bluuebunny/crossref_metadata_2025 huggingface dataset:
The origin and evolution of the gonococcal beta-lactamase plasmid, and implications for public health
Authors: Elsener T. A. , Cehovin A. , Philp C. , Fortney K. , Spinola S.M. , Maiden M.C.J. , Tang C.M.
Published: January 2025

Neisseria gonorrhoeaeis a leading cause of sexually transmitted infection (STI) and a priority AMR pathogen. Two narrow host range plasmids, pblaand pConj, have contributed to ending penicillin and tetracycline therapy, respectively, and undermine current prevention strategies including Doxy-PEP. Here, we investigated the origin and evolution of the beta-lactamase plasmid, pbla. We show that the interplay between pblaand pConj influences their co-occurrence and the spread of pblain the gonococcal population. We demonstrate that pblawas acquired by the gonococcus on at least two occasions fromHaemophilus ducreyi, and describe the subsequent evolutionary pathways taken by the three major pblavariants. Changes that mitigate fitness costs of pblaand the emergence of TEM beta-lactamases which confer increased resistance have contributed to the success of pbla. In particular, TEM-135, which has arisen in certain pblavariants, increases resistance to beta-lactams and only requires one amino acid change to become an extended spectrum beta-lactamase (ESBL). The evolution of pblaunderscores the threat of plasmid-mediated resistance to current therapeutic and preventive strategies against gonococcal infection. Given the close relationship between pblaand pConj, widespread use of Doxy-PEP is likely to promote spread of pConj and pbla, and emergence of plasmid-mediated ESBL in the gonococcus, with dire public health consequences.
Allosteric Residue Dynamics in Insulin: Temperature Induces Shift from Dihexamer to Hexamer Collective Motion
Authors: Ayan Esra , Kepceoglu Abdullah
Published: January 2025

Structures using X-ray diffraction data collected to 2.3 Å, 2.85 Å, and 2.88 Å resolutions have been determined for the long-acting dihexamer insulin at three different temperatures ranging from 100°K to 300°K. It is determined that the unit-cell value of insulin crystal at 100°K temperature has changed at 200°K temperature. This change might be due primarily to subtle repacking of the molecule and loss of noncovalent interactions of myristic acid that binds two hexamers, exhibiting the largest movements. Computational analyses show that allosteric residues and fatty-acid binding residue of insulin hexamers display reduced overall collectivity and inter-residue coupling, likely arising from crystal mosaicity increase and structural fluctuations through elevated thermal motion. This breakpoint has been observed at a characteristic temperature of 200°K, perhaps emphasizing underlying alterations in the dynamic structure of the fatty acid-solvent interface in dimer of hexamer. Combined with computational analysis, findings reveal key insights into thermal stability mechanisms crucial for developing thermostable insulin formulations in industrial applications.

Teaser

Temperature-driven shifts in insulin’s structure reveal dynamic changes crucial for enhancing thermal stability in drug formulations.
DeepPROTECTNeo: A Deep learning-based Personalized and RV-guided Optimization tool for TCR Epitope interaction using Context-aware Transformers
Authors: Das Debraj , Bhaduri Soumyadeep , Pramanick Avik , Mitra Pralay
Published: January 2025

The development of personalized cancer vaccines relies heavily on accurately identifying neoepitopes capable of eliciting strong immune responses. Traditional methods primarily focus on predicting interactions between major histocompatibility complex (MHC) molecules and peptides, often neglecting the crucial step of T-cell receptor (TCR) binding in the context of anchor motif and hydrophobicity, which are critical variables in the elicitation of robust tumor-specific responses. T cells perpetually monitor lymphoid and peripheral organs for antigens, such as peptides or lipids, that are presented by peptide-MHC (pMHC) molecules in other cells. This oversight limits the efficacy of these vaccines in triggering a robust adaptive immune response. We introduce a stand-alone web-server DeepPROTECTNeo (https://cosmos.iitkgp.ac.in/DeepPROTECTNeo/) that processes Whole Exome Sequencing (WES) or Whole Genome Sequencing (WGS) data and mitigate the process of extracting patient-specific neoantigen candidate leveraging genomic and variational TCR information directly, a pivotal component in the development of adaptive immunity and personalized cancer vaccines. Along with traditional MHC binding and B-cell receptor (BCR) recognition, we introduce a context-aware transformer block leveraging cross-attention mechanisms to enhance the analysis of TCR-epitope interactions, thereby advancing neoepitope discovery with unparalleled precision and facilitating reverse vaccinology (RV)-guided multi-epitope vaccine design. With extensive hyperparameter tuning, our model shows exceptional generalizability in predicting TCR-peptide binding on independent test data with AUC 0.7234 and AUPRC 0.7659, substantially outperforming state-of-the-art methods. Furthermore, our pipeline successfully identified 372 neoepitopes out of 532 unique neoepitopes presented in the TESLA benchmark dataset, with 24 true neoantigens, demonstrating its high efficacy and precision in neoepitope discovery.

