tbuckley/cabot-search huggingface dataset:
CRISPR-Cas9 mediated proteinase 3 autoantigen deletion as a treatment strategy for anti-neutrophil cytoplasmic autoantibody-associated vasculitis
Authors: Uwe Jerke, Claudia Eulenberg-Gustavus, Dimitrios Laurin Wagner, Adrian Schreiber, Ralph Kettritz
Journal: Kidney International (2025)

Proteinase 3 (PR3) is a major autoantigen in patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Here, we performed a proof-of-principle study using ex vivo CRISPR-Cas9 guided gene editing to eliminate the PR3 autoantigen as an alternative to suppressing the autoimmune response to PR3. A ribonucleoprotein (RNP) complex of Cas9 protein and a PR3-specific single guide-RNA was transfected into human CD34+ hematopoietic stem and progenitor cells (HSPC) by electroporation. Effects on PR3 protein abundance, neutrophil differentiation, and ANCA-dependent and -independent neutrophil responses were assessed. Gene editing introduced a frame shift in exon 2 of PRTN3. Consequently, PR3 protein was efficiently reduced in neutrophil-differentiated HSPCs as demonstrated by immunoblotting, ELISA, microscopy, and the complete absence of PR3-specific proteolytic activity. Human neutrophil elastase served as control and was not affected. PR3-deleted (PR3KO)- and PR3 wild-type (PR3WT)-HSPCs showed similar neutrophil differentiation. Importantly, general neutrophil defense functions to non-ANCA receptor-independent and -dependent stimuli were similar in PR3KO- and PR3WT-neutrophils as was constitutive apoptosis. Flow cytometry showed that cell membrane-PR3 was significantly reduced on PR3KO-neutrophils and consequent neutrophil activation to either monoclonal antibodies to PR3 or human PR3-ANCA was attenuated. In contrast, myeloperoxidase-ANCA stimulation was not affected. We show the feasibility and efficacy of depleting the PR3 autoantigen in human CD34+ HSPCs using CRISPR-Cas9. Depleting the PR3 autoantigen instead of suppressing the autoimmune response to PR3 could potentially lead to drug-free remission, particularly in patients with refractory or relapsing disease.
Bioengineered bacterial extracellular vesicles for targeted delivery of an osteoclastogenesis-inhibitory peptide to alleviate osteoporosis
Authors: Xiangxiang Kong, Han Liu, Sumeng Chen, Zhinan Liu, Qin Chen, Xiang Li, Honggang Hu, Jiacan Su, Yejiao Shi
Journal: Journal of Controlled Release (2025)
Near Infrared II Laser‐Boosted Peroxynitrite Generation Hollow Copper Single Atom Nanozyme for Effective Bacterial Infection Treatment
Authors: Wei Tang, Yuan Fang, Linhao Xie, Wanqin Cai, Guichao Liu, Yan Lu, Yongguang Guan, Wei Xue, Jianfu Zhao, Siming Yu
Journal: Advanced Healthcare Materials (2025)

Abstract The peroxynitrite anion (ONOO − ) is the product of a specific reaction between nitric oxide (NO) and the superoxide anion (O 2 •− ), showing great potential for treating multidrug‐resistant bacterial infections. However, antibacterial materials with highly efficient ONOO − controlled release properties are lacking. In this study, hollow copper single atom nanozyme (Cu HSAz) with oxidase (OXD)‐mimicking property is rationally designed and used for the first time as effective delivery carrier for the NO donor N, N ′‐di‐sec‐butyl‐ N, N ′‐dinitroso‐1, 4‐phenylenediamine (BNN6), obtaining the nanozyme Cu HSAz@BNN6. Upon near infrared (NIR)‐II laser irradiation, Cu HSAz@BNN6 simultaneously releases substantial amounts of NO and O 2 •− , which subsequently lead to the ONOO − boosting via a cascade reaction. Remarkably, ONOO − displays excellent antibacterial efficiency by considerably inhibiting the activity of methicillin‐resistant Staphylococcus aureus ( MRSA ) activity. Moreover, ONOO − is effective in treating MRSA ‐associated wound infections and promoting wound healing. An antibacterial mechanism study reveals that ONOO − triggers MRSA death by firstly damaging the MRSA membrane, followed by destructing MRSA metabolism to cut the adenosine triphosphate energy supply and boosts intracellular reactive oxygen species generation, which subsequently depletes intracellular glutathione and caused DNA breakage.
Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes
Authors: Łukasz J Sznajder, Mahreen Khan, Adam Ciesiołka, Mariam Tadross, Curtis A Nutter, Katarzyna Taylor, Christopher E Pearson, Mark H Lewis, Rochelle M Hines, Maurice S Swanson, Krzysztof Sobczak, Ryan K C Yuen
Journal: Nature Neuroscience (2025)

