tbuckley/cabot-search huggingface dataset:
Hypertension: Causes and Consequences of Circadian Rhythms in Blood Pressure
Authors: Frank M. Faraci, Frank A.J.L. Scheer
Journal: Circulation Research (2024)

Hypertension is extremely common, affecting approximately 1 in every 2 adults globally. Chronic hypertension is the leading modifiable risk factor for cardiovascular disease and premature mortality worldwide. Despite considerable efforts to define mechanisms that underlie hypertension, a potentially major component of the disease, the role of circadian biology has been relatively overlooked in both preclinical models and humans. Although the presence of daily and circadian patterns has been observed from the level of the genome to the whole organism, the functional and structural impact of biological rhythms, including mechanisms such as circadian misalignment, remains relatively poorly defined. Here, we review the impact of daily rhythms and circadian systems in regulating blood pressure and the onset, progression, and consequences of hypertension. There is an emphasis on the impact of circadian biology in relation to vascular disease and end-organ effects that, individually or in combination, contribute to complex phenotypes such as cognitive decline and the loss of cardiac and brain health. Despite effective treatment options for some individuals, control of blood pressure remains inadequate in a substantial portion of the hypertensive population. Greater insight into circadian biology may form a foundation for novel and more widely effective molecular therapies or interventions to help in the prevention, treatment, and management of hypertension and its related pathophysiology.
TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice
Authors: Danielle A. Callaway, Ian J. Penkala, Su Zhou, Jonathan J. Knowlton, Fabian Cardenas-Diaz, Apoorva Babu, Michael P. Morley, Mariana Lopes, Benjamin A. Garcia, Edward E. Morrisey
Journal: Journal of Clinical Investigation (2024)

Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-β superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-β signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-β signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.
Circadian Mechanisms in Brain Fluid Biology
Authors: Velia S. Vizcarra, Ryann M. Fame, Lauren M. Hablitz
Journal: Circulation Research (2024)

The brain is a complex organ, fundamentally changing across the day to perform basic functions like sleep, thought, and regulating whole-body physiology. This requires a complex symphony of nutrients, hormones, ions, neurotransmitters and more to be properly distributed across the brain to maintain homeostasis throughout 24 hours. These solutes are distributed both by the blood and by cerebrospinal fluid. Cerebrospinal fluid contents are distinct from the general circulation because of regulation at brain barriers including the choroid plexus, glymphatic system, and blood-brain barrier. In this review, we discuss the overlapping circadian (≈24-hour) rhythms in brain fluid biology and at the brain barriers. Our goal is for the reader to gain both a fundamental understanding of brain barriers alongside an understanding of the interactions between these fluids and the circadian timing system. Ultimately, this review will provide new insight into how alterations in these finely tuned clocks may lead to pathology.
Circadian Biology and the Neurovascular Unit
Authors: Wenlu Li, Steffen Tiedt, Jennifer H. Lawrence, Mary E. Harrington, Erik S. Musiek, Eng H. Lo
Journal: Circulation Research (2024)

Mammalian physiology and cellular function are subject to significant oscillations over the course of every 24-hour day. It is likely that these daily rhythms will affect function as well as mechanisms of disease in the central nervous system. In this review, we attempt to survey and synthesize emerging studies that investigate how circadian biology may influence the neurovascular unit. We examine how circadian clocks may operate in neural, glial, and vascular compartments, review how circadian mechanisms regulate cell-cell signaling, assess interactions with aging and vascular comorbidities, and finally ask whether and how circadian effects and disruptions in rhythms may influence the risk and progression of pathophysiology in cerebrovascular disease. Overcoming identified challenges and leveraging opportunities for future research might support the development of novel circadian-based treatments for stroke.
Stroke in the Time of Circadian Medicine
Authors: Philipp Mergenthaler, Joyce S. Balami, Ain A. Neuhaus, Amin Mottahedin, Gregory W. Albers, Peter M. Rothwell, Jeffrey L. Saver, Martin E. Young, Alastair M. Buchan
Journal: Circulation Research (2024)

Time-of-day significantly influences the severity and incidence of stroke. Evidence has emerged not only for circadian governance over stroke risk factors, but also for important determinants of clinical outcome. In this review, we provide a comprehensive overview of the interplay between chronobiology and cerebrovascular disease. We discuss circadian regulation of pathophysiological mechanisms underlying stroke onset or tolerance as well as in vascular dementia. This includes cell death mechanisms, metabolism, mitochondrial function, and inflammation/immunity. Furthermore, we present clinical evidence supporting the link between disrupted circadian rhythms and increased susceptibility to stroke and dementia. We propose that circadian regulation of biochemical and physiological pathways in the brain increase susceptibility to damage after stroke in sleep and attenuate treatment effectiveness during the active phase. This review underscores the importance of considering circadian biology for understanding the pathology and treatment choice for stroke and vascular dementia and speculates that considering a patient's chronotype may be an important factor in developing precision treatment following stroke.
Disrupted TGF-β signaling: a link between bronchopulmonary dysplasia and alveolar type 1 cells
Authors: Rongbo Li
Journal: Journal of Clinical Investigation (2024)

Bronchopulmonary dysplasia (BPD) is a chronic lung disease common in extreme preterm infants and is characterized by alveolar simplification. Current BPD research mainly focuses on alveolar type 2 (AT2) cells, myofibroblasts, and the endothelium. However, a notable gap exists in the involvement of AT1 cells, which constitute a majority of the alveolar surface area. In this issue of the JCI, Callaway and colleagues explored the role of TGF-β signaling in AT1 cells for managing the AT1-to-AT2 transition and its involvement in the integration of mechanical forces with the pulmonary matrisome during development. The findings implicate AT1 cells in the pathogenesis of BPD.
Mast cell activation disrupts interactions between endothelial cells and pericytes during early life allergic asthma
Authors: Régis Joulia, Franz Puttur, Helen Stölting, William J Traves, Lewis J Entwistle, Anastasia Voitovich, Minerva Garcia Martín, May Al-Sahaf, Katie Bonner, Elizabeth Scotney, Philip L Molyneaux, Richard J Hewitt, Simone A Walker, Laura Yates, Sejal Saglani, Clare M Lloyd
Journal: Journal of Clinical Investigation (2024)

Allergic asthma generally starts during early life and is linked to substantial tissue remodeling and lung dysfunction. Although angiogenesis is a feature of the disrupted airway, the impact of allergic asthma on the pulmonary microcirculation during early life is unknown. Here, using quantitative imaging in precision-cut lung slices (PCLSs), we report that exposure of neonatal mice to house dust mite (HDM) extract disrupts endothelial cell/pericyte interactions in adventitial areas. Central to the blood vessel structure, the loss of pericyte coverage was driven by mast cell (MC) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-cadherin. Furthermore, spatial transcriptomics of pediatric asthmatic endobronchial biopsies suggests intense vascular stress and remodeling linked with increased expression of MC activation pathways in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.
Evidence-Based Guideline for the management of osteoporosis in men
Authors: Nicholas R. Fuggle, Charlotte Beaudart, Olivier Bruyère, Bo Abrahamsen, Nasser Al-Daghri, Nansa Burlet, Manju Chandran, Mario M. Rosa, Bernard Cortet, Céline Demonceau, Willard Dere, Philippe Halbout, Mickaël Hiligsmann, John A. Kanis, Jean-Marc Kaufman, Andreas Kurth, Olivier Lamy, Andrea Laslop, Stefania Maggi, Radmila Matijevic, Eugene McCloskey, Ali Mobasheri, Maria C. Prieto Yerro, Régis P. Radermecker, Shaun Sabico, Yousef