Highlights

DeepPROTECTNeo is an all-in-one platform for neo-epitope identification from raw sequencing reads

Incorporate a novel transformer-based architecture for peptide-TCR binding affinity prediction and outperforming current methods

Accepts flexible input formats from users to provide comprehensive analysis and has a separate module for predicting peptide-TCR binding

Successfully identified 24 true neoepitopes among 37 reported in TESLA using only SNVs, indels
BICD2 is a centriolar protein that controls mother-daughter centriole engagement and the licensing of duplication
Authors: Montes-Ruiz Lídia , Gallisà-Suñé Núria , Regué Laura , Fernández-de-Larrea Lorena , Roig Joan
Published: January 2025

Centrosomes and the centrioles at their core have key cellular roles that require their duplication exactly once during each cell cycle. Abnormal centriole numbers can contribute to the onset of different pathologies and thus different mechanisms have evolved to tightly control centriole duplication. Importantly, centriole pairs are barred from duplicating until they go through a not completely understood process of licensing that includes the physical separation of older (mother) and younger (daughter) centrioles. Here we report that the dynein adaptor BICD2 is a centriolar protein with a previously unknown dynein-independent role controlling mother-daughter centriole engagement. We show that a pool of BICD2 resides at the centrosome, surrounding mother centrioles close to the daughter centriole. Removal of BICD2 results in premature centriole disengagement in G2 and early M and in centriole amplification in both non-transformed and transformed cells. We characterize the molecular determinants of BICD2 centriolar localization and suggest that this localization, and thus the role of BICD2 at the centriole, is controlled by phosphorylation. Our findings reveal a novel function of BICD2, independent of its ability to interact with dynein, which is crucial for the regulation of centriole licensing and the centrosome duplication cycle.
Studies of all-transretinoic acid transport in myopigenesis
Authors: Chatterjee Saptarshi , Roy Ankana , Yu Jianshi , Read A. Thomas , Bentley-Ford Melissa R , Pardue Machelle T. , Kane Maureen A. , Finn M. G. , Ethier C. Ross
Published: January 2025

Purpose

Myopia incidence is increasing globally. All-transretinoic acid (atRA) is important in myopigenic retinoscleral signaling, motivating research on its ocular transport. However, atRA’s weak autofluorescence limits its direct visualization in tissues. Further, atRA is hydrophobic and must bind to protein carriers for transport. We assessed a fluorescent analog of atRA (LightOxTM14, CAS:198696-03-6, referred as ‘floRA’), as an experimentally accessible atRA surrogate by: (i) evaluating its binding to carrier proteins and (ii) visualizing its distribution in ocular tissues.

Methods

Binding

We assessed atRA-carrier protein binding using fluorescence quenching assays with bovine serum albumin (BSA), high density lipoprotein (HDL), apolipoprotein A-I (Apo A-I) and retinol binding protein 4 (RBP4).

Direct visualization

Wild-type C57BL/6J mice were euthanized, eyes enucleated, and wedges containing sclera and choroid incubated for specific durations in 50 μM floRA+BSA. The wedge centers were cryo-sectioned and counterstained for nuclei. Fluorescent micrographs were acquired and analyzed using ImageJ.

Results

Association constants (Ka) for atRA and floRA binding to carrier proteins were similar and ranged from 2-13 × 105M-1, indicating non-specific binding. floRA could be visualized in sclera and choroid, yet showed significant spatial heterogeneity (enhanced fluorescence often colocalizing with nuclei).

Conclusions

floRA is a reasonable surrogate for atRA binding to BSA, HDL, Apo A-I and RBP4. Considering these proteins’ relative serum and extravascular abundances, and their similar binding affinity to atRA, we predict that serum albumin is an important atRA carrier. Use of floRA in whole tissue tracer studies shows promise but requires further refinement.
Impact of bystander intervention on clinical outcome in out-of-hospital cardiac arrest. A study of 8,253 Polish cases from the European Registry of Cardiac Arrest (2014-2022)
Authors: Żądło Anna , Wilczek Dawid , Cebula Grzegorz , Orzechowska Daria , Tokarek Tomasz
Published: January 2025

Background

Out-of-Hospital Cardiac Arrest (OCHA) remains a significant challenge for healthcare systems, with actions by witnesses playing a critical role. This study examines Polish data from the European Registry of Cardiac Arrest (EuReCa), identifying progress in updated paramedic protocols and public availability of automated external defibrillators (AED) while noting issues such as delays in emergency call localization, lack of synchronization in defibrillator maps, inadequate reporting, and absence of information on long-term neurological outcomes.

Aims

The aim of this study was to assess the role of bystanders and dispatchers in the chain of survival for OHCA.

Methods

A retrospective analysis was conducted on 8,253 patients included in the EuReCa between 2014 and 2022. Data were collected from emergency medical team reports, and survival outcomes at 30 days were obtained from the national death registry.

Results

Full cardiopulmonary resuscitation (CPR) performed by witnesses, including both chest compressions and rescue breaths, combined with the use of AED, significantly increased the likelihood of return of spontaneous circulation (ROSC) compared to chest compressions alone or no intervention. Dispatcher-guided resuscitation increased ROSC from 22.1% to 30.6% (p=0.01), though the increase in 30-day survival from 42.8% to 48.2% was not statistically significant (p=0.27). CPR by witnesses increased the number of patients transported to hospital with ROSC(74.0% vs. 26.0%; p=0.01).