Abstract Genome-wide enrichment of gene-specific tandem repeat expansions has been linked to autism spectrum disorder. One such mutation is the CTG tandem repeat expansion in the 3′ untranslated region of the DMPK gene, which is known to cause myotonic muscular dystrophy type 1. Although there is a clear clinical association between autism and myotonic dystrophy, the molecular basis for this connection remains unknown. Here, we report that sequestration of MBNL splicing factors by mutant DMPK RNAs with expanded CUG repeats alters the RNA splicing patterns of autism-risk genes during brain development, particularly a class of autism-relevant microexons. We demonstrate that both DMPK -CTG expansion and Mbnl null mouse models recapitulate autism-relevant mis-splicing profiles, along with social behavioral deficits and altered responses to novelty. These findings support our model that myotonic dystrophy-associated autism arises from developmental mis-splicing of autism-risk genes.
High-Volume Physical Activity and Clinical Coronary Artery Disease Outcomes: Findings From the Cooper Center Longitudinal Study
Authors: Jarett D. Berry, Noor Zabad, Douglas Kyrouac, David Leonard, Carolyn E. Barlow, Andjelka Pavlovic, Kerem Shuval, Benjamin D. Levine, Laura F. DeFina
Journal: Circulation (2025)

BACKGROUND: High-volume physical activity (PA) is associated with a higher prevalence of subclinical coronary artery disease (CAD). However, the clinical significance of subclinical CAD among high-volume exercisers remains incompletely understood, and the dose–response relationship between high-volume PA and clinical CAD events remains uncertain. METHODS: Individual participant data from the Cooper Center Longitudinal Study (1987–2018) were linked to Medicare claims files. PA volume was determined by self-report and categorized as &lt;500, 500 to 1499, 1500 to 2999, and ≥3000 metabolic equivalent of task (MET)-minutes per week. Subclinical CAD (coronary artery calcium [CAC]) was measured by cardiac computed tomography. All other risk factors were measured in the standard fashion. Composite CAD events (acute myocardial infarction and revascularization) and all-cause mortality were determined from Medicare claims files. A multivariable-adjusted proportional hazards illness-death model with random shared frailty was used to estimate the association between PA volume, CAC, and both clinical CAD and death. Heterogeneity in the association between CAC and clinical CAD across levels of PA was determined with multiplicative interaction terms. RESULTS: We included 26 724 participants (54 years of age; 28% women). Mean exercise volume was 1130 MET-minutes per week, with 1997 (7.5%) reporting ≥3000 MET-minutes per week. After a mean follow-up of 20.5 years, we observed 811 acute myocardial infarction events, 1636 composite CAD events, and 2857 deaths without CAD. Compared with individuals exercising &lt;500 MET-minutes per week, the lowest risk for acute myocardial infarction occurred among individuals with intermediate PA volumes (500–1499 MET-minutes per week: hazard ratio [HR], 0.77 [95% CI, 0.65–0.91]; 1500–2499 MET-minutes per week: HR, 0.78 [95% CI, 0.63–0.95]). There was no association between high-volume PA (&gt;3000 MET-minutesw per week) and risk for acute myocardial infarction (HR, 0.95 [95% CI, 0.72–1.25]). In contrast, the lowest risk for death was observed among the high-volume PA group (HR, 0.71 [95% CI, 0.60–0.83]). CAC (on log scale) was associated with a higher risk for composite CAD across all PA categories, including among the high-volume PA subgroup (HR, 1.29 [95% CI, 1.16–1.44]; P &lt;0.001; P interaction = 0.969). CONCLUSIONS: Compared with low-volume PA, high-volume PA was associated with a lower risk for all-cause mortality but a similar risk for clinical CAD. CAC was associated with an increased risk for clinical CAD regardless of the volume of PA.
Integrated analysis of molecular atlases unveils modules driving developmental cell subtype specification in the human cortex
Authors: Patricia R Nano, Elisa Fazzari, Daria Azizad, Antoni Martija, Claudia V Nguyen, Sean Wang, Vanna Giang, Ryan L Kan, Juyoun Yoo, Brittney Wick, Maximilian Haeussler, Aparna Bhaduri
Journal: Nature Neuroscience (2025)

