tbuckley/cabot-search huggingface dataset:
Exploring the Connection Between Relaxed Myosin States and the Anrep Effect
Authors: Vasco Sequeira, Christoph Maack, Gert-Hinrich Reil, Jan-Christian Reil
Journal: Circulation Research (2024)

The Anrep effect is an adaptive response that increases left ventricular contractility following an acute rise in afterload. Although the mechanistic origin remains undefined, recent findings suggest a two-phase activation of resting myosin for contraction, involving strain-sensitive and posttranslational phases. We propose that this mobilization represents a transition among the relaxed states of myosin-specifically, from the super-relaxed (SRX) to the disordered-relaxed (DRX)-with DRX myosin ready to participate in force generation. This hypothesis offers a unified explanation that connects myosin's SRX-DRX equilibrium and the Anrep effect as parts of a singular phenomenon. We underscore the significance of this equilibrium in modulating contractility, primarily studied in the context of hypertrophic cardiomyopathy, the most common inherited cardiomyopathy associated with diastolic dysfunction, hypercontractility, and left ventricular hypertrophy. As we posit that the cellular basis of the Anrep effect relies on a two-phased transition of myosin from the SRX to the contraction-ready DRX configuration, any dysregulation in this equilibrium may result in the pathological manifestation of the Anrep phenomenon. For instance, in hypertrophic cardiomyopathy, hypercontractility is linked to a considerable shift of myosin to the DRX state, implying a persistent activation of the Anrep effect. These valuable insights call for additional research to uncover a clinical Anrep fingerprint in pathological states. Here, we demonstrate through noninvasive echocardiographic pressure-volume measurements that this fingerprint is evident in 12 patients with hypertrophic obstructive cardiomyopathy before septal myocardial ablation. This unique signature is characterized by enhanced contractility, indicated by a leftward shift and steepening of the end-systolic pressure-volume relationship, and a prolonged systolic ejection time adjusted for heart rate, which reverses post-procedure. The clinical application of this concept has potential implications beyond hypertrophic cardiomyopathy, extending to other genetic cardiomyopathies and even noncongenital heart diseases with complex etiologies across a broad spectrum of left ventricular ejection fractions.
Cyclophilin A is a ligand for RAGE in thrombo-inflammation
Authors: Peter Seizer, Saskia N I von Ungern-Sternberg, Verena Haug, Valerie Dicenta, Annabelle Rosa, Elke Butt, Moritz Nöthel, Anne-Katrin Rohlfing, Manuel Sigle, Peter P Nawroth, Claudia Nussbaum, Markus Sperandio, Charly Kusch, Mara Meub, Markus Sauer, Patrick Münzer, Kristin Bieber, Anna Stanger, Andreas F Mack, René Huber, Korbinian Brand, Moritz Lehners, Robert Feil, Antti Poso, Konstantin Krutzke, Tilman E Schäffer, Bernhard Nieswandt, Oliver Borst, Andreas E May, Alma Zernecke, Meinrad Gawaz, David Heinzmann
Journal: Cardiovascular Research (2024)

Cyclophilin A (CyPA) induces leucocyte recruitment and platelet activation upon release into the extracellular space. Extracellular CyPA therefore plays a critical role in immuno-inflammatory responses in tissue injury and thrombosis upon platelet activation. To date, CD147 (EMMPRIN) has been described as the primary receptor mediating extracellular effects of CyPA in platelets and leucocytes. The receptor for advanced glycation end products (RAGE) shares inflammatory and prothrombotic properties and has also been found to have similar ligands as CD147. In this study, we investigated the role of RAGE as a previously unknown interaction partner for CyPA.
Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma
Authors: Sana Hosni, Viola Kilian, Niklas Klümper, Daniela Gabbia, Katharina Sieckmann, Dillon Corvino, Anja Winkler, Miriam Saponaro, Karin Wörsdörfer, Doris Schmidt, Oliver Hahn, Ilaria Zanotto, Marina Bertlich, Marieta Toma, Tobias Bald, Markus Eckstein, Michael Hölzel, Matthias Geyer, Manuel Ritter, Dagmar Wachten, Sara De Martin, Abdullah Alajati
Journal: Cancer Research (2024)

