tbuckley/cabot-search huggingface dataset:
Left Atrial Improvement in Patients With Secondary Mitral Regurgitation and Heart Failure
Authors: Stephan M. Pio, Diego Medvedofsky, Victoria Delgado, Jan Stassen, Neil J. Weissman, Paul A. Grayburn, Saibal Kar, D. Scott Lim, Björn Redfors, Clayton Snyder, Zhipeng Zhou, Maria C. Alu, Samir R. Kapadia, JoAnn Lindenfeld, William T. Abraham, Michael J. Mack, Federico M. Asch, Gregg W. Stone, Jeroen J. Bax
Journal: JACC. Cardiovascular imaging (2024)

Functional mitral regurgitation induces adverse effects on the left ventricle and the left atrium. Left atrial (LA) dilatation and reduced LA strain are associated with poor outcomes in heart failure (HF). Transcatheter edge-to-edge repair (TEER) of the mitral valve reduces heart failure hospitalization (HFH) and all-cause death in selected HF patients. The aim of this study was to evaluate the impact of LA strain improvement 6 months after TEER on the outcomes of patients enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial. The difference in LA strain between baseline and the 6-month follow-up was calculated. Patients with at least a 15% improvement in LA strain were labeled as "LA strain improvers." All-cause death and HFH were assessed between the 6 and 24-month follow-up. Among 347 patients (mean age 71 ± 12 years, 63% male), 106 (30.5%) showed improvement of LA strain at the 6-month follow-up (64 [60.4%] from the TEER + guideline-directed medical therapy [GDMT] group and 42 [39.6%] from the GDMT alone group). An improvement in LA strain was significantly associated with a reduction in the composite of death or HFH between the 6-month and 24-month follow-up, with a similar risk reduction in both treatment arms (Pinteraction = 0.27). In multivariable analyses, LA strain improvement remained independently associated with a lower risk of the primary composite endpoint both as a continuous variable (adjusted HR: 0.94 [95% CI: 0.89-1.00]; P = 0.03) and as a dichotomous variable (adjusted HR: 0.49 [95% CI: 0.27-0.89]; P = 0.02). The best outcomes were observed in patients treated with TEER in whom LA strain improved. In symptomatic HF patients with severe mitral regurgitation, improved LA strain at the 6-month follow-up is associated with subsequently lower rates of the composite endpoint of all-cause mortality or HFH, both after TEER and GDMT alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079)
Glycosaminoglycans' for brain health: Harnessing glycosaminoglycan based biomaterials for treating central nervous system diseases and in-vitro modeling
Authors: Austin D. Evans, Negin Pournoori, Emmi Saksala, Oommen P. Oommen
Journal: Biomaterials (2024)

Dysfunction of the central nervous system (CNS) following traumatic brain injuries (TBI), spinal cord injuries (SCI), or strokes remains challenging to address using existing medications and cell-based therapies. Although therapeutic cell administration, such as stem cells and neuronal progenitor cells (NPCs), have shown promise in regenerative properties, they have failed to provide substantial benefits. However, the development of living cortical tissue engineered grafts, created by encapsulating these cells within an extracellular matrix (ECM) mimetic hydrogel scaffold, presents a promising functional replacement for damaged cortex in cases of stroke, SCI, and TBI. These grafts facilitate neural network repair and regeneration following CNS injuries. Given that natural glycosaminoglycans (GAGs) are a major constituent of the CNS, GAG-based hydrogels hold potential for the next generation of CNS healing therapies and in vitro modeling of CNS diseases. Brain-specific GAGs not only offer structural and biochemical signaling support to encapsulated neural cells but also modulate the inflammatory response in lesioned brain tissue, facilitating host integration and regeneration. This review briefly discusses different roles of GAGs and their related proteoglycan counterparts in healthy and diseases brain and explores current trends and advancements in GAG-based biomaterials for treating CNS injuries and modeling diseases. Additionally, it examines injectable, 3D bioprintable, and conductive GAG-based scaffolds, highlighting their clinical potential for in vitro modeling of patient-specific neural dysfunction and their ability to enhance CNS regeneration and repair following CNS injury in vivo.
Increasing Phosphorylated Tau Protein Serum Levels in the Course of Chronic Heart Failure
Authors: Jan Traub, Markus Otto, Camelia Maria Monoranu, Patrick Oeckl, György Homola, Dejan Radaković, Mirko Pham, Stefan Störk, Guido Stoll, Anna Frey
Journal: JACC Heart Failure (2024)
Combination SGLT2 Inhibitor and Glucagon Receptor Antagonist Therapy in Type 1 Diabetes: A Randomized Clinical Trial
Authors: Schafer C. Boeder, Robert L. Thomas, Melissa J. Le Roux, Erin R. Giovannetti, Justin M. Gregory, Jeremy H. Pettus
Journal: Diabetes Care (2024)

