tbuckley/cabot-search huggingface dataset:
A high-resolution screen identifies a preexisting beta-lactam that specifically treats Lyme disease in mice
Authors: Maegan E. Gabby, Abey Bandara, L. M. Outrata, Osamudiamen Ebohon, Saadman S. Ahmad, Jules M. Dressler, Mecaila E. McClune, Rebecca N. Trimble, Lainey Mullen, Brandon L. Jutras
Journal: Science Translational Medicine (2025)

Lyme disease, caused by Borrelia burgdorferi in the United States, is an escalating human health problem that can cause severe disease if not properly treated. Doxycycline is the primary treatment option for Lyme disease; however, several concerns are associated with high-dose doxycycline treatment. For example, doxycycline is a broad-spectrum antibiotic and kills beneficial bacteria. Doxycycline is also known to produce unwanted off-target effects in eukaryotic cells. Some at-risk populations such as young children cannot be prescribed doxycycline, and in addition to these shortcomings, the treatment appears to fail in 10 to 20% of cases. We reasoned that safe, alternative therapies may currently exist but have not yet been found because of the challenges associated with drug screening approaches. We screened nearly 500 US Food and Drug Administration–approved compounds using an array of physiological, cellular, and molecular techniques. Top-performing candidates were counter screened to identify compounds that did not affect other bacterial phyla. Piperacillin emerged as a compound that eradicated B. burgdorferi at low-nanomolar concentrations by specifically interfering with the unusual, multizonal peptidoglycan synthesis pattern common to the Borrelia clade. Mechanistic in vitro studies identified the cellular target of piperacillin in B. burgdorferi and produced key insights that may explain both the specificity and efficacy of the compound. Further, in vivo studies using an experimental mouse infection model demonstrated that piperacillin treated animals at a 100-fold lower dose than the effective dose of doxycycline without affecting the murine microbiome. Our findings suggest that piperacillin may offer clinicians another therapeutic option for Lyme disease.
FcγR binding differentially contributes to protection by two human monoclonal antibodies targeting <i>Plasmodium falciparum</i> circumsporozoite protein
Authors: Neville K. Kisalu, Lais D. Silva Pereira, Jonathan D. Herman, Mangaiarkarasi Asokan, Keenan Ernste, Jonah Merriam, Cuiping Liu, Megan E. DeMouth, Amarendra Pegu, Mariah Lofgren, Marlon Dillon, Brian Bonilla, Ryan MacVicar, Yonatan Zur, Patience Kiyuka, Yevel Flores-Garcia, Saborni Chakraborty, Daria Nikolaeva, Rodney Ogwang, Barbara Flynn, Joseph Francica, Theodore C. Pierson, Richard A. Koup, Fidel Zavala, Taia T. Wang, Galit Alter, Azza H. Idris, Robert A. Seder
Journal: Science Translational Medicine (2025)

Antibodies mediate protection against a wide range of pathogens through binding and neutralizing the pathogen or through Fc-mediated effector functions. Human monoclonal antibodies (mAbs) CIS43LS and L9LS show high-affinity binding targeting distinct regions on the Plasmodium falciparum circumsporozoite protein (PfCSP) and are highly effective in preventing malaria in humans. However, the role of FcγR binding in protection by these mAbs has not been determined. Here, we assessed several Fc variants of CIS43LS and L9LS for protection against infection with transgenic Plasmodium berghei parasite expressing PfCSP in mice. Limiting binding to FcγRs did not reduce protection compared to the parental mAbs in mice. To determine whether protection could be improved in vivo by Fc modification, we engineered Fc variant mAbs with increased binding to distinct FcγRs. Passive transfer of CIS43LS-DE and CIS43LS-DEAL variants resulted in an approximately two- to threefold reduction in the liver-stage parasite burden in C57BL/6 or human FcγR mice compared with the parental CIS43LS after challenge. CIS43LS-DEAL also enhanced protection of mice after mosquito bite challenge. Systems serology analysis revealed that the CIS43LS-DE and CIS43LS-DEAL variants could enhance human neutrophil and monocyte phagocytosis, as well as NK cell activation, compared with CIS43LS. However, similar Fc modifications incorporated into L9LS did not increase protection compared to the parental mAb. Overall, although FcγR binding by CIS43LS and L9LS is dispensable in mouse models of malaria, enhancing the binding of CIS43LS to FcγR showed a modest increase in the potency of this mAb.
