tbuckley/cabot-search huggingface dataset:
A live bacteria enzyme assay for identification of human disease mutations and drug screening
Authors: Donghui Choe, Bernhard O Palsson
Journal: Nature Biomedical Engineering (2025)

Advances in high-throughput sequencing have enabled the identification of genetic variations associated with human disease. However, deciphering the functional significance of these variations remains challenging. Here we propose an alternative approach that uses humanized Escherichia coli to study human genetic enzymopathies and to screen candidate drug effects on metabolic targets. By replacing selected E. coli metabolic enzymes with their human orthologues and their sequence variants, we demonstrate that the growth rate of E. coli reflects the in vivo activity of heterologously expressed human enzymes. This approach accurately reflected enzyme activities of known sequence variants, enabling rapid screening of causal sequence variations associated with human diseases. This approach bridges the gap between in vitro assays and cell-based assays. Our findings suggest that the proposed approach using a humanized E. coli strain holds promise for drug discovery, offering a high-throughput and cost-effective platform for identifying new compounds targeting human enzymes. Continued research and innovation in this field have the potential to impact the development and practice of precision medicine.
Habitual Exercise Modulates Neuroimmune Interaction to Mitigate Aortic Stiffness
Authors: Jae Min Cho, Khoa Vu, Seul-Ki Park, Enbo Zhu, Yan-Ruide Li, Peng Zhao, Tomohiro Yokota, Lili Yang, Rong Lu, Yang Kevin Xiang, Ying H. Shen, Mark W. Chapleau, Tzung K. Hsiai
Journal: Circulation Research (2025)

BACKGROUND: Exercise augments hemodynamic shear to activate mechano-sensitive molecular transducers in the vascular endothelium. Recently, the central nervous system has been reported to mediate neuroimmune interaction in the aortic adventitia (AA). Whether exercise modulates the sympathetic nerve interaction with the immune cells to mitigate aortic stiffness remains unknown. METHODS AND RESULTS: Four weeks of Ang II (angiotensin II) infusion to C57BL/6 mice increased neural activation to increase the expression of TH (tyrosine hydroxylase) for sympathetic nerve axons and norepinephrine levels along with the colocalization of synapsin and β2-AR (β2-adrenergic receptor)–positive macrophages in the AA. This Ang II–mediated sympathetic nerve and macrophage interaction activated fibroblasts to increase vascular fibrosis and arterial pulse wave velocity. Sympathetic denervation with celiac ganglionectomy or 6-hydroxydopamine treatment abrogated Ang II–mediated TH + , AA thickness, and pulse wave velocity. Single-cell RNA sequencing analyses of the AA revealed that Ang II increased the circulating monocyte-derived macrophages (Ccr2 + CD80) but reduced the resident macrophages (Lyve1 + CD163). Gene ontology analysis of differentially expressed genes unveiled that voluntary wheel running mitigated Ang II–mediated increase in Ccr2 + CD80 macrophages, cytokine-mediated signaling pathways in macrophages, and extracellular matrix deposition in fibroblasts. Macrophage depletion with Ki20227 (colony stimulating factor 1 receptor inhibitor) reduced Ang II–mediated synapsin + macrophages. Using the Ccr2 knock-in ( Ccr2 gfp )/knock-out ( Ccr2 KO ) mice, we observed that Ang II–mediated increases in Ccr2 + macrophages were expressed in Ccr2 gfp mice but were absent in Ccr2 KO mice. Also, Ang II–induced increases in synapsin expression, neighboring Ccr2 + cells, AA thickness, and pulse wave velocity were reduced in Ccr2 KO mice. Both Ki20227 and Ccr2 KO reduced the Ang II–mediated increase in TH levels. Furthermore, voluntary wheel running–mediated reduction in vascular fibrosis and aortic stiffness were mitigated by a β2-AR agonist, terbutaline, indicating β2-AR in neuroimmune modulation. CONCLUSIONS: Exercise mitigates Ang II–mediated sympathetic axon interaction with the circulating monocyte-derived macrophages in the AA to attenuate vascular fibrosis and aortic stiffness.
Overload of Neprilysin in Placental Extracellular Vesicles Disrupts CNP-NPRB-Mediated Communication Between Vascular Endothelial and Smooth Muscle Cells: A Trigger for Symptoms of Preeclampsia
Authors: Chengjin He, Yi Du, Ruixin Chen, Yuhan Qiu, Jiayu Huang, Li Lin, Mark D. Kilby, Yong Fu, Hongbo Qi, Philip N. Baker, Chao Tong
Journal: Circulation Research (2025)