Conclusions

Bystanders and dispatchers are pivotal in the chain of survival. Improving the quality of reporting on actions taken by witnesses, including dispatcher-assisted resuscitation and the use of automated defibrillators, is critical for identifying effective strategies and allocating resources to improve survival and outcomes for cardiac arrest outside hospitals in Poland.
NfκBin: A Machine Learning based Method for Screening Nf-κB Inhibitors
Authors: Jain Shipra , Tomer Ritu , Patiyal Sumeet , Raghava Gajendra P. S.
Published: January 2025

Nuclear Factor kappa B (NF-κB) is a transcription factor whose upregulation is associated in chronic inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and asthma. In order to develop therapeutic strategies targeting NF-κB-related diseases, we developed a computational approach to predict drugs capable of inhibiting NF-κB signaling pathways. In this study, we utilized a dataset comprising 1,149 inhibitors and 1,332 non-inhibitors retrieved from PubChem. Chemical descriptors were computed using the PaDEL software, and relevant features were selected using advanced feature selection techniques. Initially, machine learning models were constructed using 2D descriptors, 3D descriptors, and molecular fingerprints, achieving maximum AUC values of 0.66, 0.56, and 0.66, respectively. To improve feature selection, we applied univariate analysis and SVC-L1 regularization to identify features that can effectively differentiate inhibitors from non-inhibitors. Using these selected features, we developed machine learning models, our support vector classifier achieved an AUC of 0.75 on the validation dataset. All models were trained using five-fold cross-validation and rigorously evaluated on an independent validation dataset, which was not used during training or hyperparameter optimization. Finally, our best-performing model was employed to screen FDA-approved drugs for potential NF-κB inhibitors. Notably, most of the predicted inhibitors corresponded to drugs previously identified as inhibitors in experimental studies, underscoring the model’s predictive reliability. Our best- performing models have been integrated into a standalone software and web server, NfκBin, to enable the scientific community to perform high-throughput screening of Nf-κB inhibitors from chemical libraries. (https://webs.iiitd.edu.in/raghava/nfkbin/).

Highlights

1)

Inhibitors of Nf-κB can be used to manage disease like rheumatoid arthritis, asthma.

2)

A novel tool NfκBin developed for screening Nf-κB inhibitors from chemical library.

3)

Cutting-edge feature selection techniques used to identify the most relevant chemical descriptors.

4)

Models were developed and validated on a robust dataset of inhibitors and non-inhibitors.

5)

Integrated best-performing models into the NfκBin software and web server.
Discovery of Expression-Governing Residues in Proteins
Authors: Jiang Fan , Li Mingchen , Wu Banghao , Zhang Liang , Zhong Bozitao , Yu Yuanxi , Hong Liang
Published: January 2025

Understanding how amino acids influence protein expression is crucial for advancements in biotechnology and synthetic biology. In this study, we introduce Venus-TIGER, a deep learning model designed to accurately identify amino acids critical for expression. By constructing a two-dimensional matrix that links model representations to experimental fitness, Venus-TIGER achieves improved predictive accuracy and enhanced extrapolation capability. We validated our approach on both public deep mutational scanning datasets and low-throughput experimental datasets, demonstrating notable performance compared to traditional methods. Venus-TIGER exhibits robust trans-ferability in zero-shot predicting scenarios and enhanced predictive performance in few-shot learning, even with limited experimental data. This capability is particularly valuable for protein design aimed at enhancing expression, where generating large datasets can be costly and time-consuming. Additionally, we conducted a statistical analysis to identify expression-associated features, such as sequence and structural preferences, distinguishing between those linked to high and low expression. Our investigation also revealed a correlation among stability, activity and expression, providing insight into their interconnected roles and underlying mechanisms.
Improving MALDI Mass Spectrometry Imaging Performance: Low-Temperature Thermal Evaporation for Controlled Matrix Deposition and Improved Image Quality
Authors: Mahamdi Toufik , Serna Cristina Gomez , Giné Roger , Rofes Jordi , Mohammed Shad Arif , Ràfols Pere , Correig Xavier , García-Altares María , Hopf Carsten , Iakab Stefania-Alexandra , Yanes Oscar
Published: January 2025

The deposition of matrix compounds significantly influences the effectiveness of matrix-assisted laser desorption/ionization (MALDI) Mass Spectrometry Imaging (MSI) experiments, impacting sensitivity, spatial resolution, and reproducibility. Dry deposition methods offer advantages by producing homogeneous matrix layers and minimizing analyte delocalization without the use of solvents. However, refining these techniques to precisely control matrix thickness, minimize heating temperatures, and ensure high-purity matrix layers is crucial for optimizing MALDI-MSI performance. Here, we present a novel approach utilizing low-temperature thermal evaporation (LTE) for organic matrix deposition under reduced vacuum pressure. Our method allows for reproducible control of matrix layer thickness, as demonstrated by linear calibration for two organic matrices, 2,5-dihydroxybenzoic acid (DHB), and 1,5-Diaminonaphthalene (DAN). The environmental scanning electron microscopy images reveal a uniform distribution of small-sized matrix crystals, consistently on the submicrometer scale, across tissue slides following LTE deposition. Remarkably, LTE serves as an additional purification step for organic matrices, producing very pure layers irrespective of initial matrix purity. Furthermore, stability assessment of MALDI-MSI data from mouse brain sections coated with LTE-deposited DHB or DAN matrix indicates minimal impact on ionization efficiency, signal intensity, and image quality even after storage at - 80°C for two weeks, underscoring the robustness of LTE-deposited matrices for MSI applications. Comparative analysis with the spray-coating method highlights several advantages of LTE deposition, including enhanced ionization, reduced analyte diffusion, and improved MSI image quality.
Structural basis of nucleosome recognition by the conserved Dsup and HMGN nucleosome-binding motif
Authors: Alegrio-Louro Jaime , Cruz-Becerra Grisel , Kadonaga James T. , Leschziner Andres E.
Published: January 2025