The peptidoglycan of <i>Borrelia burgdorferi</i> can persist in discrete tissues and cause systemic responses consistent with chronic illness
Authors: Mecaila E. McClune, Osamudiamen Ebohon, Jules M. Dressler, Marisela M. Davis, Juselyn D. Tupik, Robert B. Lochhead, Carmen J. Booth, Allen C. Steere, Brandon L. Jutras
Journal: Science Translational Medicine (2025)

Persistent symptoms after an acute infection is an emerging public health concern, but the pathobiology of such conditions is not well understood. One possible scenario involves the persistence of lingering antigen. We have previously reported that patients with postinfectious Lyme arthritis often harbor the peptidoglycan (PG) cell wall of Borrelia burgdorferi , the Lyme disease agent, in the synovial fluid of their inflamed joints after treatment. However, it is not yet known how B. burgdorferi PG persists, in what form, or if it may play a role in other postinfectious complications after Lyme disease. Using a murine model, we developed a real-time in vivo system to track B. burgdorferi PG as a function of cell wall chemistry and validated our findings using both molecular and cellular approaches. Unlike typical bacterial PG, the unique chemical properties of polymeric B. burgdorferi PG drive murine liver accumulation, where the cell wall material persists for weeks. Kupffer cells and hepatocytes phagocytose and retain B. burgdorferi PG and, although liver occupancy coincides with minimal pathology, both organ-specific and secreted protein profiles produced under these conditions bear some similarities to reported proteins enriched in patients with chronic illness after acute infection. Moreover, transcriptomic profiling indicated that B. burgdorferi PG affects energy metabolism in peripheral blood mononuclear cells. Our findings provide mechanistic insights into how a pathogenic molecule can persist after agent clearance, potentially contributing to illness after infection.
Activation and targetability of TYMP–IL-6–TF signaling in the skin microenvironment in uremic calciphylaxis
Authors: Marc Arthur Napoleon, Xiaosheng Yang, Yichi Zhang, Austin Morrissey, Scott Krinsky, Adam Lazowski, Houda Bouchouari, Abbas Malloum Brahim, Isaac Sellinger, Thierry Edwards, Asha Jose, Saran Lotfolhzadeh, Ricardo Almiron, Wenqing Yin, Jeffrey J. Siracuse, Jean Francis, Juliane Lokau, Christoph Garbers, Piqueras Maria Del Carmen, Vijaya B. Kolachalama, Ruben Dries, Rosalynn M. Nazarian, Sagar U. Nigwekar, Vipul C. Chitalia
Journal: Science Translational Medicine (2025)

Calciphylaxis is an orphan disease characterized by dermal microvessel thrombosis, inflicting painful cutaneous necrosis. It occurs predominantly in patients with end-stage kidney disease and has high mortality, elusive pathogenesis, and no approved therapies. We demonstrate that sera from patients with calciphylaxis induced de novo synthesis of interleukin-6 (IL-6) and soluble IL-6 receptor (IL-6R) and stimulated Janus kinase-2 (JAK) and signal transducer and activator of transcription (STAT)–3 phosphorylation in primary human dermal microvascular endothelial cells (ECs). Calciphylaxis skin demonstrated an altered microenvironment characterized by a gain of proximal and distal IL-6 ligand-receptor interactions. Microvessels are the predominant senders and recipients of IL-6 signaling, which, along with up-regulated A disintegrin and metalloproteinase 17 in dermal vasculature and interstitial IL-6R, supported trans–IL-6 signaling in calciphylaxis lesions. Calciphylaxis serum up-regulated thymidine phosphorylase (TYMP) in ECs. TYMP up-regulated IL-6, which activated tissue factor (TF), a primary trigger of the extrinsic coagulation cascade. IL-6–TF signaling in ECs was partially triggered by elevated IL-6 and kynurenine amounts in calciphylaxis serum and was inhibited by anti–IL-6 treatment. The TF-inducing ability of calciphylaxis serum is correlated with disease activity and response to IL-6 inhibitors in ECs. Calciphylaxis is therefore a combination of serum-inducing TYMP–IL-6–TF signaling in ECs and a heterogeneous permissive local dermal microenvironment. The latter is characterized by microvessels initiating IL-6 signaling and multiway cross-talk with adipocytes and eccrine glands, perpetuating the sinister thrombotic milieu. Our results support exploring the IL-6–TF–inducing ability of calciphylaxis serum as an activity marker and IL-6 as a therapeutic target for uremic calciphylaxis.