OBJECTIVE To examine the effects of insulin-adjunctive therapy with a sodium–glucose cotransporter 2 (SGLT2) inhibitor and a glucagon receptor antagonist (GRA) on glycemia, insulin use, and ketogenesis during insulinopenia in type 1 diabetes. RESEARCH DESIGN AND METHODS In a randomized, double-blind, placebo-controlled, crossover trial we assessed the effects of adjunctive SGLT2 inhibitor therapy (dapagliflozin 10 mg daily) alone and in combination with the GRA volagidemab (70 mg weekly) in 12 adults with type 1 diabetes. Continuous glucose monitoring, insulin dosing, and insulin withdrawal tests (IWT) for measurement of glucose and ketogenesis during insulinopenia were completed during insulin-only (Baseline), SGLT2 inhibitor, and combination (SGLT2 inhibitor + GRA) therapy periods. RESULTS Average glucose and percent time with glucose in range (70–180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 vs. 150 and 138 mg/dL [P &amp;lt; 0.001 and P = 0.01] and 86% vs. 70% and 78% [P &amp;lt; 0.001 and P = 0.03], respectively) without increased hypoglycemia. Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 vs. 0.56 and 0.52 units/kg/day [P &amp;lt; 0.001 and P = 0.002]). Peak β-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 vs. 2.4 mmol/L; P = 0.048) and similar to levels reached during the Baseline testing period (2.1 mmol/L). Participants reported enhanced treatment acceptability and satisfaction with combination therapy. CONCLUSIONS Glucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in type 1 diabetes. Combination therapy improves glycemic control, reduces insulin dosing, and suggests a strategy to unlock the benefits of SGLT2 inhibitors while mitigating the risk of diabetic ketoacidosis.
Gene therapy with phosphodiesterases 2A and 4B ameliorates heart failure and arrhythmias by improving subcellular cAMP compartmentation
Authors: Nikoleta Pavlaki, Alexander Froese, Wener Li, Kirstie A De Jong, Birgit Geertz, Hariharan Subramanian, Sanika Mohagaonkar, Xiaojing Luo, Mario Schubert, Robert Wiegmann, Jean Piero Margaria, Alessandra Ghigo, Susanne Kämmerer, Emilio Hirsch, Ali El-Armouche, Kaomei Guan, Viacheslav O Nikolaev
Journal: Cardiovascular Research (2024)

