tbuckley/cabot-search huggingface dataset:
Pyroptotic cell corpses are crowned with F-actin-rich filopodia that engage CLEC9A signaling in incoming dendritic cells
Authors: Caroline L. Holley, Mercedes Monteleone, Daniel Fisch, Alexandre E. S. Libert, Robert J. Ju, Joon H. Choi, Nicholas D. Condon, Stefan Emming, Joanna Crawford, Grace M. E. P. Lawrence, Jared R. Coombs, James G. Lefevre, Rinie Bajracharya, Mireille H. Lahoud, Alpha S. Yap, Nicholas Hamilton, Samantha J. Stehbens, Jonathan C. Kagan, Nicholas Ariotti, Sabrina S. Burgener, Kate Schroder
Journal: Nature Immunology (2024)

Abstract While apoptosis dismantles the cell to enforce immunological silence, pyroptotic cell death provokes inflammation. Little is known of the structural architecture of cells undergoing pyroptosis, and whether pyroptotic corpses are immunogenic. Here we report that inflammasomes trigger the Gasdermin-D- and calcium-dependent eruption of filopodia from the plasma membrane minutes before pyroptotic cell rupture, to crown the resultant corpse with filopodia. As a rich store of F-actin, pyroptotic filopodia are recognized by dendritic cells through the F-actin receptor, CLEC9A (DNGR1). We propose that cells assemble filopodia before cell rupture to serve as a posthumous mark for a cell that has died by gasdermin-induced pyroptosis, or MLKL-induced necroptosis, for recognition by dendritic cells. This study reveals the spectacular morphology of pyroptosis and identifies a mechanism by which inflammasomes induce pyroptotic cells to construct a de novo alarmin that activates dendritic cells via CLEC9A, which coordinates the transition from innate to adaptive immunity 1,2 .
A multimodal machine learning model for the stratification of breast cancer risk
Authors: Xuejun Qian, Jing Pei, Chunguang Han, Zhiying Liang, Gaosong Zhang, Na Chen, Weiwei Zheng, Fanlun Meng, Dongsheng Yu, Yixuan Chen, Yiqun Sun, Hanqi Zhang, Wei Qian, Xia Wang, Zhuoran Er, Chenglu Hu, Hui Zheng, Dinggang Shen
Journal: Nature Biomedical Engineering (2024)
Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes
Authors: Jiang-An Yin, Lukas Frick, Manuel C. Scheidmann, Tingting Liu, Chiara Trevisan, Ashutosh Dhingra, Anna Spinelli, Yancheng Wu, Longping Yao, Dalila Laura Vena, Britta Knapp, Jingjing Guo, Elena De Cecco, Kathi Ging, Andrea Armani, Edward J. Oakeley, Florian Nigsch, Joel Jenzer, Jasmin Haegele, Michal Pikusa, Joachim Täger, Salvador Rodriguez-Nieto, Vangelis Bouris, Rafaela Ribeiro, Federico Baroni, Manmeet Sakshi Bedi, Scott Berry, Marco Losa, Simone Hornemann, Martin Kampmann, Lucas Pelkmans, Dominic Hoepfner, Peter Heutink, Adriano Aguzzi
Journal: Nature Biomedical Engineering (2024)

Abstract Arrayed CRISPR libraries extend the scope of gene-perturbation screens to non-selectable cell phenotypes. However, library generation requires assembling thousands of vectors expressing single-guide RNAs (sgRNAs). Here, by leveraging massively parallel plasmid-cloning methodology, we show that arrayed libraries can be constructed for the genome-wide ablation (19,936 plasmids) of human protein-coding genes and for their activation and epigenetic silencing (22,442 plasmids), with each plasmid encoding an array of four non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms. The quadruple-sgRNA libraries yielded high perturbation efficacies in deletion (75–99%) and silencing (76–92%) experiments and substantial fold changes in activation experiments. Moreover, an arrayed activation screen of 1,634 human transcription factors uncovered 11 novel regulators of the cellular prion protein PrP C , screening with a pooled version of the ablation library led to the identification of 5 novel modifiers of autophagy that otherwise went undetected, and ‘post-pooling’ individually produced lentiviruses eliminated template-switching artefacts and enhanced the performance of pooled screens for epigenetic silencing. Quadruple-sgRNA arrayed libraries are a powerful and versatile resource for targeted genome-wide perturbations.
Metastatic Prostate Carcinoma to the Ankle Seen on Bone Scintigraphy and Extended Field-of-View PSMA PET/CT
Authors: Nir Hod, Noa Shani Shrem, Daniel Levin
Journal: Clinical Nuclear Medicine (2024)