BACKGROUND: Preeclampsia is a placenta-origin pregnancy complication. Although its development has long been divided into 2 stages: abnormal placentation (stage I) and the release of factors from the hypoperfused placenta into circulation, triggering preeclampsia due to endothelial dysfunction (stage II), the placenta-derived substances coupling the 2 stages remain unclear. METHODS: Extracellular vesicles (EVs) from normal and preeclampsia-complicated placentas were intravenously administered to pregnant mice, and blood pressure was recorded throughout pregnancy. The differential cargo, including NEP (neprilysin), of placental EVs in normal and preeclamptic placentas was identified by LC-MS, and the cell types involved in NEP expression in the placenta were determined by single-cell RNA sequencing. The effects of placental EVs and recombinant mouse NEP on the uterine arteries were assessed by myography. Placenta-specific NEP overexpression mice were established by in situ injection of adenovirus. The binding affinity between NEP and the vasodilative peptides was determined using an Octet instrument. NEP-overexpressing HUVECs were established to measure CNP (C-type natriuretic peptide) release and cocultured with NPRB (natriuretic peptide receptor-B) knockdown vascular smooth muscle cells (VSMCs) to measure cGMP production in VSMCs. RESULTS: Placental EVs from preeclamptic pregnancies impaired vascular endothelium–dependent vasodilation and induced preeclampsia in mice. NEP was expressed predominantly by syncytiotrophoblasts and upregulated in placental EVs from preeclamptic pregnancies. Recombinant mouse NEP administration resulted in outcomes like those of administration of placental EVs from preeclamptic pregnancies. Placenta-specific NEP overexpression disturbed maternal hemodynamics, resulting in hypertension and proteinuria of the mice. CNP exhibited high binding affinity for NEP, and NEP upregulation in HUVECs inhibited CNP release, which further influenced the production of cGMP in VSMCs; however, this effect was largely blunted in NPRB-deficient VSMCs. CONCLUSIONS: Excessive NEP in placental EVs from preeclamptic pregnancies is transported into the endothelial cells of uterine and placental arteries to cleave and degrade CNP, resulting in compromised CNP paracrine activity and NPRB-mediated cGMP production in adjacent VSMCs and triggering the hypertensive manifestation of preeclampsia.
Single-cell genotyping and transcriptomic profiling of mosaic focal cortical dysplasia
Authors: Sara Baldassari, Esther Klingler, Lucia Gomez Teijeiro, Marion Doladilhe, Corentin Raoux, Sergi Roig-Puiggros, Sara Bizzotto, Jeanne Couturier, Alice Gilbert, Lina Sami, Théo Ribierre, Eleonora Aronica, Homa Adle-Biassette, Mathilde Chipaux, Denis Jabaudon, Stéphanie Baulac
Journal: Nature Neuroscience (2025)