The tardigrade damage suppressor (Dsup) and vertebrate high mobility group N (HMGN) proteins bind specifically to nucleosomes via a conserved motif whose structure has not been experimentally determined. Here we used cryo-EM to show that both proteins bind to the nucleosome acidic patch via analogous arginine anchors with one molecule bound to each face of the nucleosome. We additionally employed the natural promoter-containing 5S rDNA sequence for structural analysis of the nucleosome. These structures of an ancient nucle-osome-binding motif suggest that there is an untapped realm of proteins with a related mode of binding to chromatin.
An algorithm for the transformation of the Petri net models of biological signaling networks into influence graphs
Authors: Gamache-Poirier Simon , Souvane Alexia , Leclerc William , Villeneuve Catherine , Hardy Simon V.
Published: January 2025

A common depiction for biological signaling networks is the influence graph in which the activation and inhibition effects between molecular species are shown with vertices and arcs connecting them. Another formalism for reaction-based models is the Petri nets which has a graphical representation and a mathematical notation that enables structural analysis and quantitative simulation. In this paper, we present an algorithm based on Petri nets topological features for the transformation of the computational model of a biological signaling network into an annotated influence graph. We also show the transformation of the Petri nets model of the beta-adrenergic receptor activating the PKA-MAPK signaling network into its representation as an influence graph.
Chemokine induces phase transition from non-directional to directional migration during angiogenesis
Authors: Gui Ning , Sako Keisuke , Fukumoto Moe , Mochizuki Naoki , Nakajima Hiroyuki
Published: January 2025

During angiogenesis, sprouting endothelial cells (ECs) migrate and eventually connect to target vessels to form new vessel branches. However, it remains unclear how these sprouting vessels migrate toward the target vessels in three-dimensional space. We performedin vivoimaging of the cerebral capillary network formation in zebrafish to investigate how sprouting tip cells migrate toward their targets. Of note, we found that tip cells reach the target vessels through two phases: a non-directional phase and a directional phase. In the non-directional phase, sprouting tip cells dynamically extend and retract their protrusions at the leading front and have less directionality in their movement. In contrast, once tip cells enter the directional phase, they migrate directly toward the anastomotic targets. Chemokine receptor Cxcr4a and its ligand Cxcl12b are important for the phase transition to the directional phase. Incxcr4amutants, sprouting tip cells lose their directionality and tend to connect to nearby sprouting ECs, resulting in altered capillary network patterning. Furthermore, in wild-type (WT) larvae, local Ca2+oscillations were detected in protrusions of tip cells, specifically in the non-directional phase, but almost disappeared in the directional phase as a result of the Cxcr4-dependent phase transition. Thus, this study provides evidence of a chemokine-induced phase transition in migrating tip cells, which is important for proper vascular network formation in the zebrafish brain.
The Inflation Reduction Act’s Impact upon Early-stage Venture Capital Investments
Authors: Schulthess Duane G. , O’Loughlin Gwen , Askeland Madeline , Gassull Daniel , Bowen Harry P.
Published: January 2025

Background

The Congressional Budget Office has stated there is no evidence of a systematic decrease in the percentage of venture capital flowing to pharmaceutical companies since IRA’s passage. This was echoed in Prof. Rita Conti’s September 17, 2024, Senate Finance Committee testimony.

Methods

To test the IRA’s impacts on early-stage investments targeting therapeutics for the Medicare-aged population, a longitudinal dataset of commercially sponsored clinical trials by companies with a market valuation < $2 billion was obtained from the BioMedTracker database from January 1, 2018, to May 6, 2024. These trials were filtered to match early-stage investments to lead assets undergoing clinical development.

Results

From 161 lead assets with 897 investments, we find the aggregated total into large molecules in 2024 was 10 times larger than that for small molecules, which underwent a 70% decline after passage of the IRA. Individual investments made into small molecules decline by minus one-half as exposure to the Medicare-aged population increases after the passage of the IRA (p < 0.0018). Testing large molecule investments by their exposure to Medicare post IRA’s passage is statistically inconclusive.

Research Conclusions

This study presents evidence of a decline in the development of new therapies targeting the Medicare-aged population since the passage of the IRA. If these impacts were due to the economic downturn post-pandemic, we would observe statistically similar results in both large and small molecules. However, the results by molecule type diverge. Investors perceive large molecules to be of a lower investment risk relative to small molecules after IRA’s passage.
Clinical Development and Performance of the First To Know Syphilis Self-Test for Over-the-Counter Usage: a De Novo Rapid Test for Treponemal Antibody
Authors: Clark Kevin , Rabine Sharon , Qian Jianghong , Biddison Diane , Spradlin Sydney , Thompson Vicki , Shi Qinwei , Xu Jing , Pillai Raji , Zhang Lu , Brown Alicia , Nibauer Lisa , Joyee Antony George , Berry Jody D.
Published: January 2025

