tbuckley/cabot-search huggingface dataset:
Microglial circDlg1 modulates neuroinflammation by blocking PDE4B ubiquitination-dependent degradation associated with Alzheimer's disease
Authors: Jiyun Shi, Chenghuan Song, Pingao Zhang, Jing Wang, Wanying Huang, Ting Yu, Zijie Wei, Lufeng Wang, Lanxue Zhao, Rui Zhang, Lina Hou, Yongfang Zhang, Hongzhuan Chen, Hao Wang
Journal: Theranostics (2025)

Background: Abnormal activation of microglia occurs in the early stage of Alzheimer's disease (AD) and leads to subsequent neuroinflammation and major AD pathologies. Circular RNAs (circRNAs) are emerging as great potential therapeutic targets in AD. However, the extent of circRNAs entwined and the underlying mechanism in microglia-driven neuroinflammation in AD remain elusive. Methods: The circular RNA Dlg1 (circDlg1) was identified using circRNA microarray screening in magnetic-isolated microglia of APP/PS1 mice. CircDlg1 expression in microglia of APP/PS1 mice and AD patients was validated by FISH. Flow cytometry and immunostaining were conducted to explore the roles of circDlg1 in microglia. Adeno-associated virus 9 preparations for interfering with microglial circDlg1 were microinjected into mouse lateral ventricle to explore influences on microglial response, neuroinflammation and AD pathologies. Y-maze, novel object recognition and Morris water maze tasks were performed to assess cognitive performance. RNA pulldown assays, mass spectrometry analysis, RNA immunoprecipitation, and co-immunoprecipitation were performed to validate the underlying regulatory mechanisms of circDlg1. Results: A novel circular RNA circDlg1 was observed elevated using circRNA microarray screening in microglia isolated from APP/PS1 mice and validated increased in intracerebral microglia of AD patients. Microglia-specific knockdown of circDlg1 remarkably ameliorated microglial recruitment and envelopment of amyloid-β (Aβ), mitigated neuroinflammation, and prevented cognitive decline in APP/PS1 mice. Mechanistically, circDlg1 interfered with the interaction between phosphodiesterase 4b (PDE4B) and Smurf2, an E3 ubiquitin ligase of PDE4B. The formed ternary complex protected PDE4B from ubiquitination-dependent degradation via unique N-terminal targeting domain, thus consequently decreasing cAMP levels. We further confirmed that microglial circDlg1 downregulation significantly activated PKA/CREB anti-inflammatory pathway by decreasing PDE4B protein levels in APP/PS1 mice. Conclusion: The novel microglia-upregulated circDlg1 tightly involves in neuroinflammation in APP/PS1 mice via determining the protein fate of PDE4B. Microglial loss of circDlg1 promotes microglial protective response to Aβ deposition and relieves neuroinflammation, thus suggesting a potential therapeutic strategy that specifically targets the microglial response in AD.
Targeting both death and paracaspase domains of MALT1 with antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors
Authors: Yuwei Tao, Chen Tian, Shaolong Qi, Ziqi Jia, Zheng Xu, Jingjing Meng, Guoyuan Xu, Haitian Hu, Xuxiang Wang, Tengjiang Zhang, Huiwen You, Xun Lan, Xin Lin, Guocan Yu, Haitao Zhou, Jiaqi Liu, Hanqiu Zheng
Journal: Nature Cancer (2025)
The impact of interactive text communication on neonatal mortality in Kenya: a randomized controlled trial
Authors: Jennifer A. Unger, John Kinuthia, Brenda Wandika, Anna Hedstrom, Erica Wetzler, Jenna I. Udren, Millicent Masinde, Esther M. Choo, Olivia Schultes, Peninah Kithao, June Moraa, Esther Akinyi, Lusi Osborn, Emmaculate Nzove, Barbra A. Richardson, Manasi Kumar, Dalton Wamalwa, Keshet Ronen
Journal: Nature Medicine (2025)
Tuft cell IL-17RB restrains IL-25 bioavailability and reveals context-dependent ILC2 hypoproliferation
Authors: Xiaogang Feng, Tilde Andersson, Pascal Flüchter, Julia Gschwend, Ivan Berest, Julian L. Muff, Antonie Lechner, Aurelia Gondrand, Patrick Westermann, Nina Brander, Daniele Carchidi, Jeshua C. De Tenorio, Tianlang Pan, Ulrich Boehm, Christoph S. N. Klose, David Artis, Christoph B. Messner, Trese Leinders-Zufall, Frank Zufall, Christoph Schneider
Journal: Nature Immunology (2025)