Focal cortical dysplasia type II (FCDII) is a cortical malformation causing refractory epilepsy. FCDII arises from developmental somatic activating mutations in mTOR pathway genes, leading to focal cortical dyslamination and abnormal cytomegalic cells. Which cell types carry pathogenic mutations and how they affect cell-type-specific transcriptional programs remain unknown. In the present study, we combined several single-nucleus genotyping and transcriptomics approaches with spatial resolution in surgical cortical specimens from patients with genetically mosaic FCDII. Mutations were detected in distinct cell types, including glutamatergic neurons and astrocytes, and a small fraction of mutated cells exhibited cytomegalic features. Moreover, we identified cell-type-specific transcriptional dysregulations in both mutated and nonmutated FCDII cells, including synapse- and neurodevelopment-related pathways, that may account for epilepsy and dysregulation of mitochondrial metabolism pathways in cytomegalic cells. Together, these findings reveal cell-autonomous and non-cell-autonomous features of FCDII that may be leveraged for precision medicine.
Precision nutrition for cardiometabolic diseases
Authors: Marta Guasch-Ferré, Clemens Wittenbecher, Marie Palmnäs, Orly Ben-Yacov, Ellen E Blaak, Christina C Dahm, Tove Fall, Berit L Heitmann, Tine R Licht, Marie Löf, Ruth Loos, Chirag J Patel, Carmelo Quarta, Leanne M Redman, Eran Segal, Nicola Segata, Michael Snyder, Qi Sun, Deirdre K Tobias, Frank B Hu, Paul W Franks, Rikard Landberg, Jennifer L Sargent, Jordi Merino
Journal: Nature Medicine (2025)
KLRG1 identifies regulatory T cells with mitochondrial alterations that accumulate with aging
Authors: Gonzalo Soto-Heredero, Enrique Gabandé-Rodríguez, Elisa Carrasco, José Ignacio Escrig-Larena, Manuel M Gómez de Las Heras, Sandra Delgado-Pulido, Isaac Francos-Quijorna, Eva M Blanco, Álvaro Fernández-Almeida, David Abia, María Josefa Rodríguez, Cristina M Fernández-Díaz, María Beatriz Álvarez-Flores, Ana Ramírez de Molina, Sascha Jung, Antonio Del Sol, Virginia Zorita, Fátima Sánchez-Cabo, Carlos Torroja, María Mittelbrunn
Journal: Nature Aging (2025)

Recent studies using single-cell RNA sequencing technology have uncovered several subpopulations of CD4+ T cells that accumulate with aging. These age-associated T cells are emerging as relevant players in the onset of inflammaging and tissue senescence. Here, based on information provided by single-cell RNA sequencing data, we present a flow cytometry panel that allows the identification of age-associated T cell subsets in systematic larger analysis in mice. We use this panel to evaluate at the single-cell level mitochondrial and senescence marks in the different age-associated CD4+ T cell subpopulations. Our analysis identifies a subpopulation of regulatory T (Treg) cells that is characterized by the extracellular expression of the co-inhibitory molecule killer cell lectin-like receptor subfamily G member 1 (KLRG1) and accumulates with aging in humans and mice. KLRG1-expressing Treg cells display senescence features such as mitochondrial alterations, increased expression of cell-cycle regulators and genomic DNA damage. Functionally, KLRG1+ Treg cells show a reduced suppressive activity in vivo accompanied by a pro-inflammatory phenotype.
The association of COVID-19 lockdowns with adverse birth and pregnancy outcomes in 28 high-income countries: a systematic review and meta-analysis
Authors: Iona Hindes, Hawa Nuralhuda Sarwar, Benjamin Y Gravesteijn, Jennifer Jardine, Lizbeth Burgos-Ochoa, Jasper V Been, Dominik Zenner, Stamatina Iliodromiti
Journal: Nature Human Behaviour (2025)