The resurgence of syphilis in the USA and globally has hastened the need for widely available syphilis testing. Early detection of syphilis is crucial for avoiding serious clinical complications and preventing spread of infection. Self-tests enhance access to testing and promote timely treatment for positive cases. Herein we describe the performance of First to Know Syphilis Test (FTK), the first over the counter (OTC) treponemal test. A prospective multi-site clinical study with 1270 subjects was conducted, where subjects self-collected fingerstick capillary blood and self-tested without assistance. FTK test results were compared with a composite reference standard to evaluate diagnostic performance. The FTK test exhibited an overall sensitivity of 93.4% (95% CI, 87.0% to 96.8%) and specificity of 99.5% (95% CI, 98.9% - 99.8%) and accuracy of 99%. The overall agreement was 98.9%, with Cohens Kappa (ⱪ) value 0.93 (95% CI, 0.90 to 0.97) showing excellent agreement between the reference standard and FTK results. In addition, the test was validated in a panel of 125 clinically staged syphilis patient samples and the results showed 100% agreement in detecting anti-treponemal antibodies in all the samples. These data show excellent performance of the FTK Test demonstrating its utility in the screening and diagnosis of syphilis. The availability of this OTC test and its excellent performance at low prevalence, will have a profound impact on syphilis detection and prevention strategies and could reduce co morbidities such as HIV and other STI transmission.
Evaluation of Photon-Counting CT for Spectral Imaging in Cardiovascular Applications: Impact of Lumen Size, Dose, and Patient Habitus
Authors: Rybertt Martin V. , Liu Leening P. , Mathew Manoj , Sahbaee Pooyan , Litt Harold I. , Noël Peter B.
Published: January 2025

Objectives

This study evaluates the performance of a clinical dual-source photon-counting computed tomography (PCCT) system in quantifying iodine within calcified vessels, using 3D- printed phantoms with vascular-like structures lined with calcium.

Methods

Parameters assessed include lumen diameters (4, 6, 8, 10, and 12 mm), phantom sizes (S: 20×20 cm, M: 25×25 cm, L: 30×40 cm, XL: 40×50 cm, representing the 99th percentile of US patient sizes), and iodine concentrations (2, 5, and 10 mg/mL). Scans were performed at radiation dose levels of 5, 10, 15, and 20 mGy to systematically evaluate iodine quantification accuracy and spectral imaging performance.

Results

The results indicate that for lumen diameters ≥6 mm, iodine quantification remains stable across all dose levels and phantom sizes, with deviations consistently below 0.6 mg/mL. Whereas, for 4 mm lumens, stability is observed primarily in smaller to medium phantoms, highlighting the influence of patient size and radiation dose on quantification accuracy. Virtual Monoenergetic Imaging (VMI) at 70 keV showed stable performance for larger lumens (≥6 mm) with variations of 13 ± 2 HU across all conditions, while smaller lumens remained stable in medium to small phantoms.

Conclusions

These findings highlight the influence of lumen diameter, patient size, and radiation dose in optimizing PCCT protocols for spectral imaging. Importantly, the study demonstrates that PCCT delivers stable and highly accurate imaging across nearly the entire range of patient sizes in the U.S..

Advances in knowledge

This study demonstrates PCCT’s potential to enhance spectral imaging in vascular applications, surpassing conventional or Dual Energy CT.
Harnessing Mondo and the ILAE Classification for Curation and Analysis of 71,942 epilepsy patient variants
Authors: Ivaniuk Alina , Bruenger Tobias , Perez-Palma Eduardo , Xiao Junhui , St John Mark , Nascimento Fábio A. , Zhang Guo-Qiang , Lhatoo Samden , Lal Dennis
Published: January 2025

Mapping epilepsy variants in ClinVar to standard disease classifications remains challenging due to incomplete phenotype information. We integrated the Mondo Disease Ontology (Mondo) with the International League Against Epilepsy (ILAE) Classification to systematically identify, organize, and analyze age-dependent epilepsy-associated variants from the world’s largest public variant repository. Starting from over three million ClinVar entries, we filtered monogenic disorders tagged with 421 Mondo terms representing neonatal/infantile, childhood, or variable-onset epilepsy syndromes. Gene-disease validity was further refined using multiple expert-curated lists, resulting in 71,942 unique variant submissions in 171 genes. Approximately 70% of pathogenic and uncertain variants clustered in 50 genes, highlighting the concentration of clinically relevant findings in a relatively small subset of known epilepsy genes.SCN1A,GRIN2A, andDEPDC5stood out as top contributors to neonatal/infantile, childhood, and variable-onset syndromes, respectively. Notably, two-thirds of genes were specific to a single age group, but the remaining one-third spanned multiple syndromes, reflecting both phenotypic and genetic heterogeneity. We also observed substantial overlap with neurodevelopmental and autism-related genes, especially among early-onset epilepsies, emphasizing shared molecular pathways. Our Mondo-driven approach demonstrates the feasibility of large-scale, ontology-based curation of ClinVar for domain-specific analyses, offering greater clinical precision than traditional text-based queries. This resource can guide epilepsy-focused gene panel design, inform new classification updates, and pave the way for age-targeted therapeutics. By bridging the gap between extensive genomic repositories and detailed clinical ontologies, we provide a robust, standardized framework to accelerate progress in precision epilepsy genetics.
The Role ofde novoand Ultra-Rare Variants in Hirschsprung Disease (HSCR): Extended Gene Discovery for Risk Profiling of Patients
Authors: Fu Mingzhou , Berk-Rauch Hanna E , Chatterjee Sumantra , Chakravarti Aravinda
Published: January 2025

Background

Hirschsprung disease (HSCR) is a rare neurodevelopmental disorder caused by disrupted migration and proliferation of enteric neural crest cells during enteric nervous system development. Genetic studies suggest a complex etiology involving both rare and common variants, but the contribution of ultra-rare pathogenic variants (PAs) remains poorly understood.