Abstract We describe a rare case of metastatic prostate carcinoma to the heel. Bone scintigraphy revealed high uptake simulating fractures. Standard PSMA PET/CT was negative. As PSA elevated, extended field-of-view PET/CT revealed ankle uptake with virtually identical spatial distribution and intensity of both tracers. Histopathology confirmed ankle metastases of prostate carcinoma, which retrospectively was the inaugural manifestation of the metastatic skeletal disease. This case highlights the need to consider peripheral limb bone metastases in patients with biochemical recurrence. In case of focal symptoms or unexplained bone scan findings, the PSMA acquisition coverage should be extended to include the respective body part.
PSMA Accumulation in Lower Extremity Lymphedema and Hydrocele
Authors: Merve Nida Calderon Tobar, Lutfi Perktas, Hasan Önner
Journal: Clinical Nuclear Medicine (2024)

Abstract The development of radiolabeled small-molecule prostate-specific membrane antigen (PSMA) inhibitors has advanced molecular imaging in prostate cancer. The use of 177 Lu-PSMA is especially beneficial because its therapeutic β-emission combined with γ-radiation enables precise treatment and comprehensive imaging in patients with prostate cancer. We present a case of a prostate cancer patient who developed lower extremity lymphedema and hydrocele secondary to prior radiotherapy. Posttherapy whole-body imaging following 177 Lu-PSMA treatment revealed dermal backflow with a notable accumulation of soft tissue in the lower extremities and hydrocele.
Limitations of athlete-exposures as a construct for comparisons of injury rates by gender/sex: a narrative review
Authors: Ann Caroline Danielsen, Annika Gompers, Sheree Bekker, Sarah S. Richardson
Journal: British Journal of Sports Medicine (2024)

High rates of anterior cruciate ligament (ACL) injuries in girls’ and women’s sports have garnered significant attention from researchers, sport organisations and the media. Gender/sex disparities in ACL injury rates are often estimated using the construct of athlete-exposures (AEs), a widely used measure of exposure time in sports science and epidemiology that is defined as one athlete participating in one practice or competition. In this narrative review, we explain the limitations of AEs as a measure of exposure time and develop a series of conceptual critiques regarding the use of AEs for the purposes of comparing injury rates by gender/sex. We show that the differing training-to-match ratio and average team size between women and men—rooted in persistent gendered inequities in sports participation and professionalisation—may jeopardise the validity of using AEs for cross-gender comparisons and skew gender/sex disparities in ACL injury rates. To avoid bias, we invite researchers interested in gender/sex disparities in injury rates to collect finer-grained data including individual-level AEs disaggregated by training and competition, as well as to appropriately control for team size and training-to-match ratio at the data analysis stage. Any quantitative comparisons of injury rates should also thoroughly contextualise the limitations of AEs, including their inability to capture the potential qualitative differences between women’s and men’s training and sporting environments that may influence injury rates.
GSK3β Deficiency Expands Obese Adipose Vasculature to Mitigate Metabolic Disorders
Authors: Li Wang, Jiajia Li, Ping Tang, Dongliang Zhu, Lixin Tai, Yuan Wang, Tsukiko Miyata, James R. Woodgett, Li-jun Di
Journal: Circulation Research (2024)

