tbuckley/cabot-search huggingface dataset:
Voclosporin Overdose-Induced Peroxisomal Structural Changes and AKI Are Prevented by Renal Indole Detoxifier, INMT
Authors: Kazuhiro Hasegawa, Yusuke Sakamaki, Masanori Tamaki, Shu Wakino
Journal: Journal of the American Society of Nephrology (2025)

Background: The novel calcineurin inhibitor (CNI) voclosporin is effective in treating lupus nephritis but has been associated with acute kidney injury (AKI) through largely unknown mechanisms. Voclosporin-induced AKI revealed that voclosporin reduces the expression of indolethylamine N-methyltransferase (Inmt), an enzyme responsible for detoxifying local uremic toxins such as indole. This study investigates whether Inmt overexpression can protect against high-dose voclosporin-induced AKI. This study used genetically engineered mice to explore the role of Inmt in voclosporin-induced AKI. Methods: Transgenic mice overexpressing Inmt and conditional knockout (conditional KO) mouse models were used assess renal proximal tubule–specific Inmt function. Gene expression changes, apoptotic cell percentages, and mitochondrial DNA copy numbers were examined through RNA sequencing, histopathology, and various molecular assays. These analyses were further complemented with immunofluorescence and electron microscopy to investigate cellular and structural changes. Human clinical specimens were also investigated. Results: Inmt downregulation in high-dose voclosporin-induced AKI was associated with reduced peroxisome and mitochondrion numbers and function, increased production of reactive oxygen species, and increased tubular apoptosis, as observed in conditional KO mice. However, in transgenic mice treated with voclosporin, peroxisomal and mitochondrial integrity were preserved. Notably, electron microscopy revealed that the structural peroxisomal changes observed in mouse and human CNI-induced AKI specimens were reversed in high-dose voclosoprin-treated transgenic mice. Overall, proximal tubule–specific Inmt overexpression protects against high-dose voclosporin-induced AKI by promoting catalase upregulation, reducing H 2 O 2 levels, and restoring peroxisomal function. Conclusions: Inmt overexpression in proximal tubules prevented high-dose voclosporin-induced structural changes and AKI.
RNA Alternative Splicing and Polyadenylation and Regulation of the Glomerular Filtration Barrier
Authors: Monoj K. Das, Amy Webb, Mahika Yarram, Christian Reilly, Lalith Punepalle, Claire Bryant, Rajgopal Govindarajan, Claire L. Moore, Shipra Agrawal
Journal: Journal of the American Society of Nephrology (2025)

Background: Glomerular disease, characterized by podocyte injury and proteinuria, can lead to CKD and end-stage kidney disease. We hypothesized that the glomerular pathophysiology is associated with mRNA alternative splicing and polyadenylation of glomerular genes and of critical podocyte and slit diaphragm components that regulate the filtration barrier. Methods: Glomerular damage, accompanied by proteinuria, was induced by puromycin-aminonucleoside or adriamycin to mimic human minimal change disease or FSGS, respectively, and RNA-seq analyses was performed. Alternatively spliced and polyadenylated events through differential exon and poly(A) site usage were queried in JunctionSeq and APATrap pipelines. These events were further mapped on podocyte and glomerular landscape, analyzed and modulated for slit diaphragm components, and cis- and trans-regulatory elements were identified. Results: Altered glomerular mRNA processing by alternative splicing/polyadenylation was identified in 136/71 and 1875/746 genes in minimal change disease and FSGS models, respectively. Transcript annotation and prioritization of significant alternative splicing and polyadenylation identified key events in several podocyte and slit diaphragm genes with novel and established roles. Alternative splicing of critical slit diaphragm components, the junction protein TJP1/ZO1 and microtubule associating protein ITM2B was further characterized. Alternative polyadenylation of core members of the slit diaphragm, NPHS1 , NPHS2 and NEPH1 was analyzed with potential alteration of microRNA binding sites between the proximal vs distal poly (A) site usage in their mRNAs. Concomitantly, dysregulation of trans-regulatory elements (polyadenylation and splicing factors), was discovered in these models of nephropathies. Additionally, beneficial proteinuria-reducing treatments, pioglitazone and GQ16 reversed many alternatively spliced and polyadenylated events. Moreover, GWAS SNPs as potential cis-regulatory elements were identified in several genes from the human nephrotic syndrome database. Finally, we demonstrated proof-of-concept principle of chemically modified splice switching oligonucleotides in modulating TJP1 splicing in podocytes. Conclusions: Findings from our studies identified that glomerular pathophysiology and disruption of the filtration barrier is associated with alternative splicing and polyadenylation of glomerular genes, many of which are crucial determinants of podocyte structure and function and the slit diaphragm complex.