Methods

We perform whole-exome sequencing (WES) on 301 HSCR probands and 109 family trios, employing advanced statistical methods and gene prioritization strategies to identify genes carryingde novoand ultra-rare coding pathogenic variants. Multiple study designs, including case-control,de novomutation analysis and joint test, are used to detect associated genes. Candidate genes are further prioritized based on their biological and functional relevance to disease associated tissues and onset period (i.e., human embryonic colon).

Results

We identify 19 risk genes enriched with ultra-rare coding pathogenic variants in HSCR probands, including four known genes (RET,EDNRB,ZEB2,SOX10) and 15 novel candidates (e.g.,COLQ,NES,FAT3) functioning in neural proliferation and neuromuscular synaptic development. These genes account for 17.5% of the population-attributable risk (PAR), with novel candidates contributing 6.5%. Notably, a positive correlation between pathogenic mutational burden and disease severity is observed. Female cases exhibit at least 42% higher ultra-rare pathogenic variant burden than males (P = 0.05).

Conclusions

This first-ever genome-wide screen of ultra-rare variants in a large, phenotypically diverse HSCR cohort highlights the substantial contribution of ultra-rare pathogenic variants to the disease risk and phenotypic variability. These findings enhance our understanding of the genetic architecture of HSCR and provide potential targets for genetic screening and personalized interventions.
Convergent genomic and molecular features predict risk of metachronous metastasis in clear cell renal cell carcinoma
Authors: Naeini Marjan M. , Pang Mengyuan , Rohatgi Neha , Kadioglu Sinem , Ghoshdastider Umesh , DiNatale Renzo G. , Mano Roy , Hakimi A Ari , Skanderup Anders Jacobsen
Published: January 2025

Understanding the molecular features that determine the risk of metachronous metastases in clear cell renal cell carcinoma (ccRCC) is crucial for improving adjuvant treatment strategies and patient outcomes. We identified convergent genomic and transcriptomic alterations in chromosome 1p, implicating dysregulation of epithelial cell polarity and fatty acid metabolism as novel risk factors for metachronous metastases. Genomic analysis revealed a significantly higher frequency of copy number loss at chromosome 1p31-36 in primary tumors that later progressed with metastases. Integrative tumor transcriptome deconvolution further uncovered cancer and stromal cell molecular features associated with metastatic risk, independently implicating dysregulation of epithelial cell polarity and fatty acid metabolism genes at chromosome 1p (including PATJ and CYP4A11, at 1p31-33). Additionally, we developed, validated, and benchmarked a compact 5-feature predictive model (5G) that outperformed existing ccRCC gene signatures in predicting metachronous metastasis risk. Together, these findings offer new opportunities for drug development and improved patient risk management.
Projecting neurons from lateral entorhinal cortex to basolateral amygdala mediate the encoding of incidental odor-taste associations
Authors: González-Parra Jose Antonio , Acciai Vittoria , Vidal-Palencia Laura , Canela Marc , Busquets-Garcia Arnau
Published: January 2025

Daily choices are determined by prior direct or indirect associations between low-salience cues and reinforcers. In this study, we used a mouse odor-taste sensory preconditioning task combined with genetic, intersectional and chemogenetic approaches to identify a novel brain circuit involved in mediated learning. We found that neuronal projections from the lateral entorhinal cortex to the basolateral amygdala are engaged during low-salience stimuli associations, which is essential for mediated learning formation.
CENdetectHOR: a comprehensive tool for CENtromere profiling and HOR detection
Authors: Daponte Alessia , Pagliuca Paolo , Vila-Verde Carlos , Montinaro Francesco , Antonacci Francesca , Ventura Mario , Ceriani Miguel , Catacchio Claudia R
Published: January 2025

Centromeres are essential for accurate chromosome segregation and are characterized by long arrays of repetitive satellite DNA, showing extensive variation in sequence, length, and organization across species. Despite extensive research, fully characterizing centromeric DNA has been challenging due to its repetitive nature and rapid evolution. Here, we present CENdetectHOR, a computational tool to identify and analyze higher-order repeat (HOR) arrays in centromeric regions across diverse organisms, requiring noa prioriinformation. We validate its efficacy using human and arabidopsis genomes, demonstrating its ability to reveal the complexity and diversity of centromeric architectures. CENdetectHOR also recognizes HOR variants, elucidating interindividual and interspecific variations in centromeric regions. These findings establish CENdetectHOR as a powerful, versatile, and rapid tool for advancing research on centromere structure, evolution, and function.
Nitrification in a Seagrass-Sponge Association
Authors: Berlinghof Johanna , Montilla Luis M. , Meador Travis B. , Gallucci Luigi , Giovannelli Donato , Gruber-Vodicka Harald , Maselli Maira , Margiotta Francesca , Wild Christian , Cardini Ulisse
Published: January 2025