Abstract The tuft cell–group 2 innate lymphoid cell (ILC2) circuit orchestrates rapid type 2 responses upon detecting microbially derived succinate and luminal helminths. Our findings delineate key mechanistic steps involving IP3R2 engagement and Ca 2+ flux, governing interleukin-25 (IL-25) production by tuft cells triggered by succinate detection. While IL-17RB has a pivotal intrinsic role in ILC2 activation, it exerts a regulatory function in tuft cells. Tuft cells exhibit constitutive Il25 expression, placing them in an anticipatory state that facilitates rapid production of IL-25 protein for ILC2 activation. Tuft cell IL-17RB is crucial for restraining IL-25 bioavailability, preventing excessive tonic ILC2 stimulation due to basal Il25 expression. Supraoptimal ILC2 stimulation by IL-25 resulting from tuft cell Il17rb deficiency or prolonged succinate exposure induces a state of hypoproliferation in ILC2s, also observed in chronic helminth infection. Our study offers critical insights into the regulatory dynamics of IL-25 in this circuit, highlighting the delicate tuning required for responses to diverse luminal states.
Cities, communities and clinics can be testbeds for human exposome and aging research
Authors: Tina Woods, Nic Palmarini, Lynne Corner, Nir Barzilai, Andrea B. Maier, Michael Sagner, Joanna Bensz, Alexey Strygin, Nikhil Yadala, Carina Kern, Peter Ward, Luigi Ferrucci, Evelyne Yehudit Bischof, Richard Barker, Paul G. Shiels, Gerome Guiot, Jennifer Monti, Jamie Justice, Brian K. Kennedy, David Furman
Journal: Nature Medicine (2025)
Corrigendum to “Cell cycle dysregulation in cancer” [Pharmacological Reviews 77 (2025) 100030]
Authors: Antonino Glaviano, Samarendra K. Singh, E. Hui Clarissa Lee, Elena Okina, Hiu Yan Lam, Daniela Carbone, E. Premkumar Reddy, Mark J. O’Connor, Andrew Koff, Garima Singh, Justin Stebbing, Gautam Sethi, Karen Carmelina Crasta, Patrizia Diana, Khandan Keyomarsi, Michael B. Yaffe, Seth A. Wander, Aditya Bardia, Alan Prem Kumar
Journal: Pharmacological Reviews (2025)
PCSK9 Promotes LDLR Degradation by Preventing SNX17-Mediated LDLR Recycling
Authors: YangYang Guan, Xiaomin Liu, Zetian Yang, Xinyu Zhu, Min Liu, Mingkun Du, Xiaowei Pan, Yan Wang
Journal: Circulation (2025)

BACKGROUND: Low-density lipoprotein (LDL) is internalized into cells mainly through LDLR (LDL receptor)–mediated endocytosis. In an acidic endosome, LDLR is released from LDL and recycles back to the cell surface, whereas LDL is left in the endosome and degraded in the lysosome. Circulating PCSK9 (proprotein convertase subtilisin/kexin 9) binds with LDLR and is internalized into the endosome, similar to LDL. In an acidic endosome, LDLR fails to disassociate from PCSK9, and both proteins are degraded in the lysosome. PCSK9 inhibitors are widely used for treating hypercholesterolemia. However, how PCSK9 diverts LDLR to the lysosome for degradation remains elusive. Some patients are resistant to PCSK9 inhibitors, for unknown reasons. METHODS: Both in vitro and in vivo approaches were used to investigate the molecular and cellular mechanisms of PCSK9-mediated LDLR degradation. LDLR containing FH sequence variations was expressed in LDLR knockout mice and knockout HuH7 cells to evaluate their response to PCSK9 and PCSK9 inhibitors. RESULTS: Acidic pH induces a conformational change in LDLR extracellular domain and promotes its interaction with SNX17 (sorting nexin 17) through the intracellular domain. Knocking down SNX17 abolishes LDLR recycling and causes accelerated degradation in the lysosome. PCSK9 prevents the acidic pH–induced conformational change in LDLR and blocks its interaction with SNX17. Knocking down SNX17 abolishes PCSK9-mediated LDLR degradation. Any FH sequence variations that disrupt LDLR recycling are unresponsive to PCSK9 or PCSK9 inhibitors, even though they can internalize LDL. CONCLUSIONS: PCSK9 promotes LDLR degradation by preventing SNX17-mediated LDLR recycling. Patients with sequence variations in FH leading to defects in LDLR recycling are resistant to PCSK9 inhibitors. Genetic diagnosis and alternative drugs independent of LDLR will be needed for treatment of these patients.
RETRACTION: ENKUR Recruits FBXW7 to Ubiquitinate and Degrade MYH9 and Further Suppress MYH9‐Induced Deubiquitination of β‐Catenin to Block Gastric Cancer Metastasis
Journal: MedComm (2025)