Abstract Aims Gene therapy with cardiac phosphodiesterases (PDEs), such as phosphodiesterase 4B (PDE4B), has recently been described to effectively prevent heart failure (HF) in mice. However, exact molecular mechanisms of its beneficial effects, apart from general lowering of cardiomyocyte cyclic adenosine monophosphate (cAMP) levels, have not been elucidated. Here, we studied whether gene therapy with two types of PDEs, namely PDE2A and PDE4B, can prevent pressure-overload-induced HF in mice by acting on and restoring altered cAMP compartmentation in distinct subcellular microdomains. Methods and results HF was induced by transverse aortic constriction followed by tail-vein injection of adeno-associated-virus type 9 vectors to overexpress PDE2A3, PDE4B3, or luciferase for 8 weeks. Heart morphology and function was assessed by echocardiography and histology which showed that PDE2A and especially PDE4B gene therapy could attenuate cardiac hypertrophy, fibrosis, and decline of contractile function. Live cell imaging using targeted cAMP biosensors showed that PDE overexpression restored altered cAMP compartmentation in microdomains associated with ryanodine receptor type 2 (RyR2) and caveolin-rich plasma membrane. This was accompanied by ameliorated caveolin-3 decline after PDE2A3 overexpression, reduced RyR2 phosphorylation in PDE4B3 overexpressing hearts, and antiarrhythmic effects of both PDEs measured under isoproterenol stimulation in single cells. Strong association of overexpressed PDE4B but not PDE2A with RyR2 microdomain could prevent calcium leak and arrhythmias in human-induced pluripotent stem-derived cardiomyocytes with the A2254V mutation in RyR2 causing catecholaminergic polymorphic ventricular tachycardia. Conclusion Our data indicate that gene therapy with phosphodiesterases can prevent HF including associated cardiac remodelling and arrhythmias by restoring altered cAMP compartmentation in functionally relevant subcellular microdomains.
The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses
Authors: David R. Martinez, Fernando R. Moreira, Nicholas J. Catanzaro, Meghan V. Diefenbacher, Mark R. Zweigart, Kendra L. Gully, Gabriela De la Cruz, Ariane J. Brown, Lily E. Adams, Boyd Yount, Thomas J. Baric, Michael L. Mallory, Helen Conrad, Samantha R. May, Stephanie Dong, D. Trevor Scobey, Cameron Nguyen, Stephanie A. Montgomery, Jason K. Perry, Darius Babusis, Kimberly T. Barrett, Anh-Hoa Nguyen, Anh-Quan Nguyen, Rao Kalla, Roy Bannister, Joy Y. Feng, Tomas Cihlar, Ralph S. Baric, Richard L. Mackman, John P. Bilello, Alexandra Schäfer, Timothy P. Sheahan
Journal: Science Translational Medicine (2024)

Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV-related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (M
Dating ammonia-oxidizing bacteria with abundant eukaryotic fossils
Authors: Tianhua Liao, Sishuo Wang, Hao Zhang, Eva E Stüeken, Haiwei Luo
Journal: Molecular Biology and Evolution (2024)

Evolution of a complete nitrogen (N) cycle relies on the onset of ammonia oxidation, which aerobically converts ammonia to nitrogen oxides. However, accurate estimation of the antiquity of ammonia-oxidizing bacteria (AOB) remains challenging because AOB-specific fossils are absent and bacterial fossils amenable to calibrate molecular clocks are rare. Leveraging the ancient endosymbiosis of mitochondria and plastid, as well as using state-of-the-art Bayesian sequential dating approach, we obtained a timeline of AOB evolution calibrated largely by eukaryotic fossils. We show that the first AOB evolved in marine Gammaproteobacteria (Gamma-AOB) and emerged between 2.1 and 1.9 billion years ago (Ga), thus postdating the Great Oxidation Event (GOE; 2.4 to 2.32 Ga). To reconcile the sedimentary N isotopic signatures of ammonia oxidation occurring near the GOE, we propose that ammonia oxidation likely occurred at the common ancestor of Gamma-AOB and Gammaproteobacterial methanotrophs, or the actinobacterial/verrucomicrobial methanotrophs which are known to have ammonia oxidation activities. It is also likely that nitrite was transported from the terrestrial habitats where ammonia oxidation by archaea took place. Further, we show that the Gamma-AOB predated the anaerobic ammonia-oxidizing (anammox) bacteria, implying that the emergence of anammox was constrained by the availability of dedicated ammonia oxidizers which produce nitrite to fuel anammox. Our work supports a new hypothesis that N redox cycle involving nitrogen oxides evolved rather late in the ocean.
Long-Term Exposure to Fine Particulate Matter and Fasting Blood Glucose and Diabetes in 20 Million Chinese Women of Reproductive Age
Authors: Yang Shen, Lifang Jiang, Xiaoxu Xie, Xia Meng, Xianrong Xu, Jing Dong, Ying Yang, Jihong Xu, Ya Zhang, Qiaomei Wang, Haiping Shen, Yiping Zhang, Donghai Yan, Lu Zhou, Yixuan Jiang, Renjie Chen, Haidong Kan, Jing Cai, Yuan He, Xu Ma
Journal: Diabetes Care (2024)