A microfluidic wearable device for wound exudate management and analysis in human chronic wounds
Authors: Canran Wang, Kexin Fan, Ehsan Shirzaei Sani, José A. Lasalde-Ramírez, Wenzheng Heng, Jihong Min, Samuel A. Solomon, Minqiang Wang, Jiahong Li, Hong Han, Gwangmook Kim, Soyoung Shin, Alex Seder, Chia-Ding Shih, David G. Armstrong, Wei Gao
Journal: Science Translational Medicine (2025)

Chronic wounds are a major global health challenge associated with substantial economic burden and a negative impact on patient quality of life. Real-time analysis of biomarkers like reactive oxygen and nitrogen species could guide treatment, but existing systems lack the capacity required for continuous monitoring. Wound exudate is secreted slowly and has a complex composition, making efficient fluid collection and real-time analysis challenging. To address these issues, we introduce iCares, a wearable device for wound exudate management and continuous in situ analysis of wound biomarkers. iCares contains a flexible nanoengineered sensor array that measures reactive species such as NO, H 2 O 2 , and O 2 , along with pH and temperature, providing multiparameter data to inform wound status. The device features pump-free triad microfluidic modules with a superhydrophobic-superhydrophilic Janus membrane, bioinspired wedge channels, and three-dimensional graded micropillars for efficient unidirectional exudate collection, transport, and refreshing. The sensors demonstrated a consistent response and analyte selectivity in vitro and in wound exudate. iCares was designed for rapid scalable manufacturing through advanced printing and laser patterning. Wireless connectivity supported long-term continuous monitoring in wounds. The iCares system real-time monitoring was tested in a murine model of diabetic skin wound during infection and antimicrobial treatment. Clinical wound evaluation was conducted in 20 patients with chronic wounds and in two patients before and after surgery. A machine learning analysis of the multiplexed data successfully classified wounds and healing times, indicating that wound exudate analysis by iCares could offer insight into chronic wound status to aid in treatment decisions.
