Analytics for Precision Diagnosis of Chronic Low Back Pain
Authors: Vickery Sam , Junker Frederick , Döding Rebekka , Belavy Daniel L , Angelova Maia , Karmakar Chandan , Becker Luis , Taheri Nima , Pumberger Matthias , Reitmaier Sandra , Schmidt Hendrik
Published: October 2024

Low back pain (LBP) is a leading cause of disability worldwide, with up to 25% of cases become chronic (cLBP). Optimal diagnostic tools for cLBP remains unclear. Here we leveraged a comprehensive multi-dimensional data-set and machine learning-based variable importance selection to identify the most effective diagnostic tools for cLBP patient stratification. The dataset included questionnaire data, clinical and functional assessments, and spino-pelvic magnetic resonance imaging (MRI), encompassing a total of 144 parameters from 1,161 adults with (n=512) and without cLBP (n=649). Boruta and random forest were utilised for variable importance selection and cLBP classification respectively. Boruta variable selection led to pronounced variable reduction (median of all 15 datasets: 63.3%), while performing comparable to using all variables across all modality datasets. Boruta selected key variables from questionnaire, clinical, and MRI data were the most effective in distinguishing cLBP patients from controls. The most robust variables (n=9) across the whole dataset identified were psychosocial factors, neck and hip mobility, as well as lower lumbar disc herniation and degeneration. These critical variables outperformed all parameters in an unseen holdout dataset, demonstrating superior patient delineation. Paving the way for targeted diagnosis and personalized treatment strategies, ultimately enhancing clinical outcomes for cLBP patients.
The novel CFAbd-Score.kid©reveals a significant decline of abdominal symptoms in children with Cystic fibrosis aged 6 through 11 years on Elexacaftor/Tezacaftor/Ivacaftor – first results
Authors: Mainz Jochen G. , Sadrieh Pauline , Bechinger Lilith , Duckstein Franziska , Barucha Anton , Polte Louise , Naehrlich Lutz , Eickmeier Olaf , van Dullemen Suzanne , Graepler-Mainka Ute , Zagoya Carlos
Published: October 2024

Background

Recently, elexacaftor/tezacaftor/ivacaftor (ETI), the turning point in the course of Cystic fibrosis (CF), was also approved for children with CF (cwCF) aged 6-11years carrying at least one F508del-mutation. Modulating the causative deficiency in the CF transmembrane conductance regulator channel was found to substantially improve the crucially affected respiratory and digestive CF-manifestations. In this regard, for people with CF aged ≥12years, we previously found that ETI decreases significantly abdominal symptoms (AS) using the CFAbd-Score©.

Aims

Assessing changes in AS after ETI initiation in cwCF aged 6-11years with the novel pediatric Patient-Reported Outcome Measure CFAbd-Score.kid©.

Methods

The CFAbd-Score.kid©, specially developed for cwCF aged <12years, implements pictograms, easy language and children-oriented response strategies, comprising 29 CF-specific gastrointestinal items from five domains. Its scoring algorithm developed following FDA guidelines weights items and domains differently, reaching a maximum of 100 points. CwCF completing at least one questionnaire before ETI initiation and another one during ETI therapy were included.

Results

In four German CF centers, a total of n=52 cwCF (mean age 8.3±2.2years) were included, completing a total of n=293 questionnaires. During ETI therapy, significant decreases were observed for mean total CFAbd-Score.kid©(−31%/p<0.0001) as well as for mean sub-scores of “pain” (−26%/p<0.01), “QoL impairment” (−48%/p<0.01), “disorders of bowel movement” (−32%/p≤0.0001) and “disorders of appetite” (−42%/p<0.05).

Conclusion

Among cwCF aged 6-11years, AS captured with the novel CFAbd-Score.kid©significantly decreased during the novel ETI treatment. Simultaneously, CFAbd-Score.kid©proved to be sensitive to ETI-induced changes in AS. Further validation steps and international implementation are currently in progress.