OBJECTIVE Evidence of the associations between fine particulate matter (PM2.5) and diabetes risk from women of reproductive age, in whom diabetes may have adverse long-term health effects for both themselves and future generations, remains scarce. We therefore examined the associations of long-term PM2.5 exposure with fasting blood glucose (FBG) level and diabetes risk in women of reproductive age in China. RESEARCH DESIGN AND METHODS This study included 20,076,032 women age 20–49 years participating in the National Free Preconception Health Examination Project in China between 2010 and 2015. PM2.5 was estimated using a satellite-based model. Multivariate linear and logistic regression models were used to examine the associations of PM2.5 exposure with FBG level and diabetes risk, respectively. Diabetes burden attributable to PM2.5 was estimated using attributable fraction (AF) and attributable number. RESULTS PM2.5 showed monotonic relationships with elevated FBG level and diabetes risk. Each interquartile range (27 μg/m3) increase in 3-year average PM2.5 concentration was associated with a 0.078 mmol/L (95% CI 0.077, 0.079) increase in FBG and 18% (95% CI 16%, 19%) higher risk of diabetes. The AF attributed to PM2.5 exposure exceeding 5 μg/m3 was 29.0% (95% CI 27.5%, 30.5%), corresponding to an additional 78.6 thousand (95% CI 74.5, 82.6) diabetes cases. Subgroup analyses showed more pronounced diabetes risks in those who were overweight or obese, age &amp;gt;35 years, less educated, of minority ethnicity, registered as a rural household, and residing in western China. CONCLUSIONS We found long-term PM2.5 exposure was associated with higher diabetes risk in women of reproductive age in China.
Enhancing Infected Diabetic Wound Healing through Multifunctional Nanocomposite‐Loaded Microneedle Patch: Inducing Multiple Regenerative Sites
Authors: Daojiang Yu, Lei Chen, Tao Yan, Yuanyuan Zhang, Xiaodong Sun, Guozhong Lv, Shuyu Zhang, Yong Xu, Changlong Li
Journal: Advanced Healthcare Materials (2024)

Abstract Infected diabetic wound (DW) presents a prolonged and challenging healing process within the field of regenerative medicine. The effectiveness of conventional drug therapies is hindered by their limited ability to reach deep tissues and promote adequate wound healing rates. Therefore, there is an imperative to develop drug delivery systems that can penetrate deep tissues while exhibiting multifunctional properties to expedite wound healing. In this study, w e devised a soluble microneedle (MN) patch made of γ‐PGA, featuring multiple arrays, which w as loaded with core‐shell structured nanoparticles (NPs) known as Ag@MSN@CeO 2 , to enhance the healing of infected DWs. The NP comprises a cerium dioxide (CeO 2 ) core with anti‐inflammatory and antioxidant properties, a mesoporous silica NP (MSN) shell with angiogenic characteristics, and an outermost layer doped with Ag to combat bacterial infections. W e demonstrated that the MN platform loaded with Ag@MSN@CeO 2 successfully penetrated deep tissues for effective drug delivery. These MN tips induced the formation of multiple regenerative sites at various points, leading to antibacterial, reactive oxygen species‐lowering, macrophage ecological niche‐regulating, vascular regeneration‐promoting, and collagen deposition‐promoting effects, thus significantly expediting the healing process of infected DWs. Considering these findings, the multifunctional MN@Ag@MSN@CeO 2 patch exhibits substantial potential for clinical applications in the treatment of infected DW.
Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell–engaging bispecific antibody targeting human claudin 6
Authors: Christiane R. Stadler, Ursula Ellinghaus, Leyla Fischer, Hayat Bähr-Mahmud, Martin Rao, Claudia Lindemann, Anuhar Chaturvedi, Caroline Scharf, Imke Biermann, Bernhard Hebich, Alexandra Malz, Georg Beresin, Georg Falck, Aline Häcker, Astrid Houben, Michael Erdeljan, Kristina Wolf, Maximilian Kullmann, Philip Chang, Özlem Türeci, Uğur Şahin
Journal: Science Translational Medicine (2024)