Abstract

In the Mediterranean Sea, the demospongeChondrilla nuculacan occur in close association with the native seagrassPosidonia oceanica.C. nuculaharbors a diverse and abundant microbial community, including potential nitrifiers. Thus, the sponge may contribute to the nitrogen (N) demand of the seagrass holobiont. In this study, we investigated potential nitrification rates (PNR) and inorganic N fluxes within this association at a site whereC. nuculacovered 18 ± 3 % of the seagrass meadow area, during plant growth (spring) and senescence (autumn). Using incubation experiments with15N-labeled ammonium, we measured PNR and inorganic N of the seagrass-sponge association, and of sponge and seagrass independently, under light and dark conditions. We supplemented these experiments with 16s rRNA gene amplicon sequencing to characterize the microbial community of the sponge. PNR was exclusively measured when the sponge was present (alone or in association with the seagrass). PNR was highest in the dark and whenC. nuculawas associated with the seagrass, ranging from 21 ± 7 to 267 ± 33 nmol N g DW-1h-1in spring and autumn, respectively. Sponge-mediated PNR can support 8% of the N demand of theP. oceanicaholobiont during growth and 47 % during senescence. We identified key nitrifying bacterial and archaeal groups as members of the sponge’s microbial community. WhileC. nuculareleased inorganic N, potentially sustaining the seagrass, it benefitted from dissolved organic carbon released byP. oceanica. These results suggest that the interaction betweenC. nuculaandP. oceanicais mutually beneficial, ultimately supporting and stabilizing the seagrass ecosystem.
Cancer associated fibroblasts drive epithelial to mesenchymal transition and classical to basal change in pancreatic ductal adenocarcinoma cells with loss of IL-8 expression
Authors: Guinn Samantha , Perez Brayan , Tandurella Joseph A. , Ramani Mili , Lee Jae W. , Zabransky Daniel J. , Kartalia Emma , Patel Jignasha , Zlomke Haley , Nicolson Norman , Shin Sarah , Barrett Benjamin , Sun Nicholas , Hernandez Alexei , Coyne Erin , Cannon Courtney , Gross Nicole E. , Charmsaz Soren , Cho Yeonju , Leatherman James , Lyman Melissa , Mitchell Jacob , Kagohara Luciane T. , Goggins Michael G. , Lafaro Kelly J. , He Jin , Shubert Christopher , Burns William , Zheng Lei , Fertig Elana J. , Jaffee Elizabeth M. , Burkhart Richard A. , Ho Won Jin , Zimmerman Jacquelyn W.
Published: January 2025

Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, in part resulting from cellular heterogeneity that supports overall tumorigenicity. Cancer associated fibroblasts (CAF) are key determinants of PDAC biology and response to systemic therapy. While CAF subtypes have been defined, the effects of patient-specific CAF heterogeneity and plasticity on tumor cell behavior remain unclear. Here, multi-omics was used to characterize the tumor microenvironment (TME) in tumors from patients undergoing curative-intent surgery for PDAC. In these same patients, matched tumor organoid and CAF lines were established to functionally validate the impact of CAFs on the tumor cells. CAFs were found to drive epithelial-mesenchymal transition (EMT) and a switch in tumor cell classificiaton from classical to basal subtype. Furthermore, we identified CAF-specific interleukin 8 (IL-8) as an important modulator of tumor cell subtype. Finally, we defined neighborhood relationships between tumor cell and T cell subsets.

Statement of Significance

This multidimensional analysis highlights the diverse role CAFs have in influencing other cell types in the TME, including epithelial-derived tumor and infiltrating immune cells. Our methods provide a platform for evaluating emerging therapeutic approaches and for studying mechanisms that dictate tumor behavior in a manner that reflects patient-specific heterogeneity.
Variant effects depend on polygenic background: experimental, clinical, and evolutionary implications
Authors: Chapel Madison , Dennis Jessica , de Boer Carl G.
Published: January 2025

Both rare and common genetic variants contribute to human disease, and emerging evidence suggests that they combine additively to influence disease liability. However, due to the non-linear relationship between disease liability and disease prevalence, risk variants have more severe phenotypic consequences in high-risk polygenic backgrounds. Consequently, selecting individuals with appropriate polygenic backgrounds may improve variant characterization experiments, as disease-relevant phenotypes may be masked or revealed in different genomic contexts. Simultaneously, selection has limited power to eliminate risk variants because they have minimal impact in low polygenic risk backgrounds, yet is more powerful with higher polygenicity because more individuals achieve genetic and phenotypic extremes. This dependence on polygenic background means that selection acting on an allele should be modeled as a distribution that differs across populations, time, environments, and individuals rather than as a single value. Overall, considering polygenic backgrounds will be critical when investigating the origins of complex traits.
Prognostic and Diagnostic Utility of Heart Rate Variability to Predict and Understand Change in Cancer and Chemotherapy Related Fatigue, Pain, and Neuropathic Symptoms: A Systematic Review
Authors: Bolanos Jessica , Hneiny Layal , Gonzalez Juan , O’Malley Max , Wong Marlon L
Published: January 2025

Advances in early cancer detection and treatment have significantly improved survival rates, resulting in over 18.1 million cancer survivors in the United States. Many of these survivors experience chronic pain, fatigue, and neuropathic symptoms related to cancer or its treatments. Emerging evidence suggests that autonomic nervous system dysfunction plays a crucial role in these symptoms. Heart rate variability (HRV), a measure of autonomic function, has shown potential in predicting the onset of somatic symptoms in cancer patients. This systematic review aimed to assess the association of HRV with pain, fatigue, and neuropathy in cancer patients and survivors.

A comprehensive search was conducted across multiple databases, yielding 19 studies that met inclusion criteria. These studies varied in cancer types, stages, and HRV measurement methods. Most studies focused on breast cancer and reported a predominant female population. Fatigue was the most studied symptom, followed by pain. HRV measures included both time and frequency domain variables, with significant variability in measurement duration and control for confounding factors.