Abstract Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic urothelial cancer (mUC), and blocking the FGF/FGFR signaling axis is used as a targeted therapeutic strategy for treating patients. Erdafitinib is a pan-FGFR inhibitor, which has recently been approved by the FDA for mUC with FGFR2/3 alterations. Although mUC patients show initial response to erdafitinib, acquired resistance rapidly develops. Here, we found that adipocyte precursors promoted resistance to erdafitinib in FGFR-dependent bladder and lung cancer in a paracrine manner. Moreover, neuregulin 1 (NRG1) secreted from adipocyte precursors was a mediator of erdafitinib resistance by activating human epidermal growth factor receptor 3 (ERBB3; also known as HER3) signaling, and knockdown of NRG1 in adipocyte precursors abrogated the conferred paracrine resistance. NRG1 expression was significantly downregulated in terminally differentiated adipocytes compared with their progenitors. Pharmacologic inhibition of the NRG1/HER3 axis using pertuzumab reversed erdafitinib resistance in tumor cells in vitro and prolonged survival of mice bearing bladder cancer xenografts in vivo. Remarkably, data from single-cell RNA sequencing revealed that NRG1 was enriched in platelet-derived growth factor receptor-A (PDGFRA) expressing inflammatory cancer-associated fibroblasts, which is also expressed on adipocyte precursors. Together, this work reveals a paracrine mechanism of anti-FGFR resistance in bladder cancer, and potentially other cancers, that is amenable to inhibition using available targeted therapies. Significance: Acquired resistance to FGFR inhibition can be rapidly promoted by paracrine activation of the NRG1/HER3 axis mediated by adipocyte precursors and can be overcome by the combination of pertuzumab and erdafitinib treatment. See related commentary by Kolonin and Anastassiou, p. 648
Interventions addressing health-related social needs among patients with cancer
Authors: Evan M Graboyes, Simon C Lee, Stacy Tessler Lindau, Alyce S Adams, Brenda A Adjei, Mary Brown, Gelareh Sadigh, Andrea Incudine, Ruth C Carlos, Scott D Ramsey, Rick Bangs
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Health-related social needs are prevalent among cancer patients; associated with substantial negative health consequences; and drive pervasive inequities in cancer incidence, severity, treatment choices and decisions, and outcomes. To address the lack of clinical trial evidence to guide health-related social needs interventions among cancer patients, the National Cancer Institute Cancer Care Delivery Research Steering Committee convened experts to participate in a clinical trials planning meeting with the goal of designing studies to screen for and address health-related social needs among cancer patients. In this commentary, we discuss the rationale for, and challenges of, designing and testing health-related social needs interventions in alignment with the National Academy of Sciences, Engineering, and Medicine 5As framework. Evidence for food, housing, utilities, interpersonal safety, and transportation health-related social needs interventions is analyzed. Evidence regarding health-related social needs and delivery of health-related social needs interventions differs in maturity and applicability to cancer context, with transportation problems having the most maturity and interpersonal safety the least. We offer practical recommendations for health-related social needs interventions among cancer patients and the caregivers, families, and friends who support their health-related social needs. Cross-cutting (ie, health-related social needs agnostic) recommendations include leveraging navigation (eg, people, technology) to identify, refer, and deliver health-related social needs interventions; addressing health-related social needs through multilevel interventions; and recognizing that health-related social needs are states, not traits, that fluctuate over time. Health-related social needs–specific interventions are recommended, and pros and cons of addressing more than one health-related social needs concurrently are characterized. Considerations for collaborating with community partners are highlighted. The need for careful planning, strong partners, and funding is stressed. Finally, we outline a future research agenda to address evidence gaps.
Q-BioLiP: A Comprehensive Resource for Quaternary Structure-based Protein–ligand Interactions
Authors: Hong Wei, Wenkai Wang, Zhenling Peng, Jianyi Yang
Journal: Genomics Proteomics & Bioinformatics (2024)

