tbuckley/cabot-search huggingface dataset:
Allostery and Evolution: A Molecular Journey Through the Structural and Dynamical Landscape of an Enzyme Super Family
Authors: Sandrine Coquille, Caroline Simões Pereira, Jennifer Roche, Gianluca Santoni, Sylvain Engilberge, Céline Brochier-Armanet, Eric Girard, Fabio Sterpone, Dominique Madern
Journal: Molecular Biology and Evolution (2025)

Allosteric regulation is a powerful mechanism for controlling the efficiency of enzymes. Deciphering the evolutionary mechanisms by which allosteric properties have been acquired in enzymes is of fundamental importance. We used the malate (MalDH) and lactate deydrogenases (LDHs) superfamily as model to elucidate this phenomenon. By introducing a few of mutations associated to the emergence of allosteric LDHs into the non-allosteric MalDH from Methanopyrus kandleri, we have gradually shifted its enzymatic profile toward that typical of allosteric LDHs. We first investigated the process triggering homotropic activation. The structures of the resulting mutants show the typical compact organization of the R-active state of LDHs, but a distorted (T-like) catalytic site demonstrating that they corresponds to hybrid states. Molecular dynamics simulations and free energy calculations confirmed the capability of these mutants to sample the T-inactive state. By adding a final single mutation to fine-tune the flexibility of the catalytic site, we obtained an enzyme with both sigmoid (homotropic) and hyperbolic (heterotropic) substrate activation profiles. Its structure shows a typical extended T-state as in LDHs, whereas its catalytic state has as a restored configuration favorable for catalysis. Free energy calculations indicate that the T and R catalytic site configurations are in an equilibrium that depends on solvent conditions. We observed long-range communication between monomers as required for allosteric activation. Our work links the evolution of allosteric regulation in the LDH/MDH superfamily to the ensemble model of allostery at molecular level, and highlights the important role of the underlying protein dynamics.
Diagnostic performance of shape-sensing robotic-assisted bronchoscopy for pleural-based and fissure-based pulmonary lesions
Authors: Sebastian Fernandez-Bussy, Alejandra Yu Lee-Mateus, Alanna Barrios-Ruiz, Sofia Valdes-Camacho, Katherine Lin, Mohamed I Ibrahim, Bryan F Vaca-Cartagena, Rodrigo Funes-Ferrada, Janani Reisenauer, Kelly S Robertson, Britney N Hazelett, Ryan M Chadha, David Abia-Trujillo
Journal: Thorax (2025)

Background Sampling of peripheral pulmonary lesions (PPLs) abutting the pleura carries a higher risk of pneumothorax and complications. Although typically performed with image-guided transthoracic biopsy, the advent of shape-sensing robotic-assisted bronchoscopy (ssRAB) provides an alternative diagnostic procedure for this subtype of lesions. Methods A retrospective study on PPL attached to the peripheral pleura (PP), comprising costal and diaphragmatic pleura, mediastinal pleura (MP), and fissural pleura (FP) sampled by ssRAB, from January 2020 to December 2023. Clinicodemographic data, PPL characteristics and procedure-related details were recorded. Primary outcome was diagnostic yield, defined as all conclusive diagnoses, malignant or benign, over the total number of procedures. Secondary outcomes were safety profile, defined as the number of procedure-related complications, and diagnostic yield with the use of mobile cone-beam CT (mCBCT) and by biopsy tool. Results 182 nodules were sampled from 178 patients. PPLs were grouped as: PP (n=95), MP (n=30) and FP (n=57). Overall diagnostic yield was 80.2% (146/182) and sensitivity for malignancy was 83.2% (104/125). Diagnostic yield was associated with upper location (OR 2.86; 95% CI 1.35 to 6.03, p = 0.006), mCBCT (OR 2.27; 95% CI 1.06 to 4.86, p = 0.036) and cryobiopsy (OR 2.90; 95% CI 1.31 to 6.47, p = 0.009). Pneumothorax requiring chest tube was reported in five patients (2.8%), and a Nashville Scale grade 3 bleeding occurred in one patient (0.6%). Conclusion For pleural-based and fissure-based nodules, ssRAB showed a high diagnostic yield with low complications. The addition of mCBCT and cryobiopsy improved the diagnostic performance for this subtype of lesions.