Human brain development requires generating diverse cell types, a process explored by single-cell transcriptomics. Through parallel meta-analyses of the human cortex in development (seven datasets) and adulthood (16 datasets), we generated over 500 gene co-expression networks that can describe mechanisms of cortical development, centering on peak stages of neurogenesis. These meta-modules show dynamic cell subtype specificities throughout cortical development, with several developmental meta-modules displaying spatiotemporal expression patterns that allude to potential roles in cell fate specification. We validated the expression of these modules in primary human cortical tissues. These include meta-module 20, a module elevated in FEZF2+ deep layer neurons that includes TSHZ3, a transcription factor associated with neurodevelopmental disorders. Human cortical chimeroid experiments validated that both FEZF2 and TSHZ3 are required to drive module 20 activity and deep layer neuron specification but through distinct modalities. These studies demonstrate how meta-atlases can engender further mechanistic analyses of cortical fate specification.
Dynamics of glia and neurons regulate homeostatic rest, sleep and feeding behavior in Drosophila
Authors: Andres Flores-Valle, Ivan Vishniakou, Johannes D Seelig
Journal: Nature Neuroscience (2025)

Abstract Homeostatic processes, including sleep, are critical for brain function. Here we identify astrocyte-like glia (or astrocytes, AL) and ensheathing glia (EG), the two major classes of glia that arborize inside the brain, as brain-wide, locally acting homeostats for the short, naturally occurring rest and sleep bouts of Drosophila , and show that a subset of neurons in the fan-shaped body encodes feeding homeostasis. We show that the metabolic gas carbon dioxide, changes in pH and behavioral activity all induce long-lasting calcium responses in EG and AL, and that calcium levels in both glia types show circadian modulation. The homeostatic dynamics of these glia can be modeled based on behavior. Additionally, local optogenetic activation of AL or EG is sufficient to induce rest. Together, these results suggest that glial calcium levels are homeostatic controllers of metabolic activity, thus establishing a link between metabolism, rest and sleep.
Multi-omic and spatial analysis of mouse kidneys highlights sex-specific differences in gene regulation across the lifespan
Authors: Siqi Chen, Ruiyang Liu, Chia-Kuei Mo, Michael C Wendl, Andrew Houston, Preet Lal, Yanyan Zhao, Wagma Caravan, Andrew T Shinkle, Atieh Abedin-Do, Nataly Naser Al Deen, Kazuhito Sato, Xiang Li, André Luiz N Targino da Costa, Yize Li, Alla Karpova, John M Herndon, Maxim N Artyomov, Joshua B Rubin, Sanjay Jain, Xue Li, Sheila A Stewart, Li Ding, Feng Chen
Journal: Nature Genetics (2025)

There is a sex bias in the incidence and progression of many kidney diseases. To better understand such sexual dimorphism, we integrated data from six platforms, characterizing 76 kidney samples from 68 mice at six developmental and adult time points, creating a molecular atlas of the mouse kidney across the lifespan for both sexes. We show that proximal tubules have the most sex-biased differentially expressed genes emerging after 3 weeks of age and are associated with hormonal regulations. We reveal potential mechanisms involving both direct and indirect regulation by androgens and estrogens. Spatial profiling identifies distinct sex-biased spatial patterns in the cortex and outer stripe of the outer medulla. Additionally, older mice exhibit more aging-related gene alterations in loops of Henle, proximal tubules and collecting ducts in a sex-dependent manner. Our results enhance the understanding of spatially resolved gene expression and hormone regulation underlying kidney sexual dimorphism across the lifespan.
Intensive Lowering of LDL Cholesterol Levels With Evolocumab in Autoimmune or Inflammatory Diseases: An Analysis of the FOURIER Trial
Authors: Andre Zimerman, Ana Laura F. Kunzler, Brittany N. Weber, Xinhui Ran, Sabina A. Murphy, Huei Wang, Narimon Honarpour, Anthony C. Keech, Peter S. Sever, Marc S. Sabatine, Robert P. Giugliano
Journal: Circulation (2025)