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Endothelial Serotonin Receptor 1B Acts as a Mechanosensor to Drive Atherosclerosis
Authors: Minchun Jiang, Huanyu Ding, Yuhong Huang, Chi Wai Lau, Ying Guo, Jianfang Luo, Yu-Tsung Shih, Yin Xia, Xiaoqiang Yao, Jeng-Jiann Chiu, Li Wang, Shu Chien, Yu Huang
Journal: Circulation Research (2025)

BACKGROUND: Atherosclerosis is characterized by the accumulation of fatty and fibrotic plaques, which preferentially develop at curvatures and branches along the arterial trees that are exposed to disturbed flow. However, the mechanisms by which endothelial cells sense disturbed flow are still unclear. METHODS: The partial carotid ligation mouse model was used to investigate disturbed flow-induced atherogenesis. In vitro experiments were performed using the ibidi system to generate oscillatory shear stress and laminar shear stress. ApoE −/− mice with endothelium-specific knockout or overexpression of 5-HT 1B (serotonin receptor 1B) were used to investigate the role of endothelial 5-HT 1B in atherosclerosis. RNA sequencing analysis, immunofluorescence analysis, and molecular biological techniques were used to explore the role of 5-HT 1B in mechanotransduction and endothelial activation. RESULTS: The data showed that human endothelial cells express a high level of 5-HT 1B , which is a serotonin receptor subtype. Endothelial 5-HT 1B is upregulated in atherosclerotic areas of both humans and rodents and is increased by disturbed flow both in vivo and in vitro. Endothelium-specific overexpression of 5-HT 1B exacerbates, whereas knockout or knockdown of 5-HT 1B in endothelium inhibits disturbed flow-induced endothelial inflammation and atherogenesis in both male and female ApoE −/− mice. We reveal a previously unknown role of 5-HT 1B as a mechanosensor in endothelial cells in response to mechanical stimuli. Upon activation by oscillatory shear stress, 5-HT 1B recruits β-arrestin, orchestrates RhoA, and then activates mechanosensitive YAP (yes-associated protein), thereby enhancing endothelial inflammation and monocyte infiltration. Pharmacological blockade of 5-HT 1B suppresses endothelial activation and atherogenesis via inhibition of YAP. CONCLUSIONS: Taken together, these results uncover that endothelial 5-HT 1B acts as a mechanosensor for disturbed flow and contributes to atherogenesis. Inhibition of 5-HT 1B could be a promising therapeutic strategy for atherosclerosis.
Myeloid Fatty Acid Metabolism Activates Neighboring Hematopoietic Stem Cells to Promote Heart Failure With Preserved Ejection Fraction
Authors: Mallory Filipp, Zhi-Dong Ge, Matthew DeBerge, Connor Lantz, Kristofor Glinton, Peng Gao, Sasha Smolgovsky, Jingbo Dai, You-Yang Zhao, Laurent Yvan-Charvet, Pilar Alcaide, Samuel E. Weinberg, Gabriele G. Schiattarella, Joseph A. Hill, Matthew J. Feinstein, Sanjiv J. Shah, Edward B. Thorp
Journal: Circulation (2025)