Secondary lesions and sensitivity to signaling inhibitors in iAMP21 acute lymphoblastic leukemia
Authors: Femke M. Hormann, Anna Østergaard, Stijn van den Broek, Aurélie Boeree, Cesca van de Ven, Gabriele Escherich, Edwin Sonneveld, Judith M. Boer, Monique L. den Boer
Journal: HemaSphere (2025)

Abstract Intrachromosomal amplification of chromosome 21 (iAMP21) B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) in children is a high‐risk subtype for which targeted drugs are lacking. In this study, we determined the frequency of secondary lesions in 28 iAMP21 BCP‐ALL patient samples and investigated cellular sensitivity for candidate‐targeted drugs. iAMP21 was enriched in FLT3 aberrations (10.7% vs. 50.0%, p = 0.003) and SH2B3 inactivation (7.14% vs. 46.4%, p = 0.002), compared with 28 B‐other cases, and these alterations co‐occurred in 21.4%. The occurrence of lesions in CRLF2 and IL7R was similar between iAMP21 and B‐other cases (25% vs. 17.9%, p = 0.746 and 7.14% vs. 0%, p = 0.491 respectively) as were mutations in JAK1 and JAK2 (3.57% vs. 0% and 10.7% vs. 10.7%, p = 1 for both). Sensitivity to the FLT3 inhibitor gilteritinib did not differ between iAMP21 and B‐other cases irrespective of FLT3 status. However, iAMP21 samples harboring both FLT3‐ ITD and SH2B3 lesions showed the highest sensitivity. CRLF2‐ rearranged iAMP21 samples were slightly more sensitive to JAK inhibitor ruxolitinib than those without, although a lack of sensitivity was present in 50% of iAMP21 cases. Trametinib sensitivity varied among iAMP21 samples with over half of iAMP21 samples being sensitive irrespective of RAS‐pathway mutation status or other secondary lesions. In summary, iAMP21 leukemias were enriched in FLT3 and in SH2B3 lesions, which when co‐occurring affected sensitivity to FLT3 inhibition by gilteritinib but not JAK inhibition by ruxolitinib. Together, our results suggest that FLT3 and RAS signaling inhibitors are of interest for further (pre)clinical evaluation in iAMP21 BCP‐ALL.
Reinvestigation into the role of lipopolysaccharide Glycosyltransferases in <i>Helicobacter pylori</i> protein glycosylation
Authors: Hong Li, Xiaoqiong Tang, Tiandi Yang, Tingting Liao, Aleksandra W. Debowski, Tiankuo Yang, Yalin Shen, Hans-Olof Nilsson, Stuart M. Haslam, Barbara Mulloy, Anne Dell, Keith A. Stubbs, Wolfgang Fischer, Rainer Haas, Hong Tang, Barry J. Marshall, Mohammed Benghezal
Journal: Gut Microbes (2025)

Protein glycosylation has been considered as a fundamental phenomenon shared by all domains of life. In Helicobacter pylori, glycosylation of flagellins A and B with pseudaminic acid have been rigorously confirmed and shown to be essential for flagella assembly and bacterial colonization. In addition to flagellins, several other proteins including RecA, AlpA/B, and BabA/B in H. pylori have also been reported to be glycosylated and to be dependent on the lipopolysaccharide (LPS) biosynthetic pathway. However, these proteins have not been purified for sugar-specific staining or structural analysis to confirm the existence of carbohydrate motifs. Here, using a combined approach of genetics, protein purification, and sugar-specific staining, we demonstrate that RecA is not a glycoprotein. Moreover, using LPS-protein reconstitution experiments, we demonstrate that the presence of O-antigen containing full-length LPS interferes with the electrophoretic mobility of H. pylori RecA and many other proteins including AlpA/B on SDS-PAGE. Finally, we demonstrate that full-length LPS extracted from E. coli affects electrophoretic migration of H. pylori proteins, while full-length LPS extracted from H. pylori similarly influences the electrophoretic migration of E. coli proteins. The impact is more subtle with E. coli LPS compared to H. pylori LPS, indicating that the magnitude of effect of LPS effects on protein mobility is dependent on bacterial source of the LPS. These findings suggest that the effects of full-length LPS on protein electrophoresis may represent a more general phenomenon. As LPS is a unique component of virtually all Gram-negative bacteria, our data suggest that when observing protein electrophoretic mobility shifts between wild-type and LPS mutant strains or between subcellular fractionation samples, the influence of LPS on protein electrophoretic migration should be considered first, rather than interpreting it as potential protein glycosylation that is dependent upon LPS biosynthetic pathway.
