bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of immunogenic HLA-A*02:01 epitopes associated with HCC for immunotherapy development
Authors: Maino Anthony , Bourov﻿a-Flin Ekaterina , Decaens Thomas , Khochbin Saadi , Macek Jilkova Zuzana , Rousseaux Sophie , Plumas Joel , Saas Philippe , Chaperot Laurence , Manches Olivier
Published: February 2025

Background:

HCC is the most common form of primary liver cancer, and despite recent advances in cancer treatment, it remains associated with poor prognosis and a lack of response to conventional therapies. Immunotherapies have emerged as a promising approach for cancer treatment, especially through the identification of tumor-specific immunogenic epitopes that can trigger a targeted immune response. This study aimed to identify immunogenic epitopes associated with HCC for the development of specific immunotherapies.

Methods:

We used high-throughput data screening and bioinformatics tools for antigens and epitope selection. The immunogenicity of the selected epitopes was studied after coculture of peripheral blood mononuclear cells obtained from healthy donors or HCC patients with a plasmacytoid dendritic cell line loaded with the selected peptides. Specific CD8+ T cell amplification and functionality were determined by labeling with tetramers and by IFN-γ and CD107a expression (flow cytometry and ELISpot).

Results:

We analyzed the transcriptional gene expression landscape of HCC to screen for a set of 16 ectopically expressed genes in a majority of HCC samples. Epitopes predicted to bind to HLA-A*02:01 with high affinity were further validated for their immunogenicity using the previously described plasmacytoid dendritic cell line in ex vivo CD8+ activation assays using patient immune cells. Three out of the 30 tested epitopes, namely FLWGPRALV (MAGE-A3), FMNKFIYEI (AFP), and KMFHTLDEL (LRRC46), elicited a strong T-cell response, in activation assays, degranulation assays, and IFN-γ secretion assays.

Conclusions:

These results highlight the potential of these peptides to be considered as targets for immunotherapies. The discovery of such immunogenic epitopes should improve immune-based treatments for liver cancer in combination with the current treatment approach.
Repression of the ERRγ-CYP2E1 pathway by fibroblast growth factor 4 mitigates alcoholic liver injury
Authors: Wang Luyao , Dong Wenliya , Fan Lei , Kong Hongru , Liang Siyu , Huang Zhuobing , Chen Jie , Zhi Sisi , Xu Siyan , Qiu Qiaoling , Yang Miaomiao , Hou Yushu , Hu Yue , Pan Tongtong , Zheng Minghua , Li Xiaokun , Huang Zhifeng , Song Lintao
Published: February 2025

Background and Aims:

Alcoholic liver disease (ALD) represents a critical global health challenge characterized by liver damage resulting from excessive alcohol consumption. Early detection and timely intervention are essential for optimizing patient outcomes. However, the mechanisms underlying alcohol-induced liver injury have not been fully elucidated. Fibroblast growth factor 4 (FGF4) has been implicated in the progression of various liver diseases. This study aims to elucidate the role of FGF4 in the pathogenesis of ALD.

Approach and Results:

We analyzed human liver specimens and observed significant upregulation of FGF4 mRNA and protein levels in patients with ALD. Consistent findings were noted in mouse models subjected to a Lieber-DeCarli liquid diet. Importantly, hepatic FGF4 expression exhibited a positively correlated with ALD severity in both human subjects and murine models. Hepatocyte-specific deletion of Fgf4 (Fgf4-LKO) exacerbated alcohol-induced liver injury through increased oxidative stress, inflammation, and apoptosis. Specifically, Fgf4-LKO mice demonstrated heightened susceptibility to ethanol plus CCl4-induced fibrosis and liver injury. However, treatment with the ERRγ inverse agonist GSK5182 and CYP2E1 inhibitor chlormethiazole (CMZ) mitigated the exacerbated liver injury associated with Fgf4 deficiency. Mechanistic investigations revealed that FGFR4 phosphorylates ERRγ, promoting its ubiquitination and degradation in hepatocytes. Hepatic-specific knockout of Fgfr4 intensified alcohol-induced liver injury and nullified the protective conferred of recombinant FGF4△NT.

Conclusions:

Our study identifies FGF4 as a stress-responsive regulator in liver pathophysiology, operating via an FGFR4-mediated ERRγ-CYP2E1 signaling pathway. These results underscore the potential of FGF4 and its downstream pathways as therapeutic targets for ALD treatment.
Review of the Current Clinical and Preclinical Evidence Pertaining to the Immunomodulatory Effects of Black Seeds (Nigella sativa)
Authors: Balasubramanian Rajkapoor , Maideen Naina Mohamed Pakkir , Shanmugam Arun
Published: February 2025

Humans and other vertebrates are safeguarded from invading pathogenic microbes by the immune system. Black seed, scientifically known as Nigella sativa, has garnered attention for its potential immunomodulatory effects in both clinical and preclinical studies. This comprehensive review aims to consolidate and analyze the existing body of evidence surrounding the immunological impact of black seeds. In this review, we analyze the immunomodulatory potentials of black seeds (N. sativa). For the purpose of finding pertinent publications, the literatures was searched in web-based databases, including Web of Science, Medline/PMC/PubMed, Embase, EBSCO, Google Scholar, Science Direct, and reference lists. Several clinical, in vivo, and in vitro studies have demonstrated that supplementation with black seeds (N. sativa) has potential immunomodulatory activity. Black seeds (N. sativa) may influence immune responses through a variety of mechanisms. By synthesizing and critically assessing the current state of knowledge on the immunomodulatory effects of black seeds, this review aims to provide valuable insights into the potential therapeutic uses and future research directions for harnessing the immunological benefits of this natural remedy.