mTORc1 in Distal Convoluted Tubule (DCT) and Renal Potassium (K+) Handling
Authors: Yu Xiao, Xin-Peng Duan, Cheng-Biao Zhang, Wen-Hui Wang, Dao-Hong Lin
Journal: Journal of the American Society of Nephrology (2025)

Background: Mechanistic-target-of-rapamycin-complex-1 (mTORc1) plays a role in maintaining K + homeostasis. We now examine whether mTORc1 of distal-convoluted-tubule (DCT) regulates Kir4.1/Kir5.1 channels and thiazide-sensitive-Na-Cl cotransporter, which plays a role in regulating renal K + excretion. Methods: We used patch-clamp-technique to examine basolateral Kir4.1/Kir5.1 in early-DCT, immunoblotting to examine NCC expression and in vivo measurement of urinary K + -excretion to determine baseline renal K + -excretion (E K ) in the mice treated with rapamycin and in DCT-specific r egulatory- a ssociated- p rotein-of-mechanisticc- t arget- o f- r apamycin knockout mice (DCT-RAPTOR-KO). Results: Application of rapamycin decreased Kir4.1/Kir5.1-mediated K + -currents and depolarized DCT-membrane-potential in Fkbp1a flox/flox mice. However, the effect of rapamycin on Kir4.1/Kir5.1 was absent in kidney-specific-FKBP12-knockout mice (Ks-FKBP12-KO). Rapamycin decreased basolateral 40-pS K + -channel activity (Kir4.1/Kir5.1 heterotetramer) of the DCT. This effect was absent in the DCT treated with H 2 O 2 which stimulated the 40-pS K + -channel activity, suggesting the role of reactive-oxygen-species (ROS) in mediating the effect of mTORc1 on Kir4.1/Kir5.1. Rapamycin treatment significantly decreased the abundance of both phosphorylated-NCC and total-NCC in Fkbp1a flox/flox mice but not in Ks-FKBP12-KO mice. Moreover, in vivo measurement of urinary Na + -excretion and urinary K + -excretion demonstrated that rapamycin treatment decreased hydrochlorothiazide-induced natriuresis but increased renal K + -excretion in Fkbp1a flox/flox mice. Moreover, Kir4.1/Kir5.1 mediated K + -currents of the DCT were lower and DCT membrane potential was less negative in DCT-RAPTOR-KO than those of Ncc-Cre-Raptor flox/flox mice. Also, the abundance of phosphorylated-NCC was lower in DCT-RAPTOR-KO mice than Ncc-Cre-Raptor flox/flox mice. In contrast, the abundance of phosphorylated-NKCC2 was the same between two genotypes while cleaved αENaC abundance was higher in DCT-RAPTOR-KO mice than Ncc-Cre-Raptor flox/flox mice. Consequently, DCT-RAPTOR-KO mice had a higher urinary K + -excretion and lower plasma K + concentrations than Ncc-Cre-Raptor flox/flox . Conclusions: mTORc1 in the DCT plays a significant role in maintaining K + homeostasis by controlling the basolateral Kir4.1/Kir5.1 of the DCT and NCC.