We conducted a systematic review and meta-analysis to review the association of lockdowns with adverse birth and pregnancy outcomes (ABPOs) and related inequalities, in high-income countries (HICs). Databases (EMBASE, MEDLINE/PubMed and Web of Science) were searched from 1 January 2019 to 22 June 2023 for original observational studies based in HICs that compared the rates of ABPOs, before and during lockdowns. The risk of bias was assessed using the Newcastle-Ottawa tool for cohort studies. We ran random-effects meta-analyses and subgroup analyses per region, lockdown period, ethnicity group and deprivation level and adjusted for underlying temporal trends. A total of 132 studies were meta-analysed from 28 HICs. Reduced rates of preterm birth (reported by 26 studies) were associated with the first lockdown (relative risk 0.96, 95% confidence interval 0.93-0.99), 11 studies adjusted for long-term trends and the association remained (0.97, 0.95-0.99), and subgroup analysis found that this association varied by continental region. Ten studies reported positive screening rates for possible depression antenatally, and lockdown was associated with increases in positive screening rates (1.37, 1.06-1.78). No other ABPOs were associated with lockdowns. Investigation of inequalities was limited due to data availability and heterogeneity; further research is warranted on the effect of lockdowns on health inequalities. This study was funded by the National Institute of Health Research, School of Primary Care Research and registered on PROSPERO (CRD42022327448).
Low versus high positive end expiratory pressure in noninvasive ventilation for hypoxemic respiratory failure: a multicenter randomized controlled trial
Authors: Jun Duan, Xiaoyi Liu, Weiwei Shu, Shijing Tian, Mingjin Yang, Mengyi Ma, Anchao Song, Qin Liu, Ke Wang, Fuxun Yang, Tao Huang, Lei Jiang, Yueling Hong, Xiaoli Han, Zhi Ao, Linfu Bai, Yiwei Min, Wenhui Hu, Jiao He
Journal: Intensive Care Medicine (2025)
Compelling Evidence: A Critical Update on the Therapeutic Potential of Carbon Monoxide
Authors: Nicola Bauer, Qiyue Mao, Aditi Vashistha, Anupamaa Seshadri, Yi‐Chieh Nancy Du, Leo Otterbein, Chalet Tan, Mark P. de Caestecker, Binghe Wang
Journal: Medicinal Research Reviews (2025)

ABSTRACT Carbon monoxide (CO) is an endogenous signaling molecule. It is produced via heme degradation by heme oxygenase (HMOX), releasing stoichiometric amounts of CO, iron, and biliverdin (then bilirubin). The HMOX‐CO axis has long been shown to offer beneficial effects by modulating inflammation, proliferation and cell death as they relate to tissue and organ protection. Recent years have seen a large number of studies examining CO pharmacology, its molecular targets, cellular mechanisms of action, pharmacokinetics, and detection methods using various delivery modalities including inhaled CO gas, CO solutions, and various types of CO donors. Unfortunately, one widely used donor type includes four commercially available carbonyl complexes with metal or borane, CORM‐2 (Ru 2+ ), CORM‐3 (Ru 2+ ), CORM‐A1 (BH 3 ), and CORM‐401 (Mn + ), which have been shown to have minimal and/or unpredictable CO production and extensive CO‐independent chemical reactivity and biological activity. As a result, not all “CO biological activities” in the literature can be attributed to CO. In this review, we summarize key findings based on CO gas and CO in solution for the certainty of the active principal and to avoid data contamination resulting from the confirmed or potential reactivities and activities of the “carrier” portion of CORMs. Along a similar line, we discuss interesting potential research areas of CO in the brain including a newly proposed CO/HMOX/dopamine axis and the role of CO in cognitive stimulation and circadian rhythm. This review is critical for the future development of the CO field by steering clear of complications caused by chemically reactive donor molecules.
Occupational exposures and incidence of asthma over two decades in the European Community Respiratory Health Survey
Authors: Sheikh M Alif, Geza Benke, Hans Kromhout, Michael J Abramson, Manolis Kogevinas, Debbie Jarvis, Nicole Le Moual, Shyamali Dharmage, Vivi Schlünssen, Kjell Torén, Dan Norback, Theodore Lytras, Anne-Elie Carsin, Cecilie Svanes, Mario Olivieri, Sandra Dorado-Arenas, Isabel Urrutia, Silvia Pascual Erquicia, Sofie Acke, Hayat Bentouhami, Gunilla Wieslander, Nicola Murgia, Jesús Martínez-Moratalla, Bénédicte Leynaert, Katja Radon, Jessica Gerlich, Dennis Nowak, Simona Villani, Mathias Holm, Giuseppe Verlato, Angelo D'Errico, Per Bakke, Trude Duelien Skorge, Torgeir Storaas, Anna Dahlman-Höglund, Johan Hellgren, David Miedinger, Torben Sigsgaard, Paul D Blanc, Jan-Paul Zock
Journal: Thorax (2025)