BACKGROUND: Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. Although inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear. METHODS: Comparing patient samples and animal models, we defined the innate immune response during HFpEF in situ and through flow cytometry and single-cell RNA sequencing. After identifying transcriptional and cell signatures, we implemented a high-fat diet and hypertensive model of HFpEF and tested roles for myeloid and hematopoietic stem cells during HFpEF. Contributions of macrophage metabolism were also evaluated, including through mass spectrometry and carbon labeling. Primary macrophages were studied ex vivo to gain insight into complementary cell-intrinsic mechanisms. RESULTS: Here we report evidence that patients with cardiometabolic HFpEF exhibit elevated peripheral blood hematopoietic stem cells. This phenotype was conserved across species in a murine mode of high-fat diet and hypertension. Hematopoietic stem cell proliferation was coupled to striking remodeling of the peripheral hematopoietic stem cell niche and expression of the macrophage adhesion molecule Vcam1 . This could be partially inhibited by sodium-glucose cotransporter-2 inhibitors and explained by elevated fatty acid metabolism in macrophage mitochondria, which in turn remodeled the Vcam1 promoter to enhance its expression. CONCLUSIONS: These findings identify a significant new stem cell signature of cardiometabolic HFpEF and support a role for myeloid maladaptive fatty acid metabolism in the promotion of systemic inflammation and cardiac diastolic dysfunction.
A sequential drug delivery system based on silk fibroin scaffold for effective cartilage repair
Authors: Menglin Xiao, Liangyan Sun, Kang Wu, Yuqi Ding, Peipei Wang, Chuangchuang Mu, Jinrong Yao, Zhengzhong Shao, Bingjiao Zhao, Xin Chen
Journal: Bioactive Materials (2025)
Left atrial strain by vendor-neutral echocardiography software in healthy subjects: vendor comparisons and associated factors
Authors: Tiffany Dong, Aro Daniela Arockiam, Ankit Agrawal, Joseph El Dahdah, Elio Haroun, Muhammad Majid, Richard A Grimm, Luis L Rodriguez, Zoran B Popovic, Brian P Griffin, Wael A Jaber, Tom Kai Ming Wang
Journal:  (2025)

Abstract Aims Left atrial strains (reservoir LASr, conduit LAScd and contractile LASct) are increasingly utilized, primarily in the areas of heart failure and valvulopathy. Commercially available software to measure strain are marketed as imaging machine vendor independent, although the normal ranges of their performance and external validation studies are lacking. We evaluated and compared left atrial strain values, reference ranges and associated factors using contemporary strain software. Methods Healthy subjects (n=100) undergoing transthoracic echocardiography during January-April 2023 were studied, with equal number by age-groups, sex and GE versus Philips equipment. Left atrial strains were quantified using TomTec version 51.02 (Autostrain LA), EchoPAC version 206 (AFILA), VVI version 2.00 and Epsilon version 5.0.2.11295 software. Results Means and LLNs (95%CI) of LASr (%) were 44.1 (41.9, 46.3) and 30.3 (26.4, 34.1) for TomTec; 34.8 (33.6, 36.0) and 26.3 (24.2, 28.4) for EchoPAC (on GE scans only); 42.5 (40.2, 44.8) and 28.4 (24.4, 32.4) for VVI; and 37.0 (34.9, 39.1) and 25.2 (21.5, 28.8) for Epsilon. Factors significantly associated with variability in LASr measurements and their beta-coefficients (95%CI) were age -2.37 (-3.41, -1.33) per 10 years, EchoPAC (versus TomTec) -9.63 (-12.75, -6.51) and Epsilon (versus TomTec) -7.04 (-9.40, -4.67). Reference ranges and factors significant associated with LAScd and LASct were reported. LA strain measurements and normal ranges by strain software and associated clinical and echocardiographic factors were determined. Conclusion EchoPAC and Epsilon has lower magnitude mean left atrial strain values compared to TomTec and VVI, and all software were vendor neutral except EchoPAC.
Modulation of PRL-1 in Placental MSCs: A Novel Therapeutic Strategy for Hepatic Fibrosis: Editorial on “Modulation of PRL-1 within placental MSCs instigates the transition between EMT and MET subsequent to hepatic fibrosis”
Authors: Lihai Jiang, Wenjie Zheng
Journal: Clinical and Molecular Hepatology (2025)

