bluuebunny/crossref_metadata_2025_split huggingface dataset:
Right Heart Remodeling in End-Stage Pulmonary Arterial Hypertension and the Impact of Treatment Intensity
Authors: Gong Su-Gang , Zhang Qi-Hang , Zhang Jia-Yi , Zhang Qian , Rui-Zhang  , Qiu Hong-Ling , Luo Ci-Jun , Li Hui-Ting , Wu Wen-Hui , Yuan Ping , He Jing , Xu Jian , Liu Jin-Ming , Zhao Qin-Hua , Wang Lan 
Published: February 2025

AbstractBackgroundResearch on the limits of compensatory right heart remodeling and the effects of pulmonary artery hypertension (PAH) targeted therapies on these mechanisms is limited.MethodChest x-ray and echocardiographic data were collected from 143 deceased patients with PAH confirmed by right heart catheterization at their end-stage disease. Right heart remodeling was compared across different PAH treatment strategies.ResultsThis study of 143 deceased PAH patients (49 ± 17 years, 74.1% female) characterized right heart remodeling at the time of death. Mean cardiothoracic ratio (CTR), right atrial area (RAA) and mid-cavity RV linear dimension (RVD) measured by echocardiography were 0.61±0.09, 27 cm² (median 27, IQR 21–38), and 4.97±0.97 cm, respectively, with extremes of 0.88, 102 cm², and 7.50 cm. Intensive therapy resulted in larger CTR (0.63±0.08 vs. 0.60±0.09, p=0.016), RAA (30 [24–40] vs. 25 [19–34] cm², p=0.020), and RVD (5.30±0.97 vs. 4.65±0.85 cm, p<0.001) compared with monotherapy. After adjusting for confounders, intensive therapy independently predicted increases in CTR (0.03, 95% CI 0.00-0.05, p=0.054), RAA (6.63 cm², 95% CI 1.46-11.80, p=0.013), and RVD (0.66 cm, 95% CI 0.34-0.98, p<0.001).ConclusionThese findings suggest that more aggressive PAH treatment is associated with greater right heart remodeling, highlighting the complex relationship between therapeutic intervention and disease progression in PAH patients.
Post-Zika anti-NS1 serum IgA drives increased neutrophil functions in severe dengue disease
Authors: Cardona-Ospina Jaime A. , Roy Vicky , Marcano-Jiménez Dorca E. , Bos Sandra , Duarte Elias , Zambrana José V. , Bal Agamjot , Dias Antonio Gregorio , Zhiteneva Julia , Huffaker Julia , Montenegro Carlos , Kuan Guillermina , Ramos-Benitez Marcos J. , Balmaseda Angel , Alter Galit , Harris Eva 
Published: February 2025

AbstractPrimary immunity against Zika virus (ZIKV) increases the risk of a subsequent severe dengue virus 2 (DENV2) infection, presenting a significant challenge for developing safe and effective ZIKV vaccines. However, the mechanisms driving this phenomenon remain unclear. We show that post-ZIKV infection IgA antibodies in serum targeting the DENV2 nonstructural protein 1 (NS1) drive neutrophil activation and correlate with increased risk of a subsequent severe DENV2 infection in a pediatric cohort study. Increased neutrophil degranulation correlated with IgA binding to DENV2 NS1 and preceded vascular leakage in paired acute-phase samples from the same individuals and in dengue patients after prior ZIKV infection in an orthogonal hospital-based study. Thus, serum anti-NS1 IgA enhances neutrophil activation in severe dengue, with implications for prognostics, therapeutics, and vaccines.
Inhibition of acute lung inflammation by a neuroimmune circuit induced by vagal nerve stimulation
Authors: Murray Kaitlin , Cremin Michael , Tay Emmy , Sanchez Kristina , Schreiber Sierra , Brust-Mascher Ingrid , Leigh Wesley , Ashfaq Jannat , Gareau Melanie G. , Reardon Colin 
Published: February 2025