Enhanced piezocatalytic therapy of MRSA-infected osteomyelitis using ultrasound-triggered copper nanocrystals-doped barium titanate
Authors: Yang Wu, Bei Chen, Xia Chen, Guoqiang Zhu, Wei Du, Liming Qing, Panfeng Wu, Zhenxing Wang, Juyu Tang, Hui Xie
Journal: Bioactive Materials (2025)
In vivo CRISPR activation screen identifies acyl-CoA–binding protein as a driver of bone metastasis
Authors: Hongqi Teng, Qinglei Hang, Caishang Zheng, Yuelong Yan, Shaomin Liu, Yang Zhao, Yalan Deng, Litong Nie, Weiche Wu, Marisela Sheldon, Zachary Yu, Wei Shi, Jianxuan Gao, Chenling Meng, Consuelo Martinez, Jie Zhang, Fan Yao, Yutong Sun, Di Zhao, Boyi Gan, Tong Meng, Li Ma
Journal: Science Translational Medicine (2025)

One of the most common sites of cancer metastasis is to the bone. Bone metastasis is associated with substantial morbidity and mortality, and current therapeutic interventions remain largely palliative. Metastasizing tumor cells need to reprogram their metabolic states to adapt to the nutrient environment of distant organs; however, the role and translational relevance of lipid metabolism in bone metastasis remain unclear. Here, we used an in vivo CRISPR activation screening system coupled with positive selection to identify acyl–coenzyme A (CoA) binding protein (ACBP) as a bone metastasis driver. In nonmetastatic and weakly metastatic cancer cells, overexpression of wild-type ACBP, but not the acyl-CoA–binding deficient mutant, stimulated fatty acid oxidation (FAO) and bone metastasis. Conversely, knockout of ACBP in highly bone metastatic cancer cells abrogated metastatic bone colonization. Mechanistically, ACBP-mediated FAO increased ATP and NADPH production, reduced reactive oxygen species, and inhibited lipid peroxidation and ferroptosis. We found that ACBP expression correlated with metabolic signaling, bone metastatic ability, and poor clinical outcomes. In mouse models, pharmacological blockade of FAO or treatment with a ferroptosis inducer inhibited bone metastasis. Together, our findings reveal the role of lipid metabolism in tumor cells adapting and thriving in the bone and identify ACBP as a key regulator of this process. Agents that target FAO or induce ferroptosis represent a promising therapeutic approach for treating bone metastases.
Human monoclonal antibodies targeting subdominant meningococcal antigens confer cross-protection against gonococcus
Authors: Marco Troisi, Monica Fabbrini, Samuele Stazzoni, Viola Viviani, Filippo Carboni, Valentina Abbiento, Lucia Eleonora Fontana, Sara Tomei, Martina Audagnotto, Laura Santini, Angela Spagnuolo, Giada Antonelli, Ida Paciello, Fabiola Vacca, Dario Cardamone, Eleonora Marini, Pardis Mokhtary, Francesca Finetti, Fabiola Giusti, Margherita Bodini, Giulia Torricelli, Chiara Limongi, Mariangela Del Vecchio, Sara Favaron, Simona Tavarini, Chiara Sammicheli, Alessandro Rossi, Andrea Paola Mandelli, Pietro Fortini, Carla Caffarelli, Stefano Gonnelli, Ranuccio Nuti, Adriana Efron, Cosima T. Baldari, Claudia Sala, Aldo Tagliabue, Silvana Savino, Brunella Brunelli, Nathalie Norais, Elisabetta Frigimelica, Monia Bardelli, Mariagrazia Pizza, Immaculada Margarit, Isabel Delany, Oretta Finco, Emanuele Andreano, Rino Rappuoli
Journal: Science Translational Medicine (2025)

Gonococcus, a bacterium resistant to most antibiotics, causes more than 80 million cases of gonorrhea annually and is considered a high-priority pathogen by the World Health Organization. Recently, vaccine development prospects were boosted by reports that licensed meningococcus serogroup B (MenB) vaccines provided partial protection against gonococcal infection. To determine antigens responsible for cross-protection, memory B cells isolated from 4CMenB-vaccinated volunteers were single cell–sorted to identify antibodies that kill gonococcus in a bactericidal assay. Nine different antibodies, all deriving from the IGHV4-34 germline and carrying an unusually long heavy-chain complementarity-determining region 3, recognized the PorB protein; four others recognized the lipooligosaccharide; and another four had unknown specificity. One of the PorB-specific antibodies provided protection in a mouse model of gonococcus infection. The identification of PorB and lipooligosaccharide as key antigens of gonococcal and meningococcal immunity provides a mechanistic explanation of the cross-protection observed in the clinic and shows that isolating human monoclonal antibodies from vaccinees can be instrumental for bacterial antigen discovery.