Since its establishment in 2013, BioLiP has become one of the widely used resources for protein-ligand interactions. Nevertheless, several known issues occurred with it over the past decade. For example, the protein-ligand interactions are represented in the form of single chain-based tertiary structures, which may be inappropriate as many interactions involve multiple protein chains (known as quaternary structures). We sought to address these issues, resulting in Q-BioLiP, a comprehensive resource for quaternary structure-based protein-ligand interactions. The major features of Q-BioLiP include: (1) representing protein structures in the form of quaternary structures rather than single chain-based tertiary structures; (2) pairing DNA/RNA chains properly rather than separation; (3) providing both experimental and predicted binding affinities; (4) retaining both biologically relevant and irrelevant interactions to alleviate the wrong justification of ligands' biological relevance; and (5) developing a new quaternary structure-based algorithm for the modelling of protein-ligand complex structure. With these new features, Q-BioLiP is expected to be a valuable resource for studying biomolecule interactions, including protein-small molecule interaction, protein-metal ion interaction, protein-peptide interaction, protein-protein interaction, protein-DNA/RNA interaction, and RNA-small molecule interaction. Q-BioLiP is freely available at https://yanglab.qd.sdu.edu.cn/Q-BioLiP/.
NextPolish2: A Repeat-aware Polishing Tool for Genomes Assembled Using HiFi Long Reads
Authors: Jiang Hu, Zhuo Wang, Fan Liang, Shan-Lin Liu, Kai Ye, De-Peng Wang
Journal: Genomics Proteomics & Bioinformatics (2024)

Abstract The high-fidelity (HiFi) long-read sequencing technology developed by PacBio has greatly improved the base-level accuracy of genome assemblies. However, these assemblies still contain base-level errors, particularly within the error-prone regions of HiFi long reads. Existing genome polishing tools usually introduce overcorrections and haplotype switch errors when correcting errors in genomes assembled from HiFi long reads. Here, we describe an upgraded genome polishing tool — NextPolish2, which can fix base errors remaining in those “highly accurate” genomes assembled from HiFi long reads without introducing excessive overcorrections and haplotype switch errors. We believe that NextPolish2 has a great significance to further improve the accuracy of telomere-to-telomere (T2T) genomes. NextPolish2 is freely available at https://github.com/Nextomics/NextPolish2.
Deciphering the role of rapidly evolving conserved elements in primate brain development and exploring their potential involvement in Alzheimer’s disease
Authors: Benxia Hu, Xiao-Lin Zhuang, Long Zhou, Guojie Zhang, David N Cooper, Dong-Dong Wu
Journal: Molecular Biology and Evolution (2024)

Abstract Although previous studies have identified human-specific accelerated regions as playing a key role in the recent evolution of the human brain, the characteristics and cellular functions of rapidly evolving conserved elements (RECEs) in ancestral primate lineages remain largely unexplored. Here, based on large-scale primate genome assemblies, we identify 888 RECEs that have been highly conserved in primates that exhibit significantly accelerated substitution rates in the ancestor of the Simiiformes. This primate lineage exhibits remarkable morphological innovations, including an expanded brain mass. Integrative multiomic analyses reveal that RECEs harbor sequences with potential cis-regulatory functions that are activated in the adult human brain. Importantly, genes linked to RECEs exhibit pronounced expression trajectories in the adult brain relative to the fetal stage. Furthermore, we observed an increase in the chromatin accessibility of RECEs in oligodendrocytes from individuals with Alzheimer's disease (AD) compared to that of a control group, indicating that these RECEs may contribute to brain aging and AD. Our findings serve to expand our knowledge of the genetic underpinnings of brain function during primate evolution.
The interaction of Synapsin 2a and Synaptogyrin-3 regulates fear extinction in mice
Authors: Xi-Ya Shen, Juan Zhang, He-Zhou Huang, Shao-Dan Li, Ling Zhou, Shi-Ping Wu, Cheng Tang, Xian Huang, Zhi-Qiang Liu, Zi-Yuan Guo, Xiang Li, Heng-Ye Man, You-Ming Lu, Ling-Qiang Zhu, Dan Liu
Journal: Journal of Clinical Investigation (2024)