AbstractVagus nerve stimulation (VNS) has been shown to limit immune cell activity across several pathologies ranging from sepsis to auto-immune diseases. While stimulation of vagal efferent neurons has been previously demonstrated to reduce maladaptive host responses during endotoxemia, only selective stimulation of vagal afferent neurons was able to inhibit TLR7-induced macrophage activation and neutrophil recruitment in the lung. These anti-inflammatory actions are facilitated by systemic increases in epinephrine, as VNS significantly increased epinephrine in the serum and bronchoalveolar lavage fluid, and inhibition of epinephrine production eliminated the protection afforded by VNS. Selective afferent VNS induced activation in the nucleus tractus solitarius and the rostral ventrolateral medulla. Inhibition of neuronal activity in this brain region that controls peripheral sympathetic nervous system activity rendered VNS ineffective. Activation of the β2-adrenergic receptor (β2AR) is critical for innate immune cell suppression, as the anti-inflammatory effects of VNS were eliminated in β2AR-knock out mice, and with pharmacological inhibition of the β2AR. Analysis of the immune cells responding to R848 critically identified that plasmacytoid dendritic cells were refractive to inhibition by VNS, and this corresponded to lack of β2AR expression. These findings demonstrate a novel neuro-immune circuit elicited by VNS that can control acute lung inflammation.SummaryWe have identified a novel neuro-immune circuit activated by afferent vagus nerve stimulation to reduce acute lung inflammation. This effect was dependent on vagal-induced adrenal gland-derived epinephrine release that initiates anti-inflammatory β2-adrenergic receptor signaling in innate immune cells within the lung.
High throughput isolation of male gametophyte cells ofSolanum lycopersicumvar. Micro-Tom by fluorescence-activated cell sorting
Authors: Flores-Tornero María , Sapeta Helena , Lobato-Gómez Maria , Teixeira Beatriz , Monteiro Marta , Granell Antonio , Becker Jörg D. 
Published: February 2025

ABSTRACTEfficient isolation of male gametes has enabled unprecedented advances in omics research, crucial for elucidating the molecular mechanisms governing male gametogenesis and fertilization. In this study, we developed a method for isolating generative and sperm cells from the economically important cropSolanum lycopersicum.A double fluorescent marker line was generated in the tomato variety Micro-Tom, employing mTurquoise and mScarlet-I fluorescent proteins under the control of promoters exhibiting preferential activity in generative and sperm cells, respectively. Then we developed a protocol that combines male gamete release from pollen of this line and SYTOX Red live/dead cell stain to obtain viable cells by Fluorescence-activated cell sorting. This allows the isolation of generative cells from mature pollen grains, and of sperm cells from pollen tubes after semi-in vivogrowth, both in high quantity and purity. Additionally, an unexpected mScarlet-I signal in the vegetative nucleus, that persists until the sperm cells are formed, allows the sorting of vegetative nuclei.We anticipate that our novel double-marker line will accelerate research into tomato male gametogenesis, thereby enhancing efforts to improve the resilience of fertilization processes to climate change.
Host-microbe mutualism drives urea carbon salvage and acetogenesis during hibernation
Authors: Regan Matthew D. , Chiang Edna , Grahn Michael , Tonelli Marco , Assadi-Porter Fariba M. , Suen Garret , Carey Hannah V. 
Published: February 2025

AbstractHibernation is a wintertime survival strategy employed by certain mammals that, through torpor use, reduces overall energy expenditure and permits long-term fasting. Although fasting resolves the challenge of winter food scarcity, it also removes dietary carbon, a critical biomolecular building block. Here, we demonstrate a process of urea carbon salvage (UCS) in the 13-lined ground squirrel, whereby urea carbon is reclaimed through gut microbial ureolysis and used in reductive acetogenesis, producing acetate—a short-chain fatty acid (SCFA) of major value to the host and its microbial community. We find that urea carbon incorporation into acetate is more efficient during hibernation than the summer active season, and that while both host and gut microbes oxidize acetate for energy throughout the year, the host’s ability to absorb and oxidize acetate is highest during hibernation. Metagenomic data of the gut microbiome indicate retention during hibernation of genes involved in the degradation of gut mucin, an abundant endogenous nutrient. The hydrogen disposal associated with reductive acetogenesis from urea carbon provides a luminal environment that sustains fermentation of mucin oligosaccharides, thereby generating SCFAs and other metabolites usable by both the host and its gut microbes. Our findings introduce UCS as a novel mechanism that enables hibernating squirrels and their gut microbes to exploit two key endogenous nutrient sources – urea and mucins – in the resource-limited hibernation season.
Significant variations in tolerance to clothianidin and pirimiphos-methyl inAnopheles gambiaeandAnopheles funestuspopulations during a dramatic malaria resurgence despite sustained indoor residual spraying in Uganda
Authors: Oruni Ambrose , Arinaitwe Emmanuel , Adiga James , Otto Geoffrey , Kyagamba Patrick , Okoth Joseph , Ayo Daniel , Asiimwe Jackson Rwatooro , Zedi Maato , Rek John , Walker Kyle J , Braithwaite Ashlee , Kayondo Jonathan , Conrad Melissa D , Bousema Teun , Paine Mark J I , Ismail Hanafy M , Krezanoski Paul , Wondji Charles S. , Kamya Moses R. , Dorsey Grant , Donnelly Martin J. 
Published: February 2025