BACKGROUND: Patients with an autoimmune or inflammatory disease (AIID) are at increased cardiovascular risk and may benefit more from statin therapy. In the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab lowered low-density lipoprotein cholesterol levels, but not hsCRP (high-sensitivity C-reactive protein) levels, and reduced the risk of cardiovascular events. METHODS: FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with stable atherosclerosis who were taking statins. This analysis focused on the effect of evolocumab in patients with or without an AIID, defined as any autoimmune or chronic inflammatory condition. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization. RESULTS: At baseline, 889 patients (3.2%) had an AIID, most commonly rheumatoid arthritis (33.7%) or psoriasis (15.6%). Median (interquartile range) low-density lipoprotein cholesterol levels were 90.0 mg/dL (79.5–105.5) and 91.5 mg/dL (79.5–108.5) in patients with or without an AIID, respectively ( P =0.025), and the placebo-adjusted percent reduction with evolocumab was consistent (60.2% versus 59.0%; P =0.57). Baseline hsCRP was higher in patients with an AIID (median 2.1 versus 1.7 mg/L; P &lt;0.001) and did not significantly change with evolocumab in either group. Compared with placebo, evolocumab reduced the rate of the primary end point by 14% in patients without an AIID (hazard ratio, 0.86 [95% CI, 0.80–0.93]) and by 42% in patients with an AIID (hazard ratio, 0.58 [95% CI, 0.38–0.89]; P interaction =0.066). Likewise, evolocumab reduced the key secondary end point of cardiovascular death, myocardial infarction, or stroke by 19% in patients without an AIID (hazard ratio, 0.81 [95% CI, 0.74–0.89]) and 58% in those with an AIID (hazard ratio, 0.42 [95% CI, 0.24–0.74]; P interaction =0.022). CONCLUSIONS: Intensive lowering of low-density lipoprotein cholesterol levels with evolocumab may lead to greater relative reduction in cardiovascular events in patients with an AIID. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.
Mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction according to body weight
Authors: Jawad H. Butt, Scott D. Solomon, Muthiah Vaduganathan, Dirk J. van Veldhuisen, Lars Køber, Bertram Pitt, Faiez Zannad, Pardeep S. Jhund, John J.V McMurray
Journal: European Journal of Heart Failure (2025)
The interaction between atrial fibrillation and mitral regurgitation: Insights from the <scp>CABANA</scp> randomized clinical trial
Authors: Sebastiaan Dhont, Philippe B. Bertrand, Jonas Erzeel, Sébastien Deferm, Laurent Pison, Pieter M. Vandervoort, Wilfried Mullens, W.H. Wilson Tang, Pieter Martens
Journal: European Journal of Heart Failure (2025)

Abstract Aims Atrial fibrillation (AF) and mitral regurgitation (MR) frequently coexist. While catheter ablation is a key rhythm‐control strategy in AF, its impact on MR severity remains uncertain. This study evaluates the effects of catheter ablation on AF recurrence, functional status, and MR progression in patients with AF and baseline MR. Methods and results This sub‐analysis included 1423 patients (65% of the overall CABANA cohort) with available baseline echocardiography. Participants were randomized to catheter ablation or pharmacological therapy. The primary endpoint was the composite of all‐cause mortality and cardiovascular hospitalization. Secondary endpoints included AF recurrence, changes in MR severity, and functional status. At baseline, 722 patients (52%) had MR, including 582 with mild and 140 with ≥moderate MR, with characteristics suggestive of an atrial functional mechanism. Catheter ablation significantly reduced AF recurrence compared to pharmacological therapy (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.50–0.62, p &lt; 0.001). The presence or absence of MR did not interact with randomization in terms of its neutral effect on all‐cause mortality and cardiovascular hospitalization ( p for interaction = 0.115). Baseline MR increased the risk of AF recurrence (OR 1.46, 95% CI 1.40–1.74, p &lt; 0.001). However, the benefit of ablation on functional status was greater in patients with MR compared to those without ( p for interaction &lt; 0.001). Follow‐up echocardiography ( n = 248) showed a greater reduction in MR severity in the ablation group versus drug therapy ( p for interaction = 0.040). Conclusion Catheter ablation was superior to pharmacological therapy in rhythm control and may reduce MR severity over time. These findings highlight ablation's potential structural and symptomatic benefits, pending specifically designed clinical trials.
Abstract 106: Growth-associated protein 43 (GAP-43): the link to Ewing sarcoma bone metastasis
Authors: Tyler Biermann, Nicholas Cohen, Yasmine Wazni, Stefano Vicini, Jason Tilan, Joanna Kitlinska
Journal: Cancer Research (2025)