Predicting survival in patients with severe heart failure: Risk score validation in the <scp>HELP</scp>‐<scp>HF</scp> cohort
Authors: Mauro Chiarito, Davide Stolfo, Alessandro Villaschi, Samantha Sartori, Luca Baldetti, Carlo Mario Lombardi, Marianna Adamo, Ferdinando Loiacono, Antonio Maria Sammartino, Mauro Riccardi, Daniela Tomasoni, Riccardo Maria Inciardi, Marta Maccallini, Gaia Gasparini, Benedetta Grossi, Stefano Contessi, Daniele Cocianni, Maria Perotto, Giuseppe Barone, Marco Merlo, Alberto Maria Cappelletti, Gianfranco Sinagra, Daniela Pini, Marco Metra, Matteo Pagnesi
Journal: European Journal of Heart Failure (2025)

Abstract Aims Accurate selection of patients with severe heart failure (HF) who might benefit from advanced therapies is crucial. The present study investigates the performance of the available risk scores aimed at predicting the risk of mortality in patients with severe HF. Methods and results The risk of 1‐year mortality was estimated in patients with severe HF enrolled in the HELP‐HF cohort according to the MAGGIC, 3‐CHF, ADHF/NT‐proBNP, and GWTG‐HF risk scores, the number of criteria of the 2018 HFA‐ESC definition of advanced HF, I NEED HELP markers, domains fulfilled of the 2019 HFA‐ESC definition of frailty, the frailty index, and the INTERMACS profile. In addition, we tested the performance of different machine learning (ML)‐based models to predict 1‐year mortality. At 1‐year follow‐up, 265 patients (23.1%) died. The prognostic accuracy, tested in the subgroup of patients with completeness of all data regarding the variables included in the scores (497/1149 patients), resulted moderate for MAGGIC, GWTG‐HF, and ADHF/NT‐proBNP scores (area under the curve [AUC] ≥0.70) and only poor for the other tools. All the scores lost accuracy in estimating the rate of 1‐year mortality in patients at the highest risk. Support vector machine‐based model had the best AUC among ML‐based models, slightly outperforming most of the tested risk scores. Conclusion Most of the scores used to predict the risk of mortality in HF performed poorly in real‐world patients with severe HF and provided inaccurate estimate of the risk of 1‐year mortality in patients at the highest risk. ML‐based models did not significantly outperform the currently available risk scores and their use must be validated in large cohort of patients.
Remote patient monitoring in heart failure: A comprehensive meta‐analysis of effective programme components for hospitalization and mortality reduction
Authors: Ignace L.J. De Lathauwer, Wessel W. Nieuwenhuys, Frederique Hafkamp, Marta Regis, Rutger W.M. Brouwers, Mathias Funk, Hareld M.C. Kemps
Journal: European Journal of Heart Failure (2025)

Abstract Aims Methods of non‐invasive remote patient monitoring (RPM) for heart failure (HF) remain diverse. Understanding factors that influence the effectiveness of RPM on HF‐related and all‐cause hospitalizations, mortality, and emergency department visits is crucial for developing successful RPM interventions. This meta‐analysis aims to synthesize and compare existing literature on RPM components that impact HF‐related and all‐cause hospitalizations, mortality and emergency department visits in HF patients. Methods and results A systematic search of electronic databases (PubMed, EMBASE, CENTRAL) identified randomized controlled trials from January 2012 to June 2023, comparing non‐invasive RPM interventions for HF with usual care. A random‐effects meta‐analysis assessed outcomes, and additional analyses identified effective RPM components. A total of 41 studies with 16 312 patients (mean follow‐up: 9.88 ± 6.37 months) were included. RPM was associated with lower mortality risk (pooled odds ratio [OR] 0.81 95% confidence interval [CI] 0.69–0.95; I 2 = 0.39) and reduced first HF hospitalization risk (pooled OR 0.78, 95% CI: 0.70–0.87; I 2 = 0.21) compared to usual care. RPM interventions with a self‐management module ( p &lt; 0.001) and education module ( p = 0.028) significantly lowered HF‐related hospitalizations. Video calls during RPM interventions further reduced HF‐related ( p = 0.047) and all‐cause hospitalizations ( p &lt; 0.001). Conclusion This meta‐analysis confirms the efficacy of RPM in reducing HF‐related hospitalizations and mortality. Effective components include self‐management, education modules, and video communication. However, heterogeneity among interventions challenges the overall evaluation. Modernizing RPM with advanced technologies like non‐invasive sensors, artificial intelligence, and cardiac telerehabilitation could enhance its potential.