Findings suggest that decreased HRV is associated with increased fatigue and pain, providing potential support for a bidirectional relationship between autonomic dysfunction and these symptoms. However, the heterogeneity in HRV measurement methods and the high risk of bias in many studies highlight the need for standardized HRV protocols in cancer research. Further large-scale studies with low risk of bias are necessary to validate HRV as a reliable tool for phenotyping and managing cancer-related symptoms.
The Characteristic Timescales of the Arabidopsis thaliana Metabolism and the Phenotypic Effects of Forcing Them
Authors: Santoro Giovanni , Rolli Enrico , Ricci Ada , Cademartiri Ludovico
Published: January 2025

Response mechanisms preserve steady states in complex systems (including living systems). These mechanisms respond with characteristic timescales. Therefore, they can be identified and probed with oscillatory forcing. This approach is rarely used in plant biology.

Sub-circadian intermittent illumination (i.e., square waves of light/dark periods of equal duration) ofArabidopsis thalianaplants cause remarkable phenotypical effects. We show these effects are highly dependent on the duration of the light-dark cycle, identifying characteristic timescales in three distinct windows (10.5-42 s, 168-336 s, and 1350-5400 s). Among these effects is an extension of the life cycle by 60%, a 2-fold increase in flower setting, and a near complete elimination of lateral root development.

This oscillatory light forcing is compatible with vertical farming where it could reduce energy and chemical inputs and highlights the methodological value of temporal-forcing of environmental parameters on sub-circadian timescales in plant systems.
Long-term Monte Carlo-based neutrino-radiation hydrodynamics simulations for a black hole-torus system
Authors: Kawaguchi Kyohei , Fujibayashi Sho , Shibata Masaru
Published: January 2025

We present our new general relativistic Monte Carlo (MC)-based neutrino radiation hydrodynamics code designed to solve axisymmetric systems with several improvements. The main improvements are as follows: (i) the development of an extended version of the implicit MC method for multispecies radiation fields; (ii) modeling of neutrino pair process rates based on a new numerically efficient and asymptotically correct fitting function for the kernel function; (iii) the implementation of new numerical limiters on the radiation-matter interaction to ensure a stable and physically correct evolution of the system. We apply our code to a black hole (BH)-torus system with a BH mass of 3M⊙, BH dimensionless spin of 0.8, and a torus mass of 0.1M⊙, which mimics a postmerger remnant of a binary neutron star merger in the case that the massive neutron star collapses to a BH within a short timescale (∼10  ms). We follow the evolution of the BH-torus system up to more than 1 s with our MC-based radiation viscous-hydrodynamics code that dynamically takes into account nonthermal pair annihilation. We find that the system evolution and the various key quantities, such as neutrino luminosity, ejecta mass, torus Ye, and pair annihilation luminosity, are broadly in agreement with the results of the previous studies. We also find that the νeν¯e pair annihilation can launch a relativistic outflow for a timescale of ∼0.1  s, and it can be energetic enough to explain some of short-hard gamma-ray bursts and the precursors. Finally, we calculate the indicators of the fast flavor instability directly from the obtained neutrino distribution functions, which indicate that the instability can occur particularly near the equatorial region of the torus.

Published by the American Physical Society
2025
Local quantum detection of the cosmological expansion: Unruh-DeWitt detectors in spatially compact Milne cosmology
Authors: Wilkinson Adam S. , Louko Jorma
Published: January 2025

We analyze the excitations and deexcitations of an inertial Unruh-DeWitt detector in the (1+1)-dimensional expanding Milne cosmology with compact spatial sections, coupled to a real massless scalar field with either untwisted or twisted boundary conditions, prepared in the conformal vacuum. We find the detector’s response as a function of the energy gap, the Milne spatial circumference parameter, the interaction duration, the age of the Universe at the switch-on moment, the detector’s peculiar velocity at the switch-on moment, and, for the untwisted field, the state of the zero mode. Asymptotic analytic results are obtained at large energy gap and at large circumference parameter, in each case recovering the Minkowski vacuum response in the leading order, and in the double limit of small circumference parameter and late cosmological time, recovering the response in a static Minkowski cylinder. Numerical results are given in the interpolating regimes. The results confirm the detector’s sensitivity to both classical and quantum properties of its environment.

Published by the American Physical Society
2025
Perceived service quality and electronic word-of-mouth on food delivery services: extended theory of planned behaviour
Authors: Liao Shu-Hsien , Hu Da-Chian , Chen Cai-Jun
Published: January 2025

Purpose

This study proposed an extended theory of planned behaviour (TPB), that is, considering that behavioural beliefs, normative beliefs and control beliefs (beliefs) will influence perceived service quality (PSQ) on food delivery services. PSQ (behavioural intention) will influence electronic word-of-mouth (EWOM) (behaviour). In addition, exogenous variables including information from online ratings and consumer groups will affect the strength of the relationship between received service quality and EWOM on food delivery service.

Design/methodology/approach

This study aimed to investigate the mediation (PSQ) and moderation (Online ratings and consumer groups) effects on the extended TPB for Taiwanese consumers (n = 823).

Findings

This study first found a positive relationship between different beliefs and PSQ (behavioural intention). In addition, there is a positive relationship between PSQ and EWOM. Online rating has a moderating effect between PSQ and EWOM. Consumer group has a moderating relationship between PSQ and EWOM.

Originality/value

This study first found that the three stages of beliefs-intention-behaviour for consumers on food delivery service are reciprocal with two paths, starting with offline-to-online in terms of generating the positive relationship between individual belies and PSQ. Next, it can generate positive power to return online with a behaviour of EWOM. In addition, online ratings can enhance and strengthen the positive effect between PSQ and EWOM.