Pertussis Epidemic in Slovenia in 2024 – No Pertactin-Deficient or Macrolide-Resistant Bordetella pertussis Isolates Identified
Authors: Tamara Kastrin, Alex-Mikael Barkoff, Katja Seme, Luka Kosec, Tina Triglav, Nadja Šinkovec Zorko, Mojca Rožič, Jussi Mertsola, Qiushui He
Journal: Clinical Microbiology and Infection (2025)
<i>Glutathione-specific gamma–glutamylcyclotransferase 1</i> ( <i>CHAC1</i> ) increases kidney disease risk by modulating ferroptosis
Authors: Lakshmi P. Kolligundla, Katie M. Sullivan, Dhanunjay Mukhi, Magaiver Andrade-Silva, Hongbo Liu, Yuting Guan, Xiangchen Gu, Junnan Wu, Tomohito Doke, Daigoro Hirohama, Paolo Guarnieri, Jon Hill, Steven S. Pullen, Jay Kuo, Masataka Inamoto, Katalin Susztak
Journal: Science Translational Medicine (2025)

Genome-wide association studies (GWASs) have identified more than 1000 loci where genetic variants correlate with kidney function. However, the specific genes, cell types, and mechanisms influenced by these genetic variants remain largely uncharted. Here, we identified glutathione-specific gamma–glutamylcyclotransferase 1 ( CHAC1 ) on chromosome 15 as affected by GWAS variants by analyzing human kidney gene expression and methylation information. Both CHAC1 RNA and protein were expressed in the loop of Henle region in mouse and human kidneys, and CHAC1 expression was higher in patients carrying disease risk variants. Using CRISPR technology, we created mice with a single functional copy of the Chac1 gene ( Chac1 +/− ) that displayed no baseline phenotypic alterations in kidney structure or function. These mice demonstrated resilience to kidney disease in multiple models, including folic acid–induced nephropathy, adenine-induced chronic kidney disease, and uninephrectomy-streptozotocin–induced diabetic nephropathy. We further showed that CHAC1 plays a critical role in degrading the cellular antioxidant glutathione. Tubule cells isolated from Chac1 +/− mice showed increased glutathione, decreased lipid peroxidation, improved cell viability, and protection against ferroptosis. Expression of ferroptosis-associated genes was also lower in mice with only one copy of Chac1 . Higher CHAC1 protein also correlated with ferroptosis-related protein abundance in kidney biopsies from patients with kidney disease. This study positions CHAC1 as an important mediator of kidney disease that influences glutathione concentrations and ferroptosis, suggesting potential avenues to explore for the treatment of kidney diseases.
5-HT2A Receptors: Pharmacology and Functional Selectivity
Authors: Benjamin R Cummins, Gerald B Billac, David E Nichols, Charles D Nichols
Journal: Pharmacological Reviews (2025)

Serotonin 5-HT2A receptors were one of the first serotonin receptors to be pharmacologically characterized. In mammals, they are expressed throughout the body in nearly every cell and tissue type, with the highest density in cortical layer V of the brain. They are involved in several aspects of normal physiological processes and behaviors and have been implicated in the etiology of neuropsychiatric diseases such as schizophrenia. Atypical antipsychotics have targeted blockade of 5-HT2A receptors as part of their therapeutic mechanism. More recently, 5-HT2A receptors have come to prominence for their role as the primary target for psychedelic drugs, which activate this receptor subtype to produce their characteristic behavioral effects. 5-HT2A receptor agonists like psilocybin, dimethyltryptamine, and lysergic acid diethylamide have each demonstrated long-lasting therapeutic efficacy in clinical trials for psychiatric disorders such as major depression and substance use disorders. There is a significant effort in both academia and industry to develop new agonists of 5-HT2A receptors with therapeutic efficacy. There are 3 primary scaffolds for agonists: tryptamines, ergolines, and phenylalkylamines, each engaging different subsets of amino acid residues in the receptor binding pocket. Differences can lead to differential responses between ligands for functionally selective outcomes. Here, we provide a historical perspective on 5-HT2A receptors, their key structural features and motifs involved in ligand-receptor interactions, and how these interactions can affect signaling pathways downstream of the receptor. Understanding how ligands interact with the 5-HT2A receptor will fundamentally inform future drug discovery to optimize therapeutics for a variety of disorders. SIGNIFICANCE STATEMENT: Psychedelic drugs have demonstrated long-lasting therapeutic efficacy for several conditions in multiple clinical trials. Their target, serotonin 5-HT2A receptors, are GPCRs with complex pharmacology. Having knowledge of how ligands interact with 5-HT2A receptors in the orthosteric binding pocket at the structural level to induce specific signal transduction pathways will inform on efforts to design and develop functionally selective drugs to potentially treat a variety of diseases.