Graphical abstract: http://links.lww.com/AHM/A158.
The superficial capillary plexus perivascular gliosis occurring in retinitis pigmentosa revealed by multimodal retinal imaging.
Authors: Arrigo Alessandro , Aragona Emanuela , Cremona Ottavio , Antropoli Alessio , Bianco Lorenzo , Saladino Andrea , Bandello Francesco , Parodi Maurizio Battaglia
Published: February 2025

Purpose:

In this study, our goal was to deepen the understanding of the clinical significance and underlying pathogenic mechanisms of the hyperreflective ganglion cell layer (HGB) observed in optical coherence tomography (OCT) scans of patients with retinitis pigmentosa (RP).

Methods:

The study was designed as observational, cross-sectional. RP patients with and without HGB were recruited and underwent complete multimodal retinal imaging assessment, including OCT, OCT angiography (OCTA) and Dense Automatic-RealTime (DART) OCTA. Morphological outcome measures included OCTA vessel density (VD), foveal avascular zone area and ellipsoid zone (EZ) width. Functional outcome measures were LogMAR best-corrected visual acuity (BCVA) and retinal sensitivity.

Results:

Twenty eyes with HGB (20 RP patients) and 20 eyes without HGB (20 RP patients) were included. A reference control group was included as well. RP eyes with HGB were characterized by significantly worse LogMAR BCVA and retinal sensitivity, compared with RP eyes without HGB. Moreover, HGB subgroup showed significantly worse VD values of intraretinal capillary networks. The main superficial capillary plexus (SCP) VD reduction was detected in the extrafoveal region. DART OCTA allowed to support the SCP perivascular gliosis pathogenic origin of HGB. DART OCTA was able to detect (I) SCP perivascular hyperreflectivity; (II) SCP perfusion signal reduction and (III) peripheral SCP capillaries closure.

Conclusions:

The presence of HGB is identified as an adverse finding in a subset of eyes affected by RP. HGB correlates with markedly deteriorated retinal morphology and function. The possible pathogenic mechanism underlying HGB manifestation is the perivascular gliosis of the SCP.
Artificial Intelligence in Computed Tomography Image Reconstruction: A Review of Recent Advances
Authors: Zhang Ran , Szczykutowicz Timothy P. , Toia Giuseppe V.
Published: February 2025

The development of novel image reconstruction algorithms has been pivotal in enhancing image quality and reducing radiation dose in computed tomography (CT) imaging. Traditional techniques like filtered back projection perform well under ideal conditions but fail to generate high-quality images under low-dose, sparse-view, and limited-angle conditions. Iterative reconstruction methods improve upon filtered back projection by incorporating system models and assumptions about the patient, yet they can suffer from patchy image textures. The emergence of artificial intelligence (AI), particularly deep learning, has further advanced CT reconstruction. AI techniques have demonstrated great potential in reducing radiation dose while preserving image quality and noise texture. Moreover, AI has exhibited unprecedented performance in addressing challenging CT reconstruction problems, including low-dose CT, sparse-view CT, limited-angle CT, and interior tomography. This review focuses on the latest advances in AI-based CT reconstruction under these challenging conditions.
Effectiveness of CT Histogram Analysis to Differentiate Lung Metastases From Second Primary Lung Cancer to Decrease Need for Lung Biopsy
Authors: Bilgin Erkan , Yaltirik Bilgin Ezel , Bayrak Ahmet , Törenek Şahap
Published: February 2025

Objective:

Differentiating lung metastasis from second primary lung cancer is crucial for determining the appropriate treatment strategy. Lung biopsy, the gold standard for diagnosis, is an invasive procedure. This study aimed to evaluate the potential of CT histogram analysis as a noninvasive method for differentiating these 2 conditions in solitary pulmonary nodules.

Methods:

A retrospective analysis was conducted on CT images of patients with solitary pulmonary nodule, confirmed to be either lung metastasis or second primary lung cancer histopathologically. Histogram analysis features of the lesion and perilesional area were extracted from the CT images and subjected to statistical analysis to identify significant differences between the 2 groups. The performance of histogram analysis was assessed using sensitivity, specificity, and area under the ROC curve.

Results:

The data of 26 (46%) patients whose lung biopsy pathology was determined as second primary lung cancer and 30 (54%) patients defined as lung metastasis were investigated. The second primary lung cancer’s mean pathologic tumor diameter was statistically higher than the lung metastasis [25.3 (5.7) mm, 18.3(5.6) mm; P=0.003]. The mean skewness (P=0.020) and entropy (P=0.018) values in the second primary lung cancer were statistically significantly lower in the lesion area. There was a statistically significant difference in the mean measurement of SD (P=0.001), skewness (P<0.001), kurtosis (P<0.001), and entropy (P<0.001) values between the 2 groups in the perilesional area.