ABSTRACTA dramatic malaria resurgence occurred in areas of Uganda between 2020 and 2022 coincident with the switch to clothianidin-based formulations for indoor residual spraying. During the resurgence,Anopheles funestusnumbers increased but when an alternative insecticide, pirimiphos methyl, was reintroduced in 2023, both malaria cases andAn. funestusmosquito density fell. In this study, we investigated possible causes of the resurgence by assessing; 1) whether sufficient quantities of insecticide were sprayed; 2) the residual insecticide bioefficacy against wild mosquitoes and; 3) the insecticide susceptibility of vector populations using standard test tube assays and wall cone assays. In 2023, after adjusting for extraction efficiency, 70-80% of the houses had optimal residual concentrations of insecticides (clothianidin >0.3g/m2; pirimiphos methyl >0.5g/m2) with significant variations between sampling rounds and wall types. Mud walls had the lowest residual concentration of insecticides, and the lowest observed mortality in wall cone assays, compared to fired bricks with plaster/cement/paint. In the studies of residual bio efficacy, by World Health Organization (WHO) definitions,An. funestusshowed resistance to clothianidin (<80% mortality) up to 11 months and susceptibility to pirimiphos methyl (>90% mortality) when exposed to wall surfaces up to 7 months post-spray. In WHO tube tests, variations were observed in susceptibility to clothianidin inAn. funestuspopulations using dose- and time-response assays (80-98% mortality). In 2022,An. gambiaewas largely susceptible to the clothianidin-based formulation Sumishield (85-90% mortality) although the levels dropped slightly in 2023 (60-85% mortality) mainly in mud and pole houses. In contrast,An. gambiaewas mildly susceptible to the pirimiphos methyl-based formulation Actellic (∼80% mortality) and time response assays showedAn. gambiae populationshad very low knockdown and mortality at lower exposure time compared toAn. funestus. Regression models showed a positive association between residual insecticide concentration (RIC) and mortality in houses sprayed with Sumishield but not Actellic houses.Despite the possible variations observed in spray operations, the study revealed thatAn.funestusexhibited a higher tolerance to clothianidin-based formulations compared toAn. gambiae, and this might have driven the malaria resurgence observed in Uganda. However, there are signals ofAn. gambiaeresistance to pirimiphos-methyl which will require further investigation and monitoring.
Rewiring protein sequence and structure generative models to enhance protein stability prediction
Authors: Li Ziang , Luo Yunan 
Published: February 2025