Small molecular chelator for comprehensive regulation of tumor lactate levels in synergy with photodynamic therapy for cancer treatment
Authors: Haiqing Zhong, Xufang Ying, Xiaoyan Bao, Linjie Wu, Yiying Lu, Qi Dai, Qiyao Yang, Xin Tan, Donghang Xu, Jianqing Gao, Min Han
Journal: Asian Journal of Pharmaceutical Sciences (2025)
Infographic. Faculty of Sport and Exercise Medicine (FSEM) position statement: mouthguards for the prevention of orofacial trauma in sport
Authors: Lynsey Abbey Joslin, Irfan Ahmed, Julie Gallagher, Ian Needleman, Paul Ashley, Asma Aloui, John Patrick Haughey, Peter Fine, Alan Rankin, Gofrane Abdellaoui, Rachel Bower
Journal: British Journal of Sports Medicine (2025)
Long-chain sulfatide enrichment is an actionable metabolic vulnerability in intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancers
Authors: Yihui Chen, Riccardo Ballarò, Marta Sans, Fredrik Ivar Thege, Mingxin Zuo, Rongzhang Dou, Jimin Min, Michele Yip-Schneider, J Zhang, Ranran Wu, Ehsan Irajizad, Yuki Makino, Kimal I Rajapakshe, Hamid K Rudsari, Mark W Hurd, Ricardo A León-Letelier, Hiroyuki Katayama, Edwin Ostrin, Jody Vykoukal, Jennifer B Dennison, Kim-Anh Do, Samir M Hanash, Robert A Wolff, Paolo A Guerrero, Michael Kim, C Max Schmidt, Anirban Maitra, Johannes F Fahrmann
Journal: Gut (2025)

Background We conducted an integrated cross-species spatial assessment of transcriptomic and metabolomic alterations associated with progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC). Objective We aimed to uncover biochemical and molecular drivers that underlie malignant progression of IPMNs to PDAC. Design Matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) was performed on human resected IPMN/PDAC tissues (n=23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN/PDAC. Functional studies in murine IPMN/PDAC-derived Kras;Gnas cells were performed using CRISPR/cas9 technology, small interfering RNAs, and pharmacological inhibition. Results MALDI-MS analyses of patient tissues revealed long-chain hydroxylated sulfatides to be selectively enriched in the neoplastic epithelium of IPMN/PDAC. Integrated ST analyses showed cognate transcripts involved in sulfatide biosynthesis, including UGT8 , Gal3St1 , and FA2H , to co-localise with areas of sulfatide enrichment. Genetic knockout or pharmacological inhibition of UGT8 in Kras;Gnas IPMN/PDAC cells decreased protein expression of FA2H and Gal3ST1 with consequent alterations in mitochondrial morphology and reduced mitochondrial respiration. Small molecule inhibition of UGT8 elicited anticancer effects via ceramide-mediated compensatory mitophagy and activation of intrinsic apoptosis pathways. In vivo, UGT8 inhibition suppressed tumour growth in allograft models of murine IPMN/PDAC cells derived from Kras;Gnas and Kras;Tp53;Gnas mice. Conclusion Our work identifies enhanced sulfatide metabolism as an early metabolic alteration in cystic precancerous lesions of the pancreas that persists through invasive neoplasia and a potential actionable vulnerability in IPMN-derived PDAC.