BACKGROUND: Maintaining a well-developed vascular system alongside adipose tissue (AT) expansion significantly reduces the risk of metabolic complications. Although GSK3β (glycogen synthase kinase-3 beta) is known for its role in various cellular processes, its specific functions in AT and regulation of body homeostasis have not been reported. METHODS: GSK3β-floxed and GSK3α-floxed mice were crossed with adiponectin-Cre mice to generate GSK3β or GSK3α adipocyte-specific knockout mice (GSK3β ADKO and GSK3α ADKO ). A comprehensive whole-body metabolism analysis was performed on obese GSK3β ADKO mice induced by a high-fat diet. RNA sequencing was conducted on AT of both obese GSK3β ADKO and GSK3α ADKO mice. Various analyses, including vessel perfusion studies, lipolysis analysis, multiplex protein assays, in vitro protein phosphorylation assays, and whole-mount histology staining, were performed on AT of obese GSK3β ADKO mice. Tube-formation experiments were performed using 3B-11 endothelial cells cultured in the conditional medium of matured adipocytes under hypoxic conditions. Chromatin precipitation and immunofluorescence studies were conducted using cultured adipocytes with GSK3 inhibition. RESULTS: Our findings provide the first evidence that adipocyte-specific knockout of GSK3β expands AT vascularization and mitigates obesity-related metabolic disorders. GSK3β deficiency, but not GSK3α, in adipocytes activates AMPK (AMP-activated protein kinase), leading to increased phosphorylation and nuclear accumulation of HIF-2α, resulting in enhanced transcriptional regulation. Consequently, adipocytes increased VEGF (vascular endothelial growth factor) expression, which engages VEGFR2 on endothelial cells, promoting angiogenesis, expanding the vasculature, and improving vessel perfusion within obese AT. GSK3β deficiency promotes AT remodeling, shifting unhealthy adipocyte function toward a healthier state by increasing insulin-sensitizing hormone adiponectin and preserving healthy adipocyte function. These effects lead to reduced fibrosis, reactive oxygen species, and ER (endoplasmic reticulum) stress in obese AT and improve metabolic disorders associated with obesity. CONCLUSIONS: Deletion of GSK3β in adipocytes activates the AMPK/HIF-2α/VEGF/VEGFR2 axis, promoting vasculature expansion within obese AT. This results in a significantly improved local microenvironment, reducing inflammation and effectively ameliorating metabolic disorders associated with obesity.
A Vaccine Against Fibroblast Activation Protein Improves Murine Cardiac Fibrosis by Preventing the Accumulation of Myofibroblasts
Authors: Shota Yoshida, Hiroki Hayashi, Takuro Kawahara, Shunsuke Katsuki, Mitsukuni Kimura, Rissei Hino, Jiao Sun, Ryo Nakamaru, Akiko Tenma, Masayoshi Toyoura, Satoshi Baba, Munehisa Shimamura, Tomohiro Katsuya, Ryuichi Morishita, Hiromi Rakugi, Tetsuya Matoba, Hironori Nakagami
Journal: Circulation Research (2024)

BACKGROUND: Myofibroblasts are primary cells involved in chronic response-induced cardiac fibrosis. Fibroblast activation protein (FAP) is a relatively specific marker of activated myofibroblasts and a potential target molecule. This study aimed to clarify whether a vaccine targeting FAP could eliminate myofibroblasts in chronic cardiac stress model mice and reduce cardiac fibrosis. METHODS: We coadministered a FAP peptide vaccine with a CpG K3 oligonucleotide adjuvant to male C57/BL6J mice and confirmed an elevation in the anti-FAP antibody titer. After continuous angiotensin II and phenylephrine administration for 28 days, we evaluated the degree of cardiac fibrosis and the number of myofibroblasts in cardiac tissues. RESULTS: We found that cardiac fibrosis was significantly decreased in the FAP-vaccinated mice compared with the angiotensin II and phenylephrine control mice (3.45±1.11% versus 8.62±4.79%; P =4.59×10 −3 ) and that the accumulation of FAP-positive cells was also significantly decreased, as indicated by FAP immunohistochemical staining (4077±1746 versus 7327±1741 cells/mm 2 ; FAP vaccine versus angiotensin II and phenylephrine control; P =6.67×10 − 3 ). No systemic or organ-specific inflammation due to antibody-dependent cell cytotoxicity induced by the FAP vaccine was observed. Although the transient activation of myofibroblasts has an important role in maintaining the structural robustness in the process of tissue repair, the FAP vaccine showed no adverse effects in myocardial infarction and skin injury models. CONCLUSIONS: Our study demonstrates the FAP vaccine can be a therapeutic tool for cardiac fibrosis.
BHLH Transcription Factor TCF21 Inhibits Myofibroblast Formation and Cardiac Fibrosis
Authors: Anne Katrine Z. Johansen, Rajesh K. Kasam, Ronald J. Vagnozzi, Suh-Chin J. Lin, Jose G. Gomez-Arroyo, Adenike Shittu, Stephanie L.K. Bowers, Yasuhide Kuwabara, Kelly M. Grimes, Kathrynne Warrick, Michelle A. Sargent, Tanya A. Baldwin, Susan E. Quaggin, Artem Barski, Jeffery D. Molkentin
Journal: Circulation Research (2024)