AbstractPredicting changes in protein thermostability due to amino acid substitutions is essential for understanding human diseases and engineering useful proteins for clinical and industrial applications. While recent advances in protein generative models, which learn probability distributions over amino acids conditioned on structural or evolutionary sequence contexts, have shown impressive performance in predicting various protein properties without task-specific training, their strong unsupervised prediction ability does not extend to all protein functions. In particular, their potential to improve protein stability prediction remains underexplored. In this work, we present SPURS, a novel deep learning framework that adapts and integrates two general-purpose protein generative models–a protein language model (ESM) and an inverse folding model (ProteinMPNN)–into an effective stability predictor. SPURS employs a lightweight neural network module to rewire per-residue structure representations learned by ProteinMPNN into the attention layers of ESM, thereby informing and enhancing ESM’s sequence representation learning. This rewiring strategy enables SPURS to harness evolutionary patterns from both sequence and structure data, where the sequence like-lihood distribution learned by ESM is conditioned on structure priors encoded by ProteinMPNN to predict mutation effects. We steer this integrated framework to a stability prediction model through supervised training on a recently released mega-scale thermostability dataset. Evaluations across 12 benchmark datasets showed that SPURS delivers accurate, rapid, scalable, and generalizable stability predictions, consistently outperforming current state-of-the-art methods. Notably, SPURS demonstrates remarkable versatility in protein stability and function analyses: when combined with a protein language model, it accurately identifies protein functional sites in an unsupervised manner. Additionally, it enhances current low-Nprotein fitness prediction models by serving as a stability prior model to improve accuracy. These results highlight SPURS as a powerful tool to advance current protein stability prediction and machine learning-guided protein engineering workflows. The source code of SPURS is available athttps://github.com/luo-group/SPURS.
Learning maximally spanning representations improves protein function annotation
Authors: Luo Jiaqi , Luo Yunan 
Published: February 2025

AbstractAutomated protein function annotation is a fundamental problem in computational biology, crucial for understanding the functional roles of proteins in biological processes, with broad implications in medicine and biotechnology. A persistent challenge in this problem is the imbalanced, long-tail distribution of available function annotations: a small set of well-studied function classes account for most annotated proteins, while many other classes have few annotated proteins, often due to investigative bias, experimental limitations, or intrinsic biases in protein evolution. As a result, existing machine learning models for protein function prediction tend to only optimize the prediction accuracy for well-studied function classes overrepresented in the training data, leading to poor accuracy for understudied functions. In this work, we develop MSRep, a novel deep learning-based protein function annotation framework designed to address this imbalance issue and improve annotation accuracy. MSRep is inspired by an intriguing phenomenon, called neural collapse (NC), commonly observed in high-accuracy deep neural networks used for classification tasks, where hidden representations in the final layer collapse to class-specific mean embeddings, while maintaining maximal inter-class separation. Given that NC consistently emerges across diverse architectures and tasks for high-accuracy models, we hypothesize that inducing NC structure in models trained on imbalanced data can enhance both prediction accuracy and generalizability. To achieve this, MSRep refines a pre-trained protein language model to produce NC-like representations by optimizing an NC-inspired loss function, which ensures that minority functions are equally represented in the embedding space as majority functions, in contrast to conventional classification methods whose embedding spaces are dominated by overrepresented classes. In evaluations across four protein function annotation tasks on the prediction of Enzyme Commission numbers, Gene3D codes, Pfam families, and Gene Ontology terms, MSRep demonstrates superior predictive performance for both well- and underrepresented classes, outperforming several state-of-the-art annotation tools. We anticipate that MSRep will enhance the annotation of understudied functions and novel, uncharacterized proteins, advancing future protein function studies and accelerating the discovery of new functional proteins. The source code of MSRep is available athttps://github.com/luo-group/MSRep.
Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrictLegionellainfection
Authors: Vázquez Marrero Víctor R. , Doerner Jessica , Wodzanowski Kimberly A. , Zhang Jenna , Lu Allyson , Boyer Frankie D. , Vargas Isabel , Hossain Suzana , Kammann Karly B. , Dresler Madison V. , Shin Sunny 
Published: February 2025

AbstractThe innate immune system relies on pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and guard proteins to monitor pathogen disruption of host cell processes. How different immune cell types engage PRR- and guard protein-dependent defenses in response to infection is poorly understood. Here, we show that macrophages and dendritic cells (DCs) respond in distinct ways to bacterial virulence activities. In macrophages, the bacterial pathogenLegionella pneumophiladeploys its Dot/Icm type IV secretion system (T4SS) to deliver effector proteins that facilitate its robust intracellular replication. In contrast, T4SS activity triggers rapid DC death that potently restrictsLegionellareplication within this cell type. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single cell level. Initially, a subset of DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis and release IL-1βearly during infection. At later timepoints, a separate DC population undergoes apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the levels of the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrictLegionellareplication in DCs. Collectively, our work suggests a model where Mcl-1 and cFLIP guard host translation in DCs, and that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses toLegionellainfection.
Differences in cell-associated and cell-free microbial DNA in blood
Authors: Bowie Kate R. , Fischer Jared , Karstens Lisa 
Published: February 2025