The mechanisms behind a lack of efficient fear extinction in some individuals are unclear. Here, by employing a principal components analysis (PCA)-based approach, we differentiated the mice into extinction-resistant and susceptible groups. We identified that elevated synapsin 2a (Syn2a) in the infralimbic cortex (IL) to basolateral amygdala (BLA) circuit disrupted presynaptic orchestration, leading to an excitatory/inhibitory imbalance in the BLA region and causing extinction resistance. Overexpression or silencing of Syn2a levels in IL neurons replicated or alleviated behavioral, electrophysiological, and biochemical phenotypes in resistant mice. We further identified the proline-rich domain H in the C-terminal of Syn2a was indispensable for the interaction with synaptogyrin-3 (Syngr3) and demonstrated that disrupting this interaction restored extinction impairments. Molecular docking revealed ritonavir, an FDA-approved HIV drug, could disrupt Syn2a-Syngr3 binding and rescue fear extinction behavior in Syn2a-elevated mice. In summary, aberrant Syn2a elevation and its interaction with Syngr3 at the presynaptic site were crucial in fear extinction resistance, suggesting a potential therapeutic avenue for related disorders.
Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinﬂammatory syndrome
Authors: Selket Delafontaine, Alberto Iannuzzo, Tarin M. Bigley, Bram Mylemans, Ruchit Rana, Pieter Baatsen, Maria Cecilia Poli, Daisy Rymen, Katrien Jansen, Djalila Mekahli, Ingele Casteels, Catherine Cassiman, Philippe Demaerel, Alice Lepelley, Marie-Louise Frémond, Rik Schrijvers, Xavier Bossuyt, Katlijn Vints, Wim Huybrechts, Rachida Tacine, Karen Willekens, Anniek Corveleyn, Bram Boeckx, Marco Baggio, Lisa Ehlers, Sebastian Munck, Diether Lambrechts, Arnout Voet, Leen Moens, Giorgia Bucciol, Megan A. Cooper, Carla M. Davis, Jérôme Delon, Isabelle Meyts
Journal: Journal of Clinical Investigation (2024)

Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis and nephritis. We described three heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C and p.R1142X) in six children from three unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of the coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison to mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of the ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport and increased pro-inflammatory signaling.
A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice
Authors: Peter J. Metzger, Aileen Zhang, Bradley A. Carlson, Hui Sun, Zhenzhong Cui, Yongqi Li, Marshal T. Jahnke, Daniel R. Layton, Meenakshi B. Gupta, Naili Liu, Evi Kostenis, Oksana Gavrilova, Min Chen, Lee S. Weinstein
Journal: Journal of Clinical Investigation (2024)

Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP signaling, a significant proportion of obesity-associated MC4R mutations do not affect MC4R/Gsα signaling. To further explore the role of specific MC4R signaling pathways in regulation of energy balance, we examined the signaling properties of one such mutant MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/Gq/11α signaling and led to obesity, hyperphagia and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in wild-type mice in which a specific Gq/11α inhibitor was delivered to the PVN, providing evidence that a Gsα-independent signaling pathway, namely Gq/11α, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates Gq/11α may be a potential agent to treat obesity with less untoward cardiovascular and other side effects.
Clarification of Calculation Methods Added to Table
Journal: JAMA Network Open (2024)