BACKGROUND: TCF21 (transcription factor 21) is a bHLH (basic helix-loop-helix) protein required for the developmental specification of cardiac fibroblasts (CFs) from epicardial progenitor cells that surround the embryonic heart. In the adult heart, TCF21 is expressed in tissue-resident fibroblasts and is downregulated in response to injury or stimuli leading to myofibroblast differentiation. These findings led to the hypothesis that TCF21 regulates fibroblast differentiation in the adult mammalian heart to affect fibrosis. METHODS: Tamoxifen-inducible Cre genetic mouse models were used to permit either Tcf21 gene deletion or its enforced expression in adult CFs. Histological and echocardiographic analyses were used, as well as transcriptomic analysis to determine the consequences of TCF21 gain-of-function and loss-of-function in vivo. Genomic Tcf21 occupancy was identified by chromatin immunoprecipitation and sequencing in CFs. Myocardial infarction and Ang II (angiotensin II)/phenylephrine served as models of cardiac fibrosis. RESULTS: Acute and long-term deletion of Tcf21 in CFs of the adult mouse heart does not alter fibroblast numbers, myofibroblast differentiation, or fibrosis. Fibroblast-specific Tcf21 gene–deleted mice demonstrate no significant alterations in cardiac function or scar formation in response to cardiac injury compared with control mice. In contrast, enforced expression of TCF21 in CFs inhibits myofibroblast differentiation and significantly reduces cardiac fibrosis and hypertrophy in response to 1 week of Ang II/phenylephrine infusion. Mechanistically, sustained TCF21 expression prevents the induction of genes associated with fibrosis and ECM (extracellular matrix) organization. CONCLUSIONS: TCF21 expression is not required to maintain the cell state of CFs in the adult heart. However, preventing the normal downregulation of TCF21 expression with injury reduces myofibroblast formation, cardiac fibrosis, and the acute cardiac hypertrophic response following 1 week of Ang II/phenylephrine stimulation.
Autoimmune-Like Mechanism in Heart Failure Enables Preventive Vaccine Therapy
Authors: Elisa Martini, Marco Cremonesi, Arianna Felicetta, Simone Serio, Simone Puccio, Erica Pelamatti, Jasper J.P. van Beek, Vasiliki Papadopoulou, Chiara Catalano, Francesca Fanuele, Desirée Giuliano, Gianluca Basso, Cecilia Assunta Bonfiglio, Cristina Panico, Marco Vacchiano, Pierluigi Carullo, Laura Papa, Carla D’Andrea, Naz Tuzger, Sergio Marchini, Paola Magistroni, Silvia Deaglio, Antonio Amoroso, Enrico Lugli, Gianluigi Condorelli, Marinos Kallikourdis
Journal: Circulation Research (2024)