AbstractIn the absence of infection, blood has previously been understood to be free of microbes. However, with advances in sequencing technology this notion has been challenged, prompting new investigations into microbial DNA within the blood of both healthy and diseased individuals. To comprehensively survey microbial DNA in blood, we separated blood into fractions (plasma, red blood cells, and buffy coat) and assessed if the microbial-DNA is cell-free by the addition of DNase to a subset of each fraction. We measured 16S rRNA gene copy number with digital droplet PCR and identified the taxonomic origin of the microbial DNA with synthetic full-length 16S rRNA gene sequencing. As a use case, we examine microbial DNA from the blood of 5 men without prostate cancer (PC), 5 men with low-grade PC, and 5 men with high-grade PC. Our study demonstrates that the majority of microbial DNA is cell-free, indicating that it is not representative of proliferating microbes. Our analyses also revealed buffy coat had the lowest number of 16S rRNA gene copies yet highest number of genera of the fractions (median 23.3 copies/µL and 10 genera) and thus may be a useful fraction to study moving forward. Additionally, microbial DNA in blood may have utility as a biomarker, as we detected disease-associated compositional differences in the plasma and buffy coat fractions. This study lays the groundwork for rigorously studying microbial DNA in blood, however larger studies are needed to confirm our disease-association findings.ImportanceThe concept of a “blood microbiome” has sparked debate in recent years, with questions about whether microbes truly exist in circulation. This study provides a crucial evaluation of the fractions of blood and their capacity to harbor microbial DNA, offering important context for prior and future research. By using DNase to differentiate between cell-associated and cell-free microbial DNA, we show that while microbial DNA is present in blood, it is sparse and heterogenous. These findings highlight the need for rigorous study design that carefully considers both positive and negative controls, as well as the specific blood fractions being examined.
Association between fractional exhaled nitric oxide (FeNO) and peripheral eosinophils in patients with asthma: a retrospective cohort study
Authors: Habis Yahya Z. , Sakkat Abdullah , Alaidaroos Shahad H. , AlGhamdi Reema D. , Almuwalad Nada H. , Aljuhani Joud M. , Alharbi Atheer A. 
Published: February 2025

AbstractBackgroundFractional exhaled nitric oxide (FeNO) and peripheral eosinophils are important biomarkers of Type 2 inflammation in asthma. FeNO reflects airway inflammation, while eosinophil counts indicate systemic eosinophilic activity. Their combined utility in asthma management warrants further investigation.ObjectiveThis study aimed to assess and compare FeNO levels and peripheral eosinophils in asthmatic patients, examining their relationship with disease characteristics and bronchodilator responsiveness (BDR).MethodsA retrospective analysis of 101 adult asthmatic patients at King Abdulaziz University, Jeddah, was conducted. Patient data on FeNO, eosinophil counts, spirometry, and comorbidities were collected and analyzed using correlation and receiver operating characteristic (ROC) curve analysis.ResultsThe mean FeNO level was 68.9±61.3 ppb, and the mean eosinophil count was 310.5±344.2 cells/μL. FeNO levels were significantly higher in patients with eosinophil counts ≥300 cells/μL (p=0.012) and correlated positively with BDR (r=0.38, p=0.001) but not with eosinophil counts (r=0.16, p=0.11) or asthma control test (ACT) scores. Eosinophil counts were significantly associated with moderate airway obstruction (p=0.041). FeNO showed a borderline ability to differentiate allergic rhinitis (p=0.059) but limited performance in identifying other comorbidities, such as chronic rhinosinusitis (p=0.17), GERD (p=0.87), and eczema/atopic dermatitis (p=0.11 and p=0.24, respectively).ConclusionFeNO and peripheral eosinophil counts are valuable complementary biomarkers for assessing type 2 inflammation in asthma and guiding treatment. However, their variability across clinical contexts underscores the need for integration with other assessments. These findings support a multidimensional approach to asthma management and call for further research to refine their clinical applications.