We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)-formulated RNA (RNA-LNP) encoding a T cell-engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1. In vitro, RiboMab02.1 mediated CLDN6 target cell-specific activation and proliferation of T cells, and potent target cell killing. In mice and cynomolgus monkeys, intravenously administered BNT142 RNA-LNP maintained therapeutic serum concentrations of the encoded antibody. Concentrations of RNA-encoded RiboMab02.1 were maintained longer in circulation in mice than concentrations of directly injected, sequence-identical protein. Weekly injections of mice with BNT142 RNA-LNP in the 0.1- to 1-μg dose range were sufficient to eliminate CLDN6-positive subcutaneous human xenograft tumors and increase survival over controls. Tumor regression was associated with an influx of T cells and depletion of CLDN6-positive cells. BNT142 induced only transient and low cytokine production in CLDN6-positive tumor-bearing mice humanized with peripheral blood mononuclear cells (PBMCs). No signs of adverse effects from BNT142 RNA-LNP administration were observed in mice or cynomolgus monkeys. On the basis of these and other findings, a phase 1/2 first-in-human clinical trial has been initiated to assess the safety and preliminary efficacy of BNT142 RNA-LNP in patients with CLDN6-positive advanced solid tumors (NCT05262530).
Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes
Authors: Zhuo Chen, Eiichiro Satake, Marcus G. Pezzolesi, Zaipul I. Md Dom, Devorah Stucki, Hiroki Kobayashi, Anna Syreeni, Adam T. Johnson, Xiwei Wu, Emma H. Dahlström, Jaxon B. King, Per-Henrik Groop, Stephen S. Rich, Niina Sandholm, Andrzej S. Krolewski, Rama Natarajan
Journal: Science Translational Medicine (2024)

Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up. Our epigenome-wide analysis identified DNAmet at 17 CpGs (5′-cytosine-phosphate-guanine-3′ loci) associated with risk of KF independent of major clinical risk factors. DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years. Furthermore, DNAmet variations at seven KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk of KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs. A prediction model for risk of KF was developed by adding blood cell DNAmet at eight selected KF-associated CpGs to the clinical model. This updated model significantly improved prediction performance (c-statistic = 0.93) versus the clinical model (c-statistic = 0.85) at P = 6.62 × 10 −14 . In conclusion, our multiomics study provides insights into mechanisms through which variation of DNAmet may affect KF development and shows that blood cell DNAmet at certain CpGs can improve risk prediction for KF in T1D.
Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice
Authors: Jeremy M. Sullivan, Anna M. Bagnell, Jonathan Alevy, Elvia Mena Avila, Ljubica Mihaljević, Pamela C. Saavedra-Rivera, Lingling Kong, Jennifer S. Huh, Brett A. McCray, William H. Aisenberg, Aamir R. Zuberi, Laurent Bogdanik, Cathleen M. Lutz, Zhaozhu Qiu, Katharina A. Quinlan, Peter C. Searson, Charlotte J. Sumner
Journal: Science Translational Medicine (2024)

Blood-CNS barrier disruption is a hallmark of numerous neurological disorders, yet whether barrier breakdown is sufficient to trigger neurodegenerative disease remains unresolved. Therapeutic strategies to mitigate barrier hyperpermeability are also limited. Dominant missense mutations of the cation channel transient receptor potential vanilloid 4 (TRPV4) cause forms of hereditary motor neuron disease. To gain insights into the cellular basis of these disorders, we generated knock-in mouse models of TRPV4 channelopathy by introducing two disease-causing mutations (R269C and R232C) into the endogenous mouse
Niclosamide combined to Azacitidine to target TP53-mutated MDS/AML cells
Authors: Nabih Maslah, Salome Rety, Melina Bonnamy, Lorea Aguinaga, Tony Huynh, Veronique Parietti, Stephane Giraudier, Pierre Fenaux, Bruno Cassinat
Journal: Leukemia (2024)
Single-cell transcriptomic analysis identifies infiltrating plasmacytoid dendritic cells in psoriasis epidermis
Authors: Longlong Luo, Huaitao Cheng, Zhuang Liu, Pawel Olszewski, Lorenzo Pasquali, Ning Xu, Martin Enge, Andor Pivarcsi, Enikö Sonkoly
Journal: British Journal of Dermatology (2024)

Our study unveils the cellular and molecular dynamics in psoriasis epidermis, revealing diverse cell states and their interactions driving inflammation and altered developmental trajectories. Importantly, a previously overlooked plasmacytoid dendritic cell cluster with inflammatory properties was identified in the epidermis of chronic psoriasis lesions, suggesting a potential role for these cells in chronic psoriasis.