BACKGROUND: Heart failure (HF) is strongly associated with inflammation. In pressure overload (PO)–induced HF, cardiac stress triggers adaptive immunity, ablation, or inhibition, which blocks disease progression. We hypothesized that PO-HF might fulfill the often-used criteria of autoimmunity: if so, the associated adaptive immune response would be not only necessary but also sufficient to induce HF; it should also be possible to identify self-antigens driving the autoimmune response. Finally, we hypothesized that such an antigen-specific response can be manipulated to preventively reduce the severity of PO-HF in a tolerizing vaccine. METHODS: We used the transfer of lymphocytes or serum from PO-HF mice into healthy recipients to assess whether the adaptive response is sufficient to induce disease. We devised a novel pipeline to identify self-antigens driving the response. We immunized healthy mice with novel antigens to assess whether they induce disease. To determine whether these antigens could be present in human patients, we sought to detect existing responses against these antigens in patients with HF. Finally, we used the antigens in an oral tolerance protocol to preventively protect mice from subsequently induced PO-HF, analyzing the results with next-generation sequencing. RESULTS: We found that PO-HF fulfills the criteria of an autoimmune disease, albeit partially, and identified novel cardiac self-antigens, capable of inducing cardiac dysfunction. The novel antigens in a tolerizing vaccine formulation preemptively reduced the severity of disease triggered by subsequent application of PO, via induction of effector regulatory T cells, enabling a potent reduction of PO-driven loss of systolic function, cardiac inflammation, and proinflammatory CD4 + T-cell clonal expansion. CONCLUSIONS: We demonstrate that PO-HF is triggered by hemodynamic stress and then sets off an autoimmune-like response against cardiac self-antigens. The antigens can be used to reduce the severity of future-onset disease, via oral tolerization, effectively acting as a protective vaccine.
Sodium Butyrate‐Loaded Microspheres With Enhanced Bioavailability for Targeted Treatment of Intestinal Barrier Injury
Authors: Yanwei Lv, Mengni Jiang, Yongliang Ouyang, Xiaoyi Zheng, Liang Zhang, Jinpeng Yao, Lianghao Hu, Jiulong Zhao, Zhaoshen Li, Shige Wang
Journal: Advanced Healthcare Materials (2024)

Abstract Intestinal barrier dysfunction is related to diseases such as inflammatory bowel disease (IBD) and severe acute pancreatitis (SAP). Butyrate and its derivatives (e.g., sodium butyrate (SB)) can alleviate gut inflammatory responses. Nevertheless, these substances usually cannot fully exert protective effects due to low bioavailability. This research aimed to offer microspheres for treating intestinal barrier injury. Sodium alginate solution is prepared to dissolve SB, followed by mixing with chitosan (CS)‐protocatechuic aldehyde (PA)/calcium chloride solution. The required CS‐PA/calcium alginate/SB (CPC/SB) microspheres are formed in this manner. Subsequently, the therapeutic effects of CPC/SB microspheres on intestinal barrier injury through in vivo dextran sulfate sodium salt (DSS)‐induced IBD and sodium taurocholate (STC)‐induced SAP models is explored. Results: The CPC/SB microspheres exhibited excellent antioxidant properties. In vivo bioluminescence imaging experiment confirmed the microspheres effectively targeted the inflammatory gut in IBD. Further in vivo experimental results indicated the microspheres significantly repaired intestinal barrier damage, exerting protective effects in IBD and SAP. Additionally, 16S rDNA sequencing explained the microspheres can regulate the balance between harmful and beneficial bacteria (such as Alistipes, Odoribacter, and Rikenellaceae RC9). This study provides a possible synthetic strategy of microsphere carriers to serve as a potential therapeutic tool for intestinal barrier injury.
Delivery of Encapsulated Intelligent Engineered Probiotic for Inflammatory Bowel Disease Therapy
Authors: Zhen‐Ping Zou, Zhihao Cai, Xiao‐Peng Zhang, Donghui Zhang, Chu‐Ying Xu, Ying Zhou, Runhui Liu, Bang‐Ce Ye
Journal: Advanced Healthcare Materials (2024)