While short-term occupational exposures to many agents are associated with increased risk of asthma, the long-term consequences of exposure have not been well understood. We investigated the effects of occupational exposures over two decades on the incidence of asthma. This population-based, multicentre cohort was assessed at baseline (European Community Respiratory Health Survey (ECRHS)1) and followed up twice over 20 years (ECRHS2 and ECRHS3). This analysis included data for 5591 participants with complete work histories and free of asthma at baseline. Incident adult-onset asthma was defined as either an asthma attack, woken by an attack of shortness of breath and/or current asthma medication in the last 12 months before each timepoint, without asthma at a previous survey. An updated asthma-specific job exposure matrix was used to estimate exposures to asthmagens. Adjusted Poisson models were fitted with generalised estimating equations to estimate asthma incidence. Ever high exposure to high molecular weight sensitisers (rate ratio (RR)=1.31; 95% CI 1.15 to 1.63), irritants (RR=1.29; 1.09-1.54), biocides (RR=1.42; 1.12-1.79), only low exposure to low molecular weight sensitisers (RR=1.26; 1.08-1.47), mites (RR=1.48; 1.12-1.94) and reactive chemicals (RR=1.24; 1.06-1.45) were associated with increased incidence of asthma. Asthma incidence also increased with ever high or cumulative exposure to these exposures and for specific exposure to wood dust, cleaning agents and bleach. The population-attributable fraction for adult-onset asthma due to occupational exposures was 18% (16.9-19.4%). This strengthens the evidence that occupational exposures to sensitisers and chemical irritants contribute substantial risk and a substantive attributable fraction of adult-onset asthma. Control of implicated hazardous exposures and periodic screening of exposed workers should be considered.
Relationship between exhaled volatile organic compounds and lung function change in idiopathic pulmonary fibrosis
Authors: Conal Hayton, Waqar Ahmed, Dayle Terrington, Iain R White, Nazia Chaudhuri, Colm Leonard, Andrew M Wilson, Stephen J Fowler
Journal: Thorax (2025)

Volatile organic compounds (VOCs) in exhaled breath have shown promise as biomarkers in idiopathic pulmonary fibrosis (IPF). We analysed breath from 57 people with IPF using thermal desorption-gas chromatography-mass spectrometry to identify VOCs related to lung function change over 12 months. A LASSO regression model selected 63 VOCs associated with relative change in forced vital capacity (8 with correlation coefficient (CC) ≥0.20 on Spearman's rank analysis), and 28 associated with relative change in diffusion capacity of the lung for carbon monoxide % predicted (12 with CC ≥0.20). Secondary analyses demonstrated a correlation between VOCs and baseline lung function parameters and association with survival. This study suggests that there may be a volatile signature of prognosis in IPF that merits further validation.
Dual MNK/VEGFR2 Inhibitor JDB153 Enhances Immunotherapeutic Efficiency and Chemosensitivity in Lung Cancer
Authors: Maosen Xu, Li Xu, Tao Zhang, Xue Li, Ziqi Zhang, Ruolan Xia, Ning Jiang, Li Yang, Xiawei Wei
Journal: MedComm (2025)