Population genomics of premature termination codons in cavefish with substantial trait loss
Authors: Emma Y Roback, Estephany Ferrufino, Rachel L Moran, Devin Shennard, Charlotte Mulliniks, Josh Gallop, James Weagley, Jeffrey Miller, Yaouen Fily, Claudia Patricia Ornelas-García, N Rohner, Johanna E Kowalko, Suzanne E McGaugh
Journal: Molecular Biology and Evolution (2025)

Abstract Loss-of-function alleles are a pertinent source of genetic variation with the potential to contribute to adaptation. Cave-adapted organisms exhibit striking loss of ancestral traits such as eyes and pigment, suggesting that loss-of-function alleles may play an outsized role in these systems. Here, we leverage 141 whole genome sequences to evaluate the evolutionary history and adaptive potential of single nucleotide premature termination codons (PTCs) in Mexican tetra. We find that cave populations contain significantly more PTCs at high frequency than surface populations. We also find that PTCs occur more frequently in genes with inherent relaxed evolutionary constraint relative to the rest of the genome. Using SLiM to simulate PTC evolution in a cavefish population, we show that the smaller population size and increased genetic drift is sufficient to account for the observed increase in PTC frequency in cave populations without positive selection. Using CRISPR-Cas9, we show that mutation of one of these genes, pde6c, produces phenotypes in surface Mexican tetra that mimic cave-derived traits. Finally, we identify a small subset of candidate genes that contain high frequency PTCs in cave populations, occur within selective sweeps, and may contribute to beneficial traits such as reduced energy expenditure, suggesting that a handful of PTCs may be adaptive. Overall, our work provides a rare characterization of PTCs across wild populations and finds that they may have an important role in loss-of-function phenotypes, contributing to a growing body of literature showing genome evolution through relaxed constraint in subterranean organisms.
Association of muscle strength and cardiorespiratory fitness with all-cause and cancer-specific mortality in patients diagnosed with cancer: a systematic review with meta-analysis
Authors: Francesco Bettariga, Daniel Galvao, Dennis Taaffe, Chris Bishop, Pedro Lopez, Luca Maestroni, Giulia Quinto, Umberto Crainich, Enrico Verdini, Enrico Bandini, Valentina Natalucci, Robert U Newton
Journal: British Journal of Sports Medicine (2025)

Objectives To examine the association between muscle strength and cardiorespiratory fitness (CRF) with all-cause and cancer-specific mortality in patients diagnosed with cancer, and whether these associations are affected by type and/or stage of cancer. Method A systematic review with meta-analysis was carried out. Five bibliographic databases were searched to August 2023. Results Forty-two studies were included (n=46 694). Overall, cancer patients with high muscle strength or CRF levels (when dichotomised as high vs low) had a significant reduction in risk of all-cause mortality by 31–46% compared with those with low physical fitness levels. Similarly, a significant 11% reduction was found for change per unit increments in muscle strength. In addition, muscle strength and CRF were associated with an 8–46% reduced risk of all-cause mortality in patients with advanced cancer stages, and a 19–41% reduced risk of all-cause mortality was observed in lung and digestive cancers. Lastly, unit increments in CRF were associated with a significant 18% reduced risk of cancer-specific mortality. Conclusion High muscle strength and CRF were significantly associated with a lower risk of all-cause mortality. In addition, increases in CRF were associated with a reduced risk of cancer-specific mortality. These fitness components were especially predictive in patients with advanced cancer stages as well as in lung and digestive cancers. This highlights the importance of assessing fitness measures for predicting mortality in cancer patients. Given these findings, tailored exercise prescriptions to improve muscle strength and CRF in patients with cancer may contribute to reducing cancer-related mortality.