Islet transplantation in immunomodulatory nanoparticle–remodeled spleens
Authors: Mi Liu, Huiming Deng, Chunyan Liu, Lintao Wang, Zhongkai Liao, Desheng Li, Yan Chen, Jianhui Li, Jianhui Dong, Xuyong Sun, Chunming Wang, Ling Huang, Lei Dong, Jian Xiao
Journal: Science Translational Medicine (2025)

Islet transplantation is a promising therapy for insulin-dependent diabetes. However, immune rejection and insufficient vascularization hinder the survival and function of transplanted islets. Here, we show effective engraftment of vascularized and functional mouse and rat islets transplanted into biomaterial-remodeled spleens of nonimmunosuppressed rodents and human islets transplanted into the remodeled spleens of nonhuman primates (NHPs) on varying degrees of immunosuppression. We found evidence that konjac glucomannan–modified silica nanoparticles (KSiNPs) remodeled the spleen into an extracellular matrix (ECM)–rich, immunosuppressive niche to support the survival of syngeneic or xenogeneic islets. Transplanted islets in the remodeled spleens showed improved engraftment, neovascularization, and functionality and restored normoglycemia in streptozotocin (STZ)–induced type 1 diabetic models in the mice and macaques, with stable insulin and C-peptide secretion in mice for 90 days and macaques for 28 days. KSiNP injection and islet transplantation into macaque spleens under B-ultrasound guidance were preclinically feasible. These findings highlight the safety and effectiveness of spleen tissue remodeling in supporting the survival and function of transplanted islets, providing a promising strategy for treating type 1 diabetes mellitus (T1DM).
SARS-CoV-2 induces neutrophil degranulation and differentiation into myeloid-derived suppressor cells associated with severe COVID-19
Authors: Leon L. Hsieh, Elizabeth A. Thompson, Nirvani P. Jairam, Katerina Roznik, Alexis Figueroa, Tihitina Aytenfisu, Weiqiang Zhou, Naina Gour, Kuan-Hao Chao, Aaron M. Milstone, Emily Egbert, Franco D’Alessio, Petros C. Karakousis, Alvaro Ordoñez, Eileen P. Scully, Andrew Pekosz, Andrew H. Karaba, Andrea L. Cox
Journal: Science Translational Medicine (2025)

Severe COVID-19 presents with a distinct immunological profile, characterized by elevated neutrophil and reduced lymphocyte counts, seen commonly in fungal and bacterial infections. This study demonstrates that patients hospitalized with COVID-19 show evidence of neutrophil degranulation and have increased expression of neutrophil surface lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a marker of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Both early LOX-1 and programmed death-ligand 1 (PD-L1) expression on neutrophils were associated with development of severe disease. To determine whether tissue damage or inflammation is required to induce PMN-MDSCs or whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly activates neutrophils to become PMN-MDSCs, we incubated healthy human neutrophils with SARS-CoV-2. SARS-CoV-2 rapidly induced LOX-1 surface expression in healthy neutrophils independent of productive infection. LOX-1 induction was dependent on granule exocytosis and promoted up-regulation of reactive oxygen species, CD63, and PD-L1, enabling LOX-1 + neutrophils to suppress autologous T cell proliferation in vitro. These results support a role for PMN-MDSCs in mediating severe COVID-19, and inhibition of PD-L1 represents a potential therapeutic strategy for enhancing the immune response in acute SARS-CoV-2 infection.
Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer
Authors: Elena Grassi, Valentina Vurchio, George D. Cresswell, Irene Catalano, Barbara Lupo, Francesco Sassi, Francesco Galimi, Sofia Borgato, Martina Ferri, Marco Viviani, Simone Pompei, Gianvito Urgese, Bingjie Chen, Eugenia R. Zanella, Francesca Cottino, Mariangela Russo, Gianluca Mauri, Filippo Pietrantonio, Maria Giulia Zampino, Luca Lazzari, Silvia Marsoni, Alberto Bardelli, Marco Cosentino Lagomarsino, Andrea Sottoriva, Livio Trusolino, Andrea Bertotti
Journal: Science Translational Medicine (2025)

Historically, DNA sequence mutability has been considered relatively uniform and low in tumors with chromosomal instability (CIN), based on the assumption that high mutability would be detrimental in karyotypically aberrant contexts. Recent in silico analyses have challenged this view, suggesting some heterogeneity in mutation rates across CIN tumors; however, these predictions lack experimental validation. It also remains unclear how the intertumor variability of mutation rates compares to intratumor diversification and evolves along disease progression, whether mutation rates are functionally relevant in CIN cancers, and which mutational processes shape mutational accrual during CIN tumor onset and evolution. To address these gaps, we performed mutation accumulation experiments using clonal populations of patient-derived tumoroids from seven CIN, microsatellite-stable colorectal cancers (CRCs), and one microsatellite-unstable CRC. Each tumor exhibited a distinctive mutation rate footprint that was conserved among different clones from the same ancestor. In contrast, mutation rates diverged markedly across different tumors, with variations in magnitude within microsatellite-stable tumors as prominent as those distinguishing them from microsatellite-unstable tumors. New mutations reflected mutational processes associated with defective DNA replication and repair, which were not detected in normal tissues. Last, both mutation accumulation assays and high-depth whole-exome sequencing of subclonal variants showed higher mutation rates in metastatic lesions compared with matched primary tumors, suggesting positive selection for cells with increasing mutability during cancer dissemination. By providing an empirical assessment of mutation rates in human cancer, our data delineate heterogeneity, heritability, and progression-associated evolvability of DNA mutational instability as hallmarks of microsatellite-stable CRC.
Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1–induced platelet reactivity
Authors: Philipp Mourikis, Marcel Benkhoff, Laura Wildeis, Maike Barcik, Carolin Helten, Cristina Coman, Fiorella A. Solari, Daniel Krahn, Lisa Dannenberg, Samantha Ahlbrecht, Dorothee Zikeli, Amelie Utz, Kajetan Trojovsky, Hannah Richter, Gabrielle Al Kassis, René M’Pembele, Saif Zako, Tim Huckenbeck, Sofia Bauer, Danny Schmitz, Susanne Pfeiler, Norbert Gerdes, Christof Dücker, Joachim Pircher, Zhang Zhe, Manuela Thienel, Qurrat Ul Ain, Petra Keul, Nicholas Kirkby, Dennis Sohn, Wilfried Budach, Thomas Hohlfeld, Karsten Schrör, Bodo Levkau, Tobias Zeus, Steven H. L. Verhelst, Robert Ahrends, Albert Sickmann, Jane Mitchell, Samia Mora, JoAnn E. Manson, Deepak L. Bhatt, Ulf Landmesser, Steffen Massberg, Malte Kelm, Tobias Petzold, Amin Polzin
Journal: Science Translational Medicine (2025)

Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the effects of ω-3 PUFA on platelet adhesion, degranulation, and aggregation in vitro and in patients with cardiovascular disease using different formulations of ω-3 PUFA. We also investigated the effects of ω-3 PUFA in rodent models of arterial thrombosis and in tail bleeding assays, including in cyclooxygenase-1 (COX-1)–deficient animals. The ω-3 PUFA eicosapentaenoic acid (EPA) dose-dependently reduced platelet adhesion, degranulation, and aggregation in vitro. Moreover, arterial thrombus formation in wild-type mice was inhibited by oral EPA administration before thrombus formation. Photoaffinity labeling and in silico docking analyses suggested a direct, competitive interaction of EPA and arachidonic acid at the level of COX-1. The COX-1 dependency of EPA’s inhibitory effects was confirmed by platelet-specific COX-1–deficient animals that had no reduction of thrombus burden by EPA. In patients with cardiovascular disease, switching from 2 grams of EPA twice daily to 1 gram of docosahexaenoic acid (DHA) (460 milligrams of EPA and 380 milligrams of DHA) once daily completely blunted the platelet inhibition achieved by EPA. Our results may partially explain contradictory results with different ω-3 PUFA formulations in clinical trials.