Conclusion:

CT histogram analysis shows promise as a noninvasive method for differentiating lung metastasis from second primary lung cancer in solitary pulmonary nodules.
A Systematic Review and Independent Patient Data Meta-Analysis of Prophylactic Mesh Augmentation for Incisional Hernia Prevention after Abdominal Aortic Aneurysm Surgery (I-PREVENT-AAA) A Collaborative European Hernia Society Project
Authors: van den Berg Rudolf , Den Hartog Floris P J. , Baart Sara J. , Bali Christina , Matsagkas Miltiadis , Bevis Paul M. , Earnshaw Jonothan J. , Debus Eike S. , Honig Susanne , Berrevoet Frederik , Detry Olivier , Stabilini Cesare , Muysoms Filip E. , Tanis Pieter J. ,   European Hernia Society Prophylactic mesh study group collaborators
Published: February 2025

Objective:

To analyze the effectiveness of prophylactic mesh augmentation (PMA) of the abdominal wall following open aortic aneurysm repair as compared to primary sutured closure in preventing incisional hernia (IH) formation by performing an individual patient-data meta-analysis (IPDMA).

Summary Background Data:

IH is a prevalent complication after abdominal surgery, especially in high-risk groups. PMA of the abdominal wall has been studied as a preventive measure for IH-formation, but strong recommendations are lacking.

Methods:

A systematic literature search was conducted till 23 September 2024 to identify randomized controlled trials (RCTs) that compared PMA with PS after open AAA surgery. Lead authors of eligible studies were asked to share individual patient-data. A one-stage analysis was performed, and Cox-regression analyses were used to assess time-to-event outcomes.

Results:

Five randomized trials with a total of 493 patients were included. Intention to treat analysis revealed that PMA was associated with significantly lower risk of IH (hazard ratio of 0.25 (95% CI 0.12-0.50)) as compared to PS closure. Three-year incisional hernia rates were 13.2% and 39.6%, respectively, with a number needed to treat of 3.7. The effect was similar for onlay and retro-rectus PMA. PMA resulted in longer operative time (mean 27 minutes) and more seroma formation (especially onlay PMA) but did not increase the risk of surgical site infection.

Conclusions:

PMA after elective open abdominal aortic aneurysm surgery is proven to be an effective measure to reduce IH formation and should be considered in future guidelines as standard of care.
Telomere dynamics in maturing frogs vary among organs
Authors: Burraco Pablo , Metcalfe Neil B. , Monaghan Pat
Published: February 2025

It is important to know whether organs age at the same rate and are equally affected by developmental conditions as this provides insights into causes of ageing. However, data on organ-specific telomere dynamics remain scant. In a previous study of the early life of the amphibian
Xenopus laevis
, we detected changes in telomere lengths in gut cells, while liver, heart and muscle telomeres were unchanged; larval rearing temperature had minimal effects. Here, we extend that study to examine telomere dynamics in the same four organs and larval temperature treatments from 70-day post-metamorphic juvenile
Xenopus
through to sexually mature (2-year-old) adults. Telomeres shortened from juvenile to adult in the gut, heart and hindlimb muscle. In contrast, liver telomere lengths did not change with age but were shorter if the early life temperature was warm. Organ telomere lengths were influenced by sex only in adults. Warmer larval temperatures were also associated with longer gut telomeres in juveniles. Hence, pre-metamorphic conditions can influence post-metamorphic telomere dynamics, and telomere loss between juvenile and adult life stages occurs in different organs from those affected earlier in life. These findings indicate the existence of organ-dependent ageing rates across lifetimes, potentially related to developmental and environmental history.
Compartmental structure in the secondary lymphoid tissue can slow down
in vivo
HIV-1 evolution in the presence of strong CTL responses
Authors: Chung Wen-Jian , Wodarz Dominik
Published: February 2025

Human immunodeficiency virus (HIV-1) replicates in the secondary lymphoid tissues, which are characterized by complex compartmental structures. While cytotoxic T lymphocytes (CTL) readily access infected cells in the extrafollicular compartments, they do not home to follicular compartments, which thus represent an immune-privileged site. Using mathematical models, previous work has shown that this compartmental tissue structure can delay the emergence of CTL escape mutants. Here, we show computationally that the compartmental structure can have an impact on the evolution of advantageous mutants that are not related to CTL recognition: (i) compartmental structure can influence the fixation probability of an advantageous mutant, with weakened selection occurring if CTL responses are of intermediate strength; (ii) compartmental structure is predicted to reduce the rate of mutant generation, which becomes more pronounced for stronger CTL responses; and (iii) compartmental structure is predicted to slow down the overall rate of mutant invasion, with the effect becoming more pronounced for stronger CTL responses. Altogether, this work shows that
in vivo
virus evolution proceeds slower in models with compartmental structure compared with models that assume equivalent virus load in the absence of compartmental structure, especially for strong CTL-mediated virus control. This has implications for understanding the rate of disease progression.
Uncertainty minimization and pattern recognition in
Volvox carteri
and
V. aureus
Authors: Kuchling Franz , Singh Isha , Daga Mridushi , Zec Susan , Kunen Alexandra , Levin Michael
Published: February 2025

The field of diverse intelligence explores the capacity of systems without complex brains to dynamically engage with changing environments, seeking fundamental principles of cognition and their evolutionary origins. However, there are many knowledge gaps around a general behavioural directive connecting aneural to neural organisms. This study tests predictions of the computational framework of active inference based on the free energy principle in neuroscience, applied to aneural biological processes. We demonstrate pattern recognition in the green algae
Volvox
using phototactic experiments with varied light pulse patterns, measuring their phototactic bias as a readout for their preferential ability to detect and adapt to one pattern over another. Results show
Volvox
adapt more readily to regular patterns than irregular ones and even exhibit memory properties, exhibiting a crucial component of basal intelligence. Pharmacological and electric shock-based interventions and photoadaptation simulations reveal how randomized stimuli interfere with normal photoadaptation through a structured dynamic interplay of colony rotation and calcium-mediated photoreceptor-to-flagellar information transfer, consistent with uncertainty minimization. The detection of functional uncertainty minimization in an aneural organism expands concepts like uncertainty minimization beyond neurons and provides insights and novel intervention tools applicable to other living systems, similar to early learning validations in simpler neural organisms.
An integrated airborne transmission risk assessment model for respiratory viruses: short- and long-range contributions
Authors: Henriques Andre , Jia Wei , Aleixo Luis , Mounet Nicolas , Fontana Luca , Simniceanu Alice , Devine James , Elson Philip , Azzopardi Gabriella , Rognlien Markus , Andreini Marco , Tarocco Nicola , Keiser Olivia , Li Yuguo , Tang Julian W.
Published: February 2025