The Silent Threat: Unruptured Sinus of Valsalva Aneurysm Presenting as Complete Heart Block
Authors: Akshay Prashanth, Bharath Raj kidambi, Ramesh Sankaran, Nagendra Boopathy Senguttuvan, Periyasamy Thangavelu, Ranjith Karthikeyan, Vijay Kumar Muthayala
Journal:  (2025)
Chitosan/γ-PGA nanoparticles and IFN-γ immunotherapy: A dual approach for triple-negative breast cancer treatment
Authors: Flávia Castro, Marta Laranjeiro Pinto, Catarina Leite Pereira, Karine Serre, Ângela Margarida Costa, Bruno Cavadas, Mário Adolfo Barbosa, Karim Vermaelen, Sergio León, Diego Serrano, Fátima Gärtner, Alfonso Calvo, Raquel Madeira Gonçalves, Olivier De Wever, Maria José Oliveira
Journal: Journal of Controlled Release (2025)
Phase-separating Pt(IV)-graft-glycopeptides sequentially sensing pH and redox for deep tumor penetration and targeting chemotherapy
Authors: Dali Chen, Yunai Du, Xitong Wang, Huihong Li, Xinjiao Wu, Xiaoqin Kuang, Chunjiayu Li, Jianing Zhao, Yerong Xiong, Minjie Sun, Jiasheng Tu, Siyan Liu, Chunmeng Sun
Journal: Journal of Controlled Release (2025)
Smart core-shell microneedles for psoriasis therapy: In situ self-assembly of calcium ion-coordinated dexamethasone hydrogel
Authors: Xinni He, Wanchen Zhao, Huihui Xu, Hongluo Li, Minglong Chen, Yanping Fu, Shujin Liang, Shuling Li, Tingting Peng, Chao Lu, Xin Pan, Chuanbin Wu, Guilan Quan
Journal: Journal of Controlled Release (2025)
Gas-propelled anti-hair follicle aging microneedle patch for the treatment of androgenetic alopecia
Authors: Yangyan Chen, Tao Ren, Wentao Wu, Beibei Yang, Anqi Lu, Ke Pan, Jing Xu, Chao Lu, Guilan Quan, Chuanbin Wu, Xin Pan, Tingting Peng
Journal: Journal of Controlled Release (2025)
Disclosing long-term tolerance, efficacy and penetration properties of hyaluronic acid-coated latanoprost-loaded liposomes as chronic glaucoma therapy
Authors: Marco Brugnera, Marta Vicario-de-la-Torre, Miriam Ana González-Cela-Casamayor, Felipe M González-Fernández, Ilaria Ferraboschi, Vanessa Andrés-Guerrero, Sara Nicoli, Cristina Sissa, Silvia Pescina, Rocío Herrero-Vanrell, Irene Bravo-Osuna
Journal: Journal of Controlled Release (2025)
Combination of Biological Aging and Genetic Susceptibility Helps Identifying At‐Risk Population of Venous Thromboembolism: A Prospective Cohort Study of 394 041 Participants
Authors: Zhensheng Hu, Jiatang Xu, Runnan Shen, Liling Lin, Yangfan Su, Chaoyu Xie, Guochang You, Yi Zhou, Kai Huang
Journal: American Journal of Hematology (2025)

Phenotypic age acceleration (PhenoAgeAccel) is a novel clinical aging indicator. This study was carried out to investigate the relationship between PhenoAgeAccel and the incidence of VTE, as well as to integrate PhenoAgeAccel with genetic susceptibility to improve risk stratification of VTE. The study included 394 041 individuals from the UK Biobank. Phenotypic age was calculated based on actual age and clinical biomarkers. PhenoAgeAccel presents the residual obtained from a linear regression of phenotypic age against actual age, reflecting the rate of aging. Significant associations were observed between PhenoAgeAccel and higher risk of VTE (Hazard ratio [HR] 1.37, 95% CI: 1.32-1.42), deep vein thrombosis (DVT, HR 1.35, 95% CI: 1.29-1.42), and PE (pulmonary