Development and validation of the Wisconsin Sport Specialization Questionnaire (WISSQ) for older adolescent athletes
Authors: Stephanie A Kliethermes, Evan O Nelson, Kevin M Biese, Margaret Alison Brooks, Roger Brown, Timothy McGuine, Madison N Renner, Traci R Snedden, Emily Srygler, Andrew Watson, David R Bell
Journal: British Journal of Sports Medicine (2025)

Objective The proliferation of youth sport specialisation may be concerning for the overall health of adolescent athletes, but no validated tool to measure specialisation exists. We aimed to assess the measurement properties and validate the Wisconsin Sport Specialization Questionnaire (WISSQ) in older adolescent athletes. Methods Using previously developed sport specialisation items with established content validity, questionnaires were administered to 14–18-year-old athletes residing in both regional and national settings, who were participating in organised sport. Confirmatory factor analyses and Rasch partial credit modelling independently assessed structural and concurrent validity and reliability in both datasets. The best-fitting national model was then fit onto the regional data to further assess the stability of the measurement properties. Results The regional and national data included 474 (77% female, 86% non-Hispanic White) and 564 (38% female, 63% non-Hispanic White) athletes, respectively. Twelve of 25 items were retained in three domains (n=4 social, n=5 motivation, n=3 physical). One item cross-loaded on both the motivation and physical domains. The adapted regional (comparative fit index (CFI), 0.97; Tucker-Lewis index (TLI), 0.97; root mean square error of approximation (RMSEA), 0.04) and national (CFI, 0.99; TLI, 0.99; RMSEA, 0.05) datasets achieved good model fit. Internal consistency among the three subdomains ranged from Ω=0.78–0.88 (national) to Ω=0.73–0.83 (regional). All items contributed appropriately to measuring the construct of sport specialisation in the regional (infit/outfit: 0.77–1.16) and national (infit/outfit: 0.74–1.16) datasets. Conclusions We present the first validated tool to measure youth sport specialisation while considering physical, motivational and social characteristics of sport participation. The WISSQ is a valid, reliable assessment of sport specialisation in older adolescent athletes.
‘Tackling’ safety through a systems thinking approach: building safety culture within sport
Authors: Sharief Hendricks, Mitch Naughton, Paul M Salmon, Stephen W West, Lara Paul, Ben Jones, James Craig Brown, Marelise Badenhorst, Kathryn Dane, Isla Jordan Shill, Carolyn A Emery, Scott McLean
Journal: British Journal of Sports Medicine (2025)
Spatial imaging unlocks the potential of charting multiple myeloma and extramedullary disease
Authors: Vanessa Desantis, Alessandro Andriano, Tim Düking, Olga Hartwig, Giuseppe Ingravallo, Marta Biondo, Cirino Botta, Roberto Ria, Angelo Vacca, Antonio Giovanni Solimando
Journal: Journal of Hematology & Oncology (2025)

Extramedullary disease (EMD) in multiple myeloma (MM) represents a significant clinical challenge, with a limited understanding of the spatial architecture and its pathobiological impact. To address this unmet need, we examined 10 matched samples from bone marrow (BM) and cognate EMD sites. This investigation provides critical insights into the distinct features of EMD, offering potential avenues for more effective diagnosis and targeted therapies. To this aim, we employed MACSima™ Imaging Cyclic Staining (MICS) to unveil distinct biomarker expression profiles as companion diagnostics for a personalized therapeutic approach for MM. We observed elevated BCL-2 levels in EMD plasma cells (p < 0.0001), indicating the potential of BCL-2 inhibitors to target anti-apoptotic pathways in select cases. The higher expression of EZH2 in EMD compared to BM (p < 0.0001) highlights its role in sustaining aggressive tumor phenotypes and supports the use of epigenetic-targeting agents in key situations. In contrast, CD3 + T-cell distance was significantly higher in EMD, reflecting impaired immune surveillance (p < 0.0001). Across the cohort, our analysis revealed significant differences between BM and EMD regarding the expression and spatial organization of key markers. CD38 expression was markedly reduced in EMD plasma cells (p < 0.0001). These findings underscore profound biological heterogeneity in MM and its BM emancipated disease phenotype, emphasizing dysfunctional apoptosis, immune evasion and resistance to CD38-targeting therapies in EMD, conceivably informing future validations. By integrating high-dimensional data, this study provides insights into potential druggable vulnerabilities for crafted interventions, particularly challenging in EMD cases.