This study presents an advanced airborne transmission risk assessment model that integrates both short- and long-range routes in the spread of respiratory viruses, building upon the CERN Airborne Model for Indoor Risk Assessment (CAiMIRA) and aligned with the new World Health Organization (WHO) terminology. Thanks to a two-stage exhaled jet approach, the model accurately simulates short-range exposures, thereby improving infection risk predictions across diverse indoor settings. Key findings reveal that in patient wards, the short-range viral dose is 10-fold higher than the long-range component, highlighting the critical role of close proximity interactions. Implementation of FFP2 respirators resulted in a remarkable 13-fold reduction in viral dose, underscoring the effectiveness of personal protective equipment (PPE). Additionally, the model demonstrated that an 8 h exposure in a poorly ventilated office can equate to the risk of a 15 min face-to-face, mask-less interaction, emphasizing the importance of physical distancing and source control. We also found in high-risk or low-occupancy settings, that secondary transmission is driven more by overall epidemic trends than by the presence of individual superspreaders. Monte Carlo simulations across various scenarios, including classrooms and offices, validate the model’s robustness in optimizing infection prevention strategies. These findings support targeted interventions for short- and long-range exposure to reduce airborne transmission.
Rapid Raman spectroscopy-based test for antimicrobial resistance
Authors: Mushenkov Vladimir , Zhigalova Ksenia , Denisov Pavel , Gordeev Alexey , Lukyanov Dmitry , Kukushkin Vladimir , Priputnevich Tatiana , Zavyalova Elena
Published: February 2025

Antimicrobial resistance (AMR) is one of the top global health threats. In 2019, AMR was associated with 4.95 million deaths, of which 1.97 million were caused by drug-resistant infections directly. The main subset of AMR is antibiotic resistance, that is, the resistance of bacteria to antibiotic treatment. Traditional and most commonly used antibiotic susceptibility tests are based on the detection of bacterial growth and its inhibition in the presence of an antimicrobial. These tests typically take over 1–2 days to perform, so empirical therapy schemes are often administered before proper testing. Rapid tests for AMR are necessary to optimize the treatment of bacterial infection. Here, we combine the MTT test with Raman spectroscopy to provide a 1.5 h long test for minimal inhibitory concentration determination. Several
Escherichia coli
and
Klebsiella pneumoniae
strains were tested with three types of antibiotics, including ampicillin from penicillin family, kanamycin from aminoglycoside family and levofloxacin from fluoroquinolone family. The test provided the same minimal inhibitory concentrations as traditional Etest confirming its robustness.
A high-throughput protein tagging toolkit that retains endogenous untranslated regions for studying gene regulation in kinetoplastids
Authors: Carbajo Carla Gilabert , Han Xiaoyang , Savur Bhairavi , Upadhyaya Arushi , Taha Fatima , Tinti Michele , Wheeler Richard J. , Yates Phillip A. , Tiengwe Calvin
Published: February 2025

Kinetoplastid parasites cause diseases that threaten human and animal health. To survive transitions between vertebrate hosts and insect vectors, these parasites rely on precise regulation of gene expression to adapt to environmental changes. Since gene regulation in kinetoplastids is primarily post-transcriptional, developing efficient genetic tools for modifying genes at their endogenous loci while preserving regulatory mRNA elements is crucial for studying their complex biology. We present a CRISPR/Cas9-based tagging system that preserves untranslated regulatory elements and uses a viral 2A peptide from
Thosea asigna
to generate two separate proteins from a single transcript: a drug-selectable marker and a tagged protein of interest. This dual-function design maintains native control elements, allowing discrimination between regulation of transcript abundance, translational efficiency, and post-translational events. We validate the system by tagging six
Trypanosoma brucei
proteins and demonstrate (i) high-efficiency positive selection and separation of drug-selectable marker and target protein, (ii) preservation of regulatory responses to environmental cues like heat shock and iron availability, and (iii) maintenance of stage-specific regulation during developmental transitions. This versatile toolkit is applicable to all kinetoplastids amenable to CRISPR/Cas9 editing, providing a powerful reverse genetic tool for studying post-transcriptional regulation and protein function in organisms where post-transcriptional control is dominant.
The role of art knowledge training on aesthetic judgements and executive functions
Authors: Bara Ionela , Cross Emily S. , Ramsey Richard
Published: February 2025