Modulation of PRL-1 in Placental MSCs: A Novel Therapeutic Strategy for Hepatic Fibrosis: Editorial on "Modulation of PRL-1 within placental MSCs instigates the transition between EMT and MET subsequent to hepatic fibrosis"
Myocardial ketone body oxidation contributes to empagliflozin‐induced improvements in cardiac contractility in murine heart failure
Authors: Suzanne Nathalie Voorrips, Constantin Laurent Palm, Huitzilihuitl Saucedo‐Orozco, Belend Mahmoud, Elisabeth Marloes Schouten, Anna M. Feringa, Pablo I. Sanchez‐Aguilera, Kirsten T. Nijholt, Salva R. Yurista, Peter van der Meer, Herman H.W. Silljé, B. Daan Westenbrink
Journal: European Journal of Heart Failure (2025)

Abstract Aims Sodium–glucose cotransporter 2 inhibitors (SGLT2i) improve cardiac performance and clinical outcomes in patients with heart failure, yet mechanisms underlying these beneficial effects remain incompletely understood. We sought to determine whether SGLT2i‐induced improvements in cardiac function are dependent on increased cardiac oxidation of ketone bodies. Methods and results We employed a mouse model with a cardiac‐specific knock‐out of the enzyme D‐β‐hydroxybutyrate dehydrogenase‐1 (BDH1 cko ), rendering mice incapable of oxidizing the principal ketone body β‐hydroxybutyrate in cardiomyocytes. Male BDH1 cko and littermate controls underwent either permanent coronary artery ligation of the left anterior descending coronary artery to induce myocardial infarction (MI) or sham surgery. Two weeks after surgery, mice were randomized to 6 weeks of empagliflozin or vehicle treatment. Cardiac function was assessed using transthoracic echocardiography before and after treatment, and histological and molecular analyses were performed after sacrifice. Empagliflozin treatment resulted in a twofold increase in circulating ketone bodies. Mean infarct size (36 ± 4% of the left ventricle) was comparable among MI groups. In control mice, empagliflozin treatment resulted in a significant increase in left ventricular ejection fraction (LVEF) whereas LVEF remained stable in the vehicle treated group (ΔLVEF −1.1 ± 2.2% vs. 5.2 ± 1.5%, p &lt; 0.05). Empagliflozin did not influence cardiac contractility in BDH1 cko mice (ΔLVEF −5.9 ± 2.1% vs. −1.5 ± 2.8%, p = 0.213). Other echocardiographic, histological and molecular signatures of adverse myocardial remodelling were not affected by empagliflozin treatment. Conclusion The beneficial effects of empagliflozin on cardiac contractility in post‐MI heart failure are attenuated in mice which are incapable of oxidizing the ketone body β‐hydroxybutyrate in their hearts. These findings suggest that enhanced cardiac ketone body oxidation contributes to the cardioprotective effects of SGLT2i.
Update on preclinical models of cancer therapy‐related cardiac dysfunction: Challenges and perspectives. A scientific statement of the Heart Failure Association (<scp>HFA</scp>) of the <scp>ESC</scp>, the <scp>ESC</scp> Council of Cardio‐Oncology, and the <scp>ESC</scp> Working Group on Cellular Biology of the Heart
Authors: Alessandra Ghigo, Pietro Ameri, Aarti Asnani, Edoardo Bertero, Rudolf A. de Boer, Dimitrios Farmakis, Arantxa González, Stephane Heymans, Borja Ibáñez, Teresa López‐Fernández, Alexander R. Lyon, Piero Pollesello, Amina Rakisheva, Konstantinos Stellos, Katrin Streckfuss‐Bömeke, Carlo Gabriele Tocchetti, Thomas Thum, Peter van der Meer, Eva Van Rooij, Piotr Ponikowski, Marco Metra, Giuseppe Rosano, Sophie Van Linthout
Journal: European Journal of Heart Failure (2025)