Abstract Ewing Sarcoma (ES) is an aggressive pediatric tumor that arises in bone or soft tissues. ES bone metastases do not respond well to routine therapies and their frequency markedly increases upon disease recurrence, which results in a lower survival rate in patients with osseous metastases as compared to those with pulmonary dissemination. Our previous studies have determined that ES bone metastasis is initiated by hypoxia in the primary tumor site, which leads to the formation of polyploid tumor cells, the progeny of which, named HYP-4n cells, exhibit high levels of chromosomal instability. These cells metastasize almost exclusively to bone and are less sensitive to cytostatic agents. In this study, we demonstrate that HYP-4n cells exhibit an upregulation in several neuronal proteins, specifically growth-associated protein 43 (GAP-43), a membrane protein promoting axon growth in neurons and formation of microtubes connecting glioblastoma cells into invasive and therapy-resistant cellular network. Similar phenotype characterized by the presence of microtube-like cell-cell connections was also observed in ES HYP-4n cells. GAP-43 immunostaining in HYP-4n cells revealed a punctuated pattern along the protrusions that is similar to its localization in neurons. Western Blot analysis performed on HYP-4n cells revealed a membranous localization of GAP-43, which was not detectable in their normoxic diploid counterparts. The functional role of the GAP-43-positive protrusions in connecting HYP-4n cells was confirmed by the gap-junction permeable dye transfer between the cells and ion transfer detected by a patch clamp assay. DAPI staining also displayed nuclear fragments within the protrusions, suggesting the transfer of genetic material. The suppression of GAP-43 expression via siRNA was further shown to inhibit HYP-4n cell migration measured via transwell assay. In immunostained ES xenografts, GAP-43 expression was shown in HYP-4n primary and osseous metastatic tumors, with the highest membranous expression in the ES cells on the invading edge of the tumors. A similar pattern of expression of GAP-43 was noted in the human samples of ES bone metastases. This study indicates that GAP-43 is active in the membrane in HYP-4n cells and drives the formation of microtube networks promoting cell invasion. Further studies are required to prove directly the role of GAP-43 in ES bone metastasis and chemoresistance. Citation Format: Tyler Biermann, Nicholas Cohen, Yasmine Wazni, Stefano Vicini, Jason Tilan, Joanna Kitlinska. Growth-associated protein 43 (GAP-43): the link to Ewing sarcoma bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 106.
Abstract 602: Synergistic anti-tumor effects of andrographis and lactoferrin in colorectal cancer via modulation of AXIN2/Wnt/E-cadherin signaling pathway
Authors: Yuan Li, Caiming Xu, Takayuki Noma, Ajay Goel
Journal: Cancer Research (2025)

Abstract Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide and 20-25% of patients experience metastatic colorectal cancer (mCRC) at initial diagnosis. However, the high mortality rates associated with mCRC are largely due to the inadequate efficacy of current treatments and the development of acquired resistance to conventional chemotherapy. Recent studies have indicated that Lactoferrin is frequently used as a drug transport carrier, enhancing drug absorption. Natural compounds like Andrographis offer cost-effective, multi-targeted treatments for tumors. Therefore, we hypothesize that Lactoferrin might serve as a transport carrier for Andrographis, improving its bioabsorption and in offering a more pronounced anticancer activity in CRC. Methods: We conducted a series of in-vitro and in-vivo experiments to evaluate the synergistic anticancer effects of Lactoferrin and Andrographis in CRC. Furthermore, we performed a genomewide transcriptomic analysis to identified specific growth-signaling pathways targeted by the combined treatment and subsequently validated these findings in cell lines and patient-derived 3D organoids. Results: The combined treatment with Lactoferrin and Andrographis exhibited excellent synergistic anti-tumor potential, affecting cell viability, proliferation, migration, and invasion in CRC cells. In CRC, metastasis commonly occurs through the epithelial-mesenchymal transition. This combination treatment exerted the most pronounced effects on β-catenin responsive transcription and E-cadherin promoter activity. Mechanistically, transcriptomic analysis revealed that the combined treatment resulted in the inhibition of AXIN2 which resulted in E-cadherin-mediated inhibition of Wnt signaling ([FC]: 3.46, P &amp;lt; 0.005). Additionally, we observed that the expression levels of AXIN2 were significantly higher in cancer vs. normal tissues (P &amp;lt; 0.005) in the TCGA dataset. Finally, in 3D organoid models, the combined treatment exhibited superior anti-cancer activity, significantly reducing both the number and size of organoids (P &amp;lt; 0.05). These findings highlight the therapeutic potential of targeting the AXIN2/Wnt/E-cadherin axis with Lactoferrin and Andrographis in CRC. Conclusion: We present evidence that the synergistic anticancer effects of Lactoferrin and Andrographis in CRC are mediated through the AXIN2/Wnt/E-cadherin axis, highlighting their potential as a therapeutic strategy. Citation Format: Yuan Li, Caiming Xu, Takayuki Noma, Ajay Goel. Synergistic anti-tumor effects of andrographis and lactoferrin in colorectal cancer via modulation of AXIN2/Wnt/E-cadherin signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 602.