The study of how we develop art knowledge can provide valuable insights into the underlying cognitive systems that support expertise and knowledge transfer to new contexts. An important and largely unanswered question is whether art knowledge training impacts subsequent judgements of artworks and executive functions. Across three pre-registered experiments (
N
> 630 total), which used a training intervention and Bayesian regression modelling, we explore whether art knowledge training impacts subsequent judgements of artworks and executive functions. Experiments 1 and 2 revealed an effect of art training on aesthetic judgements for trained but not untrained artworks. These training effects were generalized to unseen artworks produced by the same artist (Experiment 1) or another artist with a similar style (Experiment 2), but not to different art styles. Experiment 2 also showed that with larger training ‘doses’ (>16 minutes), the generalization effects are stronger. Experiment 3 showed invariance of the attentional network to art training versus non-art training, suggesting similar sensitivity of executive functions to different types of training. This work shines new light on the cognitive systems that support learning and generalization of learning to new contexts. Likewise, from an applied perspective, it emphasizes that learning and generalization can occur rapidly with a relatively short (approx. 16 minutes) training video.
A Cretaceous sap beetle with specialized mandibles (Coleoptera : Nitidulidae)
Authors: Zhao Qian , Engel Michael S. , Huang Diying , Cai Chenyang
Published: February 2025

Sap beetles (Nitidulidae) are species-rich, highly diverse, widely distributed and exhibit varied food habits. However, studies on nitidulids in Kachin amber are scarce, particularly those involving nitidulids with specialized mandibles. Here, we report a new genus and species of Nitidulidae,
Vetunitidula mandibulata
gen. et sp. nov., from mid-Cretaceous Kachin amber (approx. 99 Ma). This species is characterized by distinctly enlarged mandibles and a loose three-article antennal club, suggesting it as a stem-group nitidulid. The enlarged mandibles may be a manifestation of sexual dimorphism, as in some extant species. Together with previous studies of fossil nitidulids, our discovery highlights the remarkable diversity and morphological disparity of sap beetles during the late Mesozoic.
Are humans facing a sleep epidemic or enlightenment? Large-scale, industrial societies exhibit long, efficient sleep yet weak circadian function
Authors: Samson David Ryan , McKinnon Leela
Published: February 2025

The Centers for Disease Control and Prevention declared sleep-related problems to be a public health epidemic. With the advent of biometric sleep tracking technology taking the sleep lab into the field, the study of human sleep is now global, and these new datasets show contrasting findings. Previous reports suggest sleep in small-scale, non-industrial societies to be short and fragmented yet characterized by greater circadian rhythmicity. However, the role of circadian rhythm indicators in understanding global variations in human sleep patterns remains unclear. We examine population-level sleep studies (
n
= 54) using polysomnography and actigraphy to test the sleep restriction epidemic hypothesis, which posits that labour demands and technological disruption in large-scale, industrial societies have reduced sleep duration. We used an actigraphy-generated circadian function index from both non-industrial and industrial societies (
n
= 866) to test the circadian mismatch hypothesis, which suggests that poor chronohygiene in regulated environments misaligns circadian rhythms in industrial societies. In rejection of the sleep restriction epidemic hypothesis, our results show that industrial societies experience the longest, most efficient sleep, whereas in support of the circadian mismatch hypothesis, sleepers in non-industrial societies are characterized by the greatest circadian function.
A Comprehensive Benchmark of Tools for Efficient Genomic Interval Querying
Authors: Schäfer Richard A. , Yang Rendong
Published: February 2025

Efficiently querying genomic intervals is fundamental to modern bioinformatics, enabling researchers to extract and analyze specific regions from large genomic datasets. While various tools have been developed for this purpose, there lacks a comprehensive comparison of their performance, memory usage, and practical utility. We present a systematic evaluation of genomic interval query tools using simulated datasets of varying sizes. Our benchmarking framework,segmeter, assesses both basic and complex interval queries, examining runtime performance, memory efficiency, and query precision across different tools and data structures. This comprehensive analysis provides insights into the strengths and limitations of different approaches to genomic interval querying, offering guidance for tool selection based on specific use cases and data requirements. Thesegmeterframework and all benchmark data are freely available, facilitating reproducibility and enabling researchers to conduct their own comparative analyses.
Literature-scaled immunological gene set annotation using AI-powered immune cell knowledge graph (ICKG)
Authors: He Shan , Tan Yukun , Ye Qing , Gubin Matthew , Rafei Hind , Peng Weiyi , Rezvani Katayoun , Mohanty Vakul , Chen Ken
Published: February 2025

Large scale application of single-cell and spatial omics in models and patient samples has led to the discovery of many novel gene sets, particularly those from an immunotherapeutic context. However, the biological meaning of those gene sets has been interpreted anecdotally through over-representation analysis against canonical annotation databases of limited complexity, granularity, and accuracy. Rich functional descriptions of individual genes in an immunological context exist in the literature but are not semantically summarized to perform gene set analysis. To overcome this limitation, we constructed immune cell knowledge graphs (ICKGs) by integrating over 24,000 published abstracts from recent literature using large language models (LLMs). ICKGs effectively integrate knowledge across individual, peer-reviewed studies, enabling accurate, verifiable graph-based reasoning. We validated the quality of ICKGs using functional omics data obtained independently from cytokine stimulation, CRISPR gene knock-out, and protein-protein interaction experiments. Using ICKGs, we achieved rich, holistic, and accurate annotation of immunological gene sets, including those that were unannotated by existing approaches and those that are in use for clinical applications. We created an interactive website (https://kchen-lab.github.io/immune-knowledgegraph.github.io/) to perform ICKG-based gene set annotations and visualize the supporting rationale.
Combining MicroED and native mass spectrometry for structural discovery of enzyme-biosynthetic inhibitor complexes
Authors: Vlahakis Niko W , Flowers Cameron W , Liu Mengting , Agdanowski Matthew , Johnson Samuel , Summers Jacob A , Keyser Catherine , Russell Phoebe , Rose Samuel , Orlans Julien , Adhami Nima , Chen Yu , Sawaya Michael R , Basu Shibom , De Sanctis Daniele , Wakatsuki Soichi , Nelson Hosea M , Loo Joseph , Tang Yi , Rodriguez Jose A
Published: February 2025