New anticancer therapies with potential cardiovascular side effects are continuously being introduced into clinical practice, with new and often unexpected toxicities becoming apparent only after clinical introduction. These unknown toxicities should be identified and understood beforehand to better prepare patients and physicians, enabling the implementation of effective treatments. Therefore, there is a crucial need for appropriate preclinical models to understand the biological basis of their cardiotoxicity. This scientific statement summarizes the preclinical models hitherto used, from in vitro two‐ and three‐dimensional human systems to small and large animals, to pinpoint the molecular mechanisms behind the cardiotoxicity of new‐generation anticancer therapies, particularly immunotherapies, and to develop potential cardioprotective strategies. Furthermore, it discusses how preclinical models have contributed to the provocative concept of heart failure being potentially tumorigenic and how the discovery of drugs with both anticancer and cardioprotective actions has revealed a common mechanistic basis for heart failure and cancer. Finally, it discusses the existing gaps between preclinical models and clinical observations in patients, how these discrepancies affect regulatory pathways and the drug development process in cardio‐oncology and provides recommendations for closing these gaps.
Methylation Profiles Differ According to Clinical Characteristics in Well-Differentiated Neuroendocrine Tumors of the Lung
Authors: Philipp Melhorn, Erwin Tomasich, Alissa Blessing, Luka Brcic, Angelika Kogler, Alexander Draschl, Peter Mazal, Anna Sophie Berghoff, Markus Raderer, Matthias Preusser, Gerwin Heller, Barbara Kiesewetter
Journal: Endocrine Pathology (2025)

Abstract Neuroendocrine tumors (NET) of the lung constitute a rare entity of primary lung malignancies that often exhibit an indolent clinical course. Epigenetics-related differences have been described previously for lung NET, but the clinical significance remains unclear. In this study, we performed genome-wide methylation analysis using the Infinium MethylationEPIC BeadChip technology on FFPE tissues from lung NET treated at two academic centers. We aimed to investigate the methylation profiles of known prognostic subgroups. In total, 54 tissue samples from primary lung NET were analyzed, of which 37 were typical carcinoids (TC) and 17 atypical carcinoids (AC). Overall, 25/53 patients (47.2%) developed metastases throughout the disease course, 14/26 (53.8%) had a positive somatostatin receptor (SSTR) scan, and 7/28 patients (25.0%) had documented endocrine activity. Analysis of the DNA methylation data showed substantial differences between TC and AC samples and revealed three distinct clusters (C1–C3): C3 ( n = 29) with 100% TC and 89.7% non-metastasized, C2 ( n = 22) with 63.6% AC and 95.5% metastasized, and C1 with three AC samples (2/3 metastasized). In subgroup analyses, distinct methylation patterns were observed based on histology, metastases, SSTR status, and endocrine activity. In the functional gene classification, the genes affected by differential methylation were mainly involved in cell signaling. DNA methylation could potentially aid in the diagnostic process of lung NET. The differences in methylation observed with respect to clinical features like SSTR expression and endocrine activity could translate into improved management of lung NET.
AI in Histopathology Explorer for comprehensive analysis of the evolving AI landscape in histopathology
Authors: Yingrui Ma, Shivprasad Jamdade, Lakshmi Konduri, Heba Sailem
Journal: npj Digital Medicine (2025)

Abstract Digital pathology and artificial intelligence (AI) hold immense transformative potential to revolutionize cancer diagnostics, treatment outcomes, and biomarker discovery. Gaining a deeper understanding of deep learning algorithm methods applied to histopathological data and evaluating their performance on different tasks is crucial for developing the next generation of AI technologies. To this end, we developed AI in Histopathology Explorer (HistoPathExplorer); an interactive dashboard with intelligent tools available at www.histopathexpo.ai . This real-time online resource enables users, including researchers, decision-makers, and various stakeholders, to assess the current landscape of AI applications for specific clinical tasks, analyze their performance, and explore the factors influencing their translation into practice. Moreover, a quality index was defined for evaluating the comprehensiveness of methodological details in published AI methods. HistoPathExplorer highlights opportunities and challenges for AI in histopathology, and offers a valuable resource for creating more effective methods and shaping strategies and guidelines for translating digital pathology applications into clinical practice.