Lung cancer continues to be the primary cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) being the predominant type. Dysregulation of protein translation that participates in cell proliferation is an important factor to define oncogenic processes and cancer development. The eukaryotic initiation factor 4E (eIF4E) regulates ribosomal translation of proteins from mRNA, and the mitogen-activated protein kinase interacting kinases (MNKs) is reported to be the only kinases that can phosphorylate eIF4E. Substantial previous work has proven that the MNK-eIF4E axis is usually dysregulated in many cancer types. Moreover, abnormal angiogenesis is essential for tumorigenesis and cancer progression, and vascular endothelial growth factors (VEGF) together with their receptors play multiple crucial roles in angiogenesis, especially VEGFR2. In this study, we report a novel dual MNK/VEGFR2 inhibitor named JDB153 and investigate its antitumor effects in NSCLC. JDB153 can effectively inhibit the phosphorylation of eIF4E and VEGFR2, suppress proliferation, migration and invasion, promote apoptosis, and induce cycle arrest of lung cancer cells. Importantly, JDB153 exhibits antitumor activity and synergizes with anti-PD-1 therapy and cisplatin with reliable safety. Our findings reveal the potential value of JDB153 in lung cancer as monotherapy or in combination with immunotherapy and chemotherapy, with the hope to provide a novel combinational strategy for NSCLC treatment clinically.
Reply to Correspondence: Causal Associations Between Chronic Spontaneous Urticaria and Thyroid Function Indicators on Different Ethnic Groups: A Bidirectional Two‐Sample Mendelian Randomization Analysis
Authors: Jiang Ji, Yuxu Yao, Lijun Deng, Naihui Zhou, Tingting Yu, Zhenzhong Lu, Qingqing Jiao
Journal: Allergy (2025)
Systematic Comparison of Commercial Uranyl‐Alternative Stains for Negative‐ and Positive‐Staining Transmission Electron Microscopy of Organic Specimens
Authors: Vera M. Kissling, Stephanie Eitner, Davide Bottone, Gea Cereghetti, Peter Wick
Journal: Advanced Healthcare Materials (2025)

Abstract Negative‐ and positive‐staining transmission electron microscopy (ns/psTEM) is a cornerstone of research and diagnostics, enabling nanometer‐resolution analysis of organic specimens from nanoparticles to cells without requiring costly cryo‐equipment. For nearly 70 years, uranyl salts like uranyl acetate (UA) have been the gold‐standard ns/psTEM‐stains. However, mounting safety concerns due to their high toxicity and radioactivity have led to stricter regulations and expensive licensing requirements. Consequently, there is an urgent global demand for safer, more sustainable stains that deliver uranyl‐comparable, high‐quality ns/psTEM. Here, the commercially available stain‐alternatives UranyLess, UAR, UA‐Zero, PTA, STAIN 77, Nano‐W, NanoVan, and lead citrate are systematically assessed against UA. The stains are evaluated regarding their contrast, resolution, stain‐distribution, and ease‐of‐use in ns/psTEM across a diverse sample set, including polymethylmethacrylate‐nanoplastics, phosphatidylcholine‐liposomes, Influenza‐A viruses, globular ferritin, fibrillar pyruvate kinase amyloids, and human lung‐carcinoma cell‐sections. It is shown that for this variety of samples, a ready‐to‐use uranyl‐alternative is commercially available with comparable or even superior ns/psTEM‐performance to UA using an efficient staining‐protocol. Furthermore, the GUIDE4U tool is developed for the fast identification of the appropriate uranyl‐replacements for each sample of interest, saving ns/psTEM‐users time and costs while ensuring excellent staining results for ultrastructural analysis, thereby further catalyzing the use of safer stains.
β‐1,3 Glucan Microparticles &amp; Nanoparticles: Fabrication Methods &amp; Applications in Immunomodulation &amp; Targeted Drug Delivery
Authors: Nate Dowdall, Todd Hoare
Journal: Advanced Healthcare Materials (2025)

Abstract Innate immune cells such as macrophages and dendritic cells play major roles in the progression of many cancerous, fibrotic, and autoimmune diseases, often due to environmental cues that skew these cells toward a phenotype that progresses or exacerbates the disease state. As such, a growing focus in treating such diseases is placed on exploiting the high plasticity of these cells to modify or reverse their pro‐disease phenotypes using immunomodulatory materials. β‐1,3 glucans are one such type of material that has exhibited diverse immunomodulatory effects on immune cells, including the mitigation or reversal of the adverse effects of dysregulated immune cells. In this review, we outline various fabrication techniques to produce β‐1,3 glucan‐derived microparticles and nanoparticles and discuss the diverse particle properties that can be obtained by tuning glucan chemistry, fabrication method, and formulation components. Furthermore, the immunomodulatory applications of β‐1,3 glucan particles are highlighted with a focus on immune cell targeting, modulation, and the delivery of small molecule and macromolecular therapeutics.