Abstract Engineered bacterial therapy holds enormous potential for treating intestinal diseases, employing synthetic biology techniques to achieve localized drug delivery within intestines. However, effective delivery of engineered bacteria to lesion sites and ensuring sustained colonization remain challenging. Here, a mucus encapsulated microsphere gel (MM) delivery system is developed to encapsulate genetically engineered bacteria capable of detecting and treating enteritis. The MM delivery system features an external mucosal coating composed of hyaluronic acid and epigallocatechin gallate, along with internal microspheres of highly biocompatible polyserine modified alginates encapsulating with the engineered probiotics. The MM delivery system effectively protects engineered bacteria harsh environment in stomach and significantly improves intestinal adhesion of the probiotics, extending colonization up to 24 h, and does not affect the entry of biomarker or release of Avcystatin. It exhibits notable diagnostic and therapeutic efficacy in inflammatory bowel disease models, thus facilitating the advancement of live biotherapeutic products toward clinical application.
Molecular Engineering of Ultrabright Biomimetic NanoGhost for Site‐Selective Tumor Imaging and Biodistribution
Authors: Rajendra Prasad, Kumari Prerna, Mayur Temgire, Pinaki Banerjee, Rohini Kumari, Gopal C Kundu, Deeksha Hattila, Chandrashekhar Venkaraddi Mangannavar, Avtar Singh Meena, Mahadeo Gorain, Jayesh Bellare, Pranjal Chandra, Vikash Kumar Dubey
Journal: Advanced Healthcare Materials (2024)

Abstract Optically active ultrabright imaging agents are shown to delineate tumor location with deep tissue visualization in pre noclinical tumor models. NanoGhosts (NGs) particles are reconstructed from the cell membrane and integrated with organic fluorophores to attain ultra‐brightness for solid tumor imaging. Moreover, the integration of amphiphilic and lipophilic molecules reveals structural characteristics of NGs (≈70 nm), which also alter their brightness. Upon intravenous administration (10 mg kg −1 single dose), these ultrabright NGs (778 MESF) enable the high‐resolution of tumor site and real‐time tracking of vital organs with high‐contrast fluorescence signals. Engineered biomimetic NGs demonstrates better resolution and tissue penetration as compared to the clinically approved indocyanine green (ICG). High precision in tumor detection (0.5 h) and strong tumor retention (24 h which is further up to 30 th day) without affecting healthy tissues ensure the future scope of NGs in early‐stage cancer imaging. These findings suggest that these NGs mimic the biological characteristics of native cells, enabling them to evade immune clearance and target the solid tumor naturally.
Locally Injectable, ROS‐Scavenging, and ROS‐/pH‐Responsive Polymeric‐Micelles‐Embedded Hydrogels for Precise Minimally Invasive and Long‐Lasting Rheumatoid Therapy
Authors: Xinhua Liu, Xing Chen, Yifan Fei, Jiamin Zhang, Ouyang Yue, Xuechuan Wang, Huie Jiang
Journal: Advanced Healthcare Materials (2024)

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovitis, bone‐erosion, and joint‐destruction. Here, we developed a locally injectable, ROS‐scavenging, and ROS‐/pH‐responsive drug‐delivery platform (HC@PTM) by bio‐compositing of aldolizing hyaluronic acid (HA) crosslinked with chitosan (CS), and ROS‐triggered/eliminated micelles (PTM) coupled with the drug methotrexate(MTX). The PTM efficiently eradicate excessive ROS in RA‐joints, precisely triggering drug‐release within inflamed arthritic‐sites and further confer exceptional antioxidant origins to HC@PTM. HC@PTM with outstanding shape‐adaptability and self‐repairing properties effectively conformed to irregular articular cartilage while resisting joint‐induced deformations. Further, the platform's pH‐responsive nature enables on‐demand drug‐release within acidic inflamed synovium, serving as a drug‐reservoir for precise and sustained therapeutic effects. Extensive in vitro and in vivo investigations confirm HC@PTM's ability to induce M2 macrophage polarization, downregulate inflammatory factor expression, and ameliorate the RA‐microenvironment, ultimately achieving synergistic therapeutic outcomes. This study represents significant advancements in precise and long‐term RA‐treatment through a minimally invasive approach, offering potential strategies for novel precision medicine.