Untargeted proteomics enables ultra-rapid variant prioritisation in mitochondrial and other rare diseases
Authors: Daniella H Hock, Nikeisha J Caruana, Liana N Semcesen, Nicole J Lake, Luke E Formosa, Sumudu S C Amarasekera, Tegan Stait, Simone Tregoning, Leah E Frajman, Adam M Bournazos, David R L Robinson, Megan Ball, Boris Reljic, Bryony Ryder, Mathew J Wallis, Anand Vasudevan, Cara Beck, Heidi Peters, Joy Lee, Natalie B Tan, Mary-Louise Freckmann, Vasiliki Karlaftis, Chantal Attard, Paul Monagle, Amanda Samarasinghe, Rosie Brown, Weimin Bi, Monkol Lek, Robert McFarland, Robert W Taylor, Michael T Ryan, Sandra T Cooper, Zornitza Stark, John Christodoulou, Alison G Compton, David R Thorburn, David A Stroud
Journal: Genome Medicine (2025)
Novel Photoreceptor-Specific Promoters for Gene Therapy in Mid-to-Late Stage Retinal Degeneration
Authors: Raghavi Sudharsan, Leonardo Murgiano, Aditi Ahuja, Yu Sato, Jennifer Kwok, Natalia Dolgova, Svetlana Savina, Morgan Sedorovitz, Valerie L Dufour, Gustavo D Aguirre, Leah C Byrne, William A Beltran
Journal: Molecular Therapy (2025)
A systematic review of developments in mHealth smartphone applications for Transgender and Gender Diverse individuals
Authors: Marina Bonato, Andrea Garolla, Marina Miscioscia
Journal: npj Digital Medicine (2025)

Transgender and gender diverse (TGD) individuals face significant healthcare barriers, resulting in inequities and unmet needs. Mobile health (mHealth) applications offer promising solutions by providing accessible, cost-effective, personalized, and gender-affirming care. This systematic review, conducted using PRISMA 2020 guidelines and the PICO framework, screened 5005 records from 4 databases and included 11 articles. The review aimed to identify key features of mHealth apps developed for TGD individuals, focusing on theoretical frameworks, design strategies, and their approaches to addressing healthcare barriers. Key challenges in developing mHealth apps include implementing systemic changes in healthcare settings to combat stigma and discrimination, grounding app development in TGD-specific theoretical frameworks, adequately addressing stressors and protective factors, and overcoming methodological limitations that hinder the evaluation of health outcomes. Overcoming these challenges requires rigorous research methodologies, inclusive designs, reliance on evidence-based TGD frameworks, and stronger collaboration among researchers, healthcare providers, and TGD communities.
Antibody polymer drug conjugates with increased drug to antibody ratio: CD38-targeting nanomedicines for innovative therapy of relapsed lymphomas
Authors: Ondřej Lidický, Nicol Renešová, Júlia Kudláčová, Marcela Filipová, Tereza Běláková, Petra Kovaříková, Dmitry Manakov, Jan Pankrác, Alexandra Dolníková, Eva Pokorna, Pavel Klener, Tomáš Etrych
Journal: Journal of Controlled Release (2025)