embolism, HR 1.41, 95% CI: 1.34-1.48) in the findings. PhenoAgeAccel exhibited a significant additive interaction with genetic susceptibility. Biologically older participants with high genetic risk have a 3.83 (95% CI: 3.51-4.18) folds risk of VTE, a 3.59 (95% CI: 3.21-4.03) folds risk of DVT, and 4.39 (95% CI: 3.88-4.98) folds risk of PE, in comparison to biologically younger participants with low genetic risk. Mediation analyses indicated that PhenoAgeAccel mediated approximately 6% of the association between cancer and VTE, and about 20% of the association between obesity and VTE. Our study indicated that PhenoAgeAccel is significantly associated with higher risk of VTE, and can be combined with genetic risk to improve VTE risk stratification. Additionally, PhenoAgeAccel holds promise as a clinical biomarker for guiding targeted prevention and treatment strategies for VTE.
Functional assessment of genetic variants in thrombomodulin detected in patients with bleeding and thrombosis
Authors: Christine Van Laer, Renaud Lavend'homme, Sarissa Baert, Koenraad De Wispelaere, Chantal Thys, Cyrielle Kint, Sam Noppen, Kathelijne Peerlinck, Chris Van Geet, Dominique Schols, Thomas Vanassche, Veerle Labarque, Peter Verhamme, Marc G Jacquemin, Kathleen Freson
Journal: Blood (2025)
CD44-Mediated Metabolic Rewiring is A Targetable Dependency of IDH-Mutant Leukemia
Authors: Junhua Lyu, Yuxuan Liu, Ningning Liu, Hieu Vu, Feng Cai, Hui Cao, Pranita Kaphle, Zheng Wu, Giovanni A Botten, Yuannyu Zhang, Jin Wang, Sarada Achyutuni, Xiaofei Gao, Ilaria Iacobucci, Charles G. Mullighan, Stephen S Chung, Min Ni, Ralph J DeBerardinis, Jian Xu
Journal: Blood (2025)

Recurrent IDH mutations catalyze NADPH-dependent production of oncometabolite R-2HG for tumorigenesis. IDH inhibition provides clinical response in a subset of acute myeloid leukemia (AML) cases; however, most patients develop resistance, highlighting the need for more effective IDH-targeting therapies. By comparing transcriptomic alterations in isogenic leukemia cells harboring CRISPR base-edited IDH mutations, we identify the activation of adhesion molecules including CD44, a transmembrane glycoprotein, as a shared feature of IDH-mutant leukemia, consistent with elevated CD44 expression in IDH-mutant AML patients. CD44 is indispensable for IDH-mutant leukemia cells through activating pentose phosphate pathway and inhibiting glycolysis by phosphorylating G6PD and PKM2, respectively. This metabolic rewiring ensures efficient NADPH generation for mutant IDH-catalyzed R-2HG production. Combining IDH inhibition with CD44 blockade enhances the elimination of IDH-mutant leukemia cells. Hence, we describe an oncogenic feedforward pathway involving CD44-mediated metabolic rewiring for oncometabolite production, representing a targetable dependency of IDH-mutant malignancies.
IL-1R1 and IL-18 Signals Regulate Mesenchymal Stromal Cells in an Aged Murine Model of Myelodysplastic Syndromes
Authors: Yuko Kawano, Hiroki Kawano, Mark W. LaMere, Elizabeth A. LaMere, Daniel K. Byun, Kathleen McGrath, James Palis, Jeevisha Bajaj, Jane L. Liesveld, Yoshio Katayama, Satoshi Yamazaki, Reuben Kapur, Laura M. Calvi, Tzu-Chieh Ho, Michael W Becker
Journal: Blood (2025)