Kevin W. McConeghy, PharmD, MS; Barbara Bardenheier, MPH, PhD; Andrew W. Huang, MS; Elizabeth M. White, APRN, PhD; Richard A. Feifer, MD, MPH; Carolyn Blackman, MD; Christopher M. Santostefano, BSN, RN; Yoojin Lee, MS; Frank DeVone, MS; Christopher W. Halladay, MS; James L. Rudolph, MD; Andrew R. Zullo, PharmD, PhD; Vincent Mor, PhD; Stefan Gravenstein, MD, MPH
Single-cell DNA sequencing reveals a high incidence of chromosomal abnormalities in human blastocysts
Authors: Effrosyni A. Chavli, Sjoerd J. Klaasen, Diane Van Opstal, Joop S.E. Laven, Geert J.P.L. Kops, Esther B. Baart
Journal: Journal of Clinical Investigation (2024)

Aneuploidy, a deviation from the normal chromosome copy number, is common in human embryos and is considered a primary cause of implantation failure and early pregnancy loss. Meiotic errors lead to uniformly abnormal karyotypes, while mitotic errors lead to chromosomal mosaicism: the presence of cells with at least two different karyotypes within an embryo. Knowledge about mosaicism in blastocysts mainly derives from bulk DNA sequencing of multicellular trophectoderm (TE) and/or inner cell mass (ICM) samples. However, this can only detect an average net gain or loss of DNA above a detection threshold of 20-30%. To accurately assess mosaicism, we separated the TE and ICM of 55 good quality surplus blastocysts and successfully applied single-cell whole genome sequencing (scKaryo-seq) on 1057 cells. Mosaicism involving numerical and structural chromosome abnormalities was detected in 82% of the embryos, where most abnormalities affected less than 20% of the cells. Structural abnormalities, potentially caused by replication stress and DNA damage, were observed in 69% of the embryos. In conclusion, our findings indicated that mosaicism is prevalent in good-quality blastocysts, while these blastocysts would likely be identified as normal with current bulk DNA sequencing techniques used for preimplantation genetic testing for aneuploidy (PGT-A).
Short Interpregnancy Intervals Among Women Experiencing Homelessness in Colorado
Authors: Rie Sakai-Bizmark, Nicholas J. Jackson, Frank Wu, Emily H. Marr, Hiraku Kumamaru, Dennys Estevez, Alison Gemmill, Jessica C. Moreno, Benjamin F. Henwood
Journal: JAMA Network Open (2024)

Short interpregnancy intervals (SIPIs) are associated with increased risk of adverse maternal and neonatal outcomes. Disparities exist across socioeconomic status, but there is little information on SIPIs among women experiencing homelessness.
Initiating Immunotherapy in the Treatment of Stage IV Cancers in the Month Before Death—A Health Care Disparities Lens
Authors: Michael Hoerger, Navya Nair, Sonia Malhotra
Journal: JAMA Oncology (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Wildfire Exposure and Lung Cancer Survival
Authors: Akihiko Ozaki, Michio Murakami, Claire Leppold
Journal: JAMA Oncology (2024)

To the Editor We congratulate Zhang and colleagues for their insightful cohort study identifying an association between wildfire exposure and survival among 466 912 lung cancer survivors in the US.1 To delve deeper into the implications of the findings, we have 3 comments.
Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US
Authors: Daniel M. Kerekes, Alexander E. Frey, Elizabeth H. Prsic, Thuy T. Tran, James E. Clune, Mario Sznol, Harriet M. Kluger, Howard P. Forman, Robert D. Becher, Kelly L. Olino, Sajid A. Khan
Journal: JAMA Oncology (2024)

While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown.
News beyond our pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2024)

IL-31 directly activates sensory neurons to induce itching and has been implicated in multiple pruritic inflammatory skin diseases. Fassett et al (Sci Immunol 2023;8:eabi6887; https://doi.org/10.1126/sciimmunol.abi6887) identified an immunoregulatory role for IL-31 in chronic allergic skin inflammation. More specifically, Il31-deficient mice exhibited decreased itching but enhanced type 2 immunopathology as compared to wild-type mice in experimental house dust mite-induced allergic dermatitis. Furthermore, elevated serum IgE and expansion of type 2 cytokine-producing CD4+ T cells and proinflammatory M2 macrophages in the skin were observed.