With the goal of accelerating the discovery of small molecule-protein complexes, we leverage fast, low-dose, event based electron counting microcrystal electron diffraction (MicroED) data collection and native mass spectrometry. This approach resolves structures of the epoxide-based cysteine protease inhibitor, and natural product, E-64, and its biosynthetic analogs bound to the model cysteine protease, papain. The combined structural power of MicroED and the analytical capabilities of native mass spectrometry (ED-MS) allows assignment of papain structures bound to E-64-like ligands with data obtained from crystal slurries soaked with mixtures of known inhibitors, and crude biosynthetic reactions. ED-MS further discriminates the highest-affinity ligand soaked into microcrystals from a broad inhibitor cocktail, and identifies multiple similarly high-affinity ligands soaked into microcrystals simultaneously. This extends to libraries of printed ligands dispensed directly onto TEM grids and later soaked with papain microcrystal slurries. ED-MS identifies papain binding to its preferred natural products, by showing that two analogues of E-64 outcompete others in binding to papain crystals, and by detecting papain bound to E-64 and an analogue from crude biosynthetic reactions, without purification. This illustrates the utility of ED-MS for natural product ligand discovery and for structure-based screening of small molecule binders to macromolecular targets.
Enhancing tandem MS sensitivity and peptide identification via ion pre-accumulation in an Orbitrap mass spectrometer
Authors: Harking Florian , Guzman Ulises H. , Kraegenbring Julia , Stewart Hamish , Aizikov Konstantin , Koch Heiner , Fort Kyle L. , Harder Alexander , Olsen Jesper V.
Published: February 2025

High-throughput mass spectrometry-based proteomics has gained increasing interest for both academic and industrial applications. As implementation of faster gradients has facilitated higher sample throughput, mass spectrometers must adapt to shorter analysis times by enhancing scanning speed and sensitivity. For Orbitrap™ mass spectrometers, faster scan rates are constrained by the need for sufficient ion accumulation time, particularly given limitations on duty cycle at high repetition rate, and transient length, which determines analyzer sensitivity and resolving power. In this context, implementing alternative ion scheduling and better ion signal-processing strategies are needed to unleash the speed of these instruments. Here, we introduce a new scanning strategy termed pre-accumulation, which enables the storage of ions in the bent flatapole in parallel to the operation of the C-trap/IRM, leading to a significant improvement in ion beam utilization and enabling for the first time scanning speeds of >70 Hz on hybrid Orbitrap instruments. The combination of pre-accumulation and increased scan speeds notably enhances peptide and protein group identifications for short LC gradients and improves sensitivity for high-throughput applications. These benefits were further amplified when coupled with the full mass range phase-constrained spectrum deconvolution method (ΦSDM), especially for fast, lower-resolving Orbitrap measurements used with short LC gradients. Overall, we demonstrate that pre-accumulation of ions in the bent flatapole offers distinct advantages, particularly for conditions with reduced signal input. Since no hardware changes are required, this approach is highly attractive for Orbitrap mass spectrometers operated with fast MS/MS acquisition methods.
Most ventral pallidal cholinergic neurons are cortically projecting bursting basal forebrain cholinergic neurons
Authors: Schlingloff Dániel , Szabó Írisz , Gulyás Éva , Király Bálint , Kispál Réka , Stephenson-Jones Marcus , Hangya Balázs
Published: February 2025

The ventral pallidum (VP) lies at the intersection of basal ganglia and basal forebrain circuitry, possessing attributes of both major subcortical systems. Basal forebrain cholinergic neurons are rapidly recruited by reinforcement feedback and project to cortical and subcortical forebrain targets; in contrast, striatal cholinergic cells are local interneurons exhibiting classical ‘pause-burst’ responses to rewards. However, VP cholinergic neurons (VPCNs) are less characterized, and it is unclear whether basal forebrain and striatal type cholinergic neurons mix in the VP. Therefore, we performed anterograde and mono-transsynaptic retrograde labeling, in vitro acute slice recordings and bulk calcium recordings of VPCNs. We found that VPCNs broadly interact with the affective circuitry that processes rewards and punishments, targeting the basolateral amygdala, the nucleus accumbens, the medial prefrontal cortex and the lateral habenula, while receiving inputs from the nucleus accumbens, hypothalamus, central amygdala, bed nucleus of stria terminalis and the ventral tegmental area. Bulk calcium recordings revealed VPCN responses to rewards, punishments and reward-predicting cues, like those of the horizontal diagonal band of Broca of the basal forebrain. Acute slice recordings showed that most VPCNs resembled the bursting type of basal forebrain cholinergic neurons (BFCNs), while a few of them were of the regular rhythmic type, which sharply differentiated most VPCNs from striatal cholinergic interneurons. These results were confirmed by in vivo electrophysiological recordings of putative VPCNs largely resembling bursting BFCNs. We conclude that most VPCNs are BFCNs with specialized connectivity to relay aversive and appetitive stimuli to the reinforcement circuitry, possibly implicated in mood disorders and addiction.
Changes in pneumococcal deaths in the United States following the COVID-19 pandemic
Authors: Shang Lianhan , Perniciaro Stephanie , Weinberger Daniel M
Published: February 2025

Background

Although changes in the rates of pneumococcal cases during the COVID-19 pandemic have been extensively described, changes in rates of death due to pneumococcus during this period are not well understood.

Methods

We obtained vital statistics data for the United States (National Center for Health Statistics), including age, sex, race/ethnicity, cause of death (ICD-10), 2014-2022. Generalized linear models were fit to the period from January 2014-February 2020 and extrapolated to March 2020-December 2022 to generate an expected number of pneumococcal deaths and a 95% prediction interval. We used a lasso regression model to identify clinical and demographic factors most strongly associated with pneumococcal deaths during the pandemic period as compared with a pre-pandemic baseline.

Results

For most of 2020, pneumococcal deaths were not notably different from the pre-pandemic period and largely followed the typical seasonal pattern. However, at the end of 2020 and early 2021, when pneumococcal deaths would typically peak, the rates of death remained lower than normal and stayed lower than expected in the spring of 2021. Starting around mid-2021, there was a notable spike above baseline that coincided with the Delta wave of COVID-19. The 2021 winter – 2022 spring peak followed the pre-pandemic trend. Some of the changes could be attributed to changes in the seasonality of respiratory viruses that interact with pneumococcus. The prevalence of certain risk factors among pneumococcal deaths elevated following the pandemic, including obesity (OR = 1.40), diabetes mellitus without complication (OR = 1.39) and heart failure (OR = 1.31).

Conclusions

The COVID-19 pandemic significantly disrupted pneumococcal mortality patterns in ways that were distinct from the changes described in clinical cases of invasive pneumococcal disease.

Key points

COVID-19 pandemic significantly disrupted pneumococcal mortality patterns. Respiratory viruses are important trigger for pneumococcal diseases.
Macrophages promote collagen deposition through circadian regulation of fibroblasts
Authors: Lowles Katherine , Cutiongco Marie F.A. , Hughes Joshua J. , Li Shiyang , Knox John , Coy Madeleine , Lin Wei-Hsiang , MacDonald Andrew S. , Kadler Karl E. , Meng Qing Jun , Hussell Tracy , Chang Joan
Published: February 2025

Collagen deposition in fibroblasts, the primary collagen-producing cells, is regulated by both macrophages and the circadian rhythm, although how these regulatory processes interact with one another is unknown. Here, we reveal that macrophage-fibroblast interaction enhances collagen deposition which requires a functional circadian rhythm. This response is also dependent on macrophage polarisation status, where M0 (naïve) and M1 (pro-inflammatory) macrophages require direct cell-cell contact; whereas M2 (anti-inflammatory) macrophages utilise an additional mechanism through secreted soluble factors that strengthen circadian rhythms and significantly increase collagen deposition in fibroblasts, independent of cell-cell contact. Using mass spectrometry proteomics analysis, we identified PDGFA as a key factor in induction of circadian amplitude in fibroblasts. Crucially, macrophages lacking PDGFA showed diminished ability to modulate fibroblast circadian rhythms and collagen production. Further, in fibroblasts with impaired circadian rhythms, neither macrophages nor macrophage-secreted factors are capable of inducing collagen deposition. These results confirmed that the collagen secretory pathway is also under circadian clock control in lung fibroblasts, and demonstrated that macrophages influence collagen deposition via circadian clock mediated mechanisms. In conclusion, our findings highlight M2-derived PDGFA as a key macrophage-derived factor in extracellular matrix remodelling.
Endogenous structure of antimalarial targetPfATP4 reveals new class of apicomplexan P-type ATPase modulators
Authors: Haile Meseret T. , Shukla Anurag , Zhen James , Mather Michael W. , Bhatnagar Suyash , Zhang Zhening , Vaidya Akhil B. , Ho Chi-Min
Published: February 2025

ThePlasmodium falciparumsodium efflux pumpPfATP4 is a leading antimalarial target, but suffers from a lack of high-resolution structural information needed to identify functionally important features in conserved regions and guide rational design of next generation inhibitors. Here, we determine a 3.7Å cryoEM structure ofPfATP4 purified from CRISPR-engineeredP. falciparumparasites, revealing a previously unknown, apicomplexan-specific binding partner,PfABP, which forms a conserved, likely modulatory interaction withPfATP4. The discovery ofPfABP presents a new avenue for designing novelPfATP4 inhibitors.
Breakdown of collinear factorization in the exclusive photoproduction of a
π0γ
pair with large invariant mass
Authors: Nabeebaccus Saad , Schönleber Jakob , Szymanowski Lech , Wallon Samuel
Published: February 2025

We study the exclusive photoproduction of a π0γ pair with large invariant mass Mγπ2, which is sensitive to the exchange of either two quarks or two gluons in the t channel. In this paper, we show that the process involving two-gluon exchanges does factorize in the Bjorken limit at the leading twist. This can be explicitly demonstrated by the fact that there exist diagrams, which contribute at the leading twist, for which are , due to the pinching of the contour integration of the plus and minus component of the Glauber gluon momentum. For the same reason, π0-nucleon scattering to two photons also suffers from the same issue. On the other hand, we stress that there are no issues with respect to collinear factorization for the quark channels. By considering an analysis of all potential reduced diagrams of leading pinch-singular surfaces, we argue that the quark channel is safe from Glauber pinches, and therefore, a collinear factorization in that case follows through without any problems. This means that processes where gluon exchanges are forbidden, such as the exclusive photoproduction of π±γ and ρ0,±γ, are unaffected by the factorization breaking effects we point out in this paper.

Published by the American Physical Society
2025
First Measurement of Missing Energy due to Nuclear Effects in Monoenergetic Neutrino Charged-Current Interactions
Authors: Marzec E. , Ajimura S. , Antonakis A. , Botran M. , Cheoun M. K. , Choi J. H. , Choi J. W. , Choi J. Y. , Dodo T. , Furuta H. , Goh J. H. , Haga K. , Harada M. , Hasegawa S. , Hino Y. , Hiraiwa T. , Hwang W. , Iida T. , Iwai E. , Iwata S. , Jang H. I. , Jang J. S. , Jang M. C. , Jeon H. K. , Jeon S. H. , Joo K. K. , Jung D. E. , Kang S. K. , Kasugai Y. , Kawasaki T. , Kim E. J. , Kim J. Y. , Kim E. M. , Kim S. Y. , Kim W. , Kim S. B. , Kinoshita H. , Konno T. , Kuwata K. , Lee D. H. , Lee S. , Lim I. T. , Little C. , Maruyama T. , Masuda S. , Meigo S. , Monjushiro S. , Moon D. H. , Nakano T. , Niiyama M. , Nishikawa K. , Noumachi M. , Pac M. Y. , Park B. J. , Park H. W. , Park J. B. , Park J. S. , Park J. S. , Park R. G. , Peeters S. J. M. , Roellinghoff G. , Rott C. , Ryu J. W. , Sakai K. , Sakamoto S. , Shima T. , Shin C. D. , Spitz J. , Stancu I. , Suekane F. , Sugaya Y. , Suzuya K. , Taira M. , Takeuchi Y. , Wang W. , Waterfield J. , Wei W. , White R. , Yamaguchi Y. , Yeh M. , Yeo I. S. , Yoo C. , Yu I. , Zohaib A. ,   JSNS2 Collaboration
Published: February 2025

We present the first measurement of the missing energy due to nuclear effects in monoenergetic, muon neutrino charged-current interactions on carbon, originating from K+→μ+νμ decay at rest (Eνμ=235.5  MeV), performed with the J-PARC Sterile Neutrino Search at the J-PARC Spallation Neutron Source liquid scintillator based experiment. Toward characterizing the neutrino interaction, ostensibly νμn→μ−p or νμC12→μ−N12, we define the energy as the energy transferred to the nucleus (ω) minus the kinetic energy of the outgoing proton(s),

E

m

≡

ω

−

∑

T

p

, and relate this to visible energy in the detector, Em=Eνμ(235.5  MeV)−mμ(105.7  MeV)+[mn−mp(1.3  MeV)]−Evis. The missing energy, which is naively expected to be zero in the absence of nuclear effects (e.g., nucleon separation energy, Fermi momenta, and final-state interactions), is uniquely sensitive to many aspects of the interaction, and has previously been inaccessible with neutrinos. The shape-only, differential cross section measurement reported, based on a (77±3)% pure double-coincidence kaon decay-at-rest signal (621 total events), provides detailed insight into neutrino-nucleus interactions, allowing even the nuclear orbital shell of the struck nucleon to be inferred. The measurement provides an important benchmark for models and event generators at hundreds of MeV neutrino energies, characterized by the difficult-to-model transition region between neutrino-nucleus and neutrino-nucleon scattering, and relevant for applications in nuclear physics, neutrino oscillation measurements, and Type-II supernova studies.

Published by the American Physical Society
2025
Extreme wave skewing and dispersion spectra of anisotropic elastic plates
Authors: Kiefer Daniel A. , Mezil Sylvain , Prada Claire
Published: February 2025

Guided wave dispersion is commonly assessed by Fourier analysis of the field along a line, resulting in frequency-wave-number dispersion curves. In anisotropic plates, a point source can generate multiple dispersion branches pertaining to the same modal surface, which arise due to the angle between the power flux and the wave vector. We show that this phenomenon is very particular near zero-group-velocity points and occurs in all directions independent of the degree of anisotropy. Stationary phase points accurately describe measurements on a monocrystalline silicon plate.

Published by the American Physical Society
2025
Causes, effects and solutions of delay and cost overruns in Iranian deep excavation projects
Authors: Bayandor Sara , Kalatehjari Roohollah , Akherati Reza , Kasebzadeh Jalal
Published: February 2025

Purpose

Through a case study for Iran, this research seeks to pinpoint the dominant causes of delay and cost overruns in two standard Support of Excavation methods (Bracing strut and top-down construction) in deep excavation projects from various points of view involving contractors, consultants and owners. This investigation identifies the root causes, compares them with existing literature to find similarities and differences with tunnelling and construction projects and proposes practical solutions.

Design/methodology/approach

The primary factors were identified after an extensive literature review and expert interview. Subsequently, a questionnaire was designed to classify related factors, considering impact indices, occurrence likelihood and overall significance. Eventually, the findings of the analysis were visually represented through cause-and-effect diagrams.

Findings

The results indicate that “inflation and exchange rate fluctuation” is the top-rated cause, followed by designers’ limited overall perspective of implementation issues. Also, comparing the roles of related teams shows that the contractor sector is the most responsible for delay and overruns in both methods. Finally, practical solutions are presented regarding the main affecting factors.

Originality/value

Prior research often addresses delay and costs in construction, but insufficient focus is given to deep excavation projects, particularly in Iran. This study not only fills the identified knowledge gap but also delves into the causes of delay, pursued until the fourth bone in some cases and proposes a solution framework derived from previous research, case studies and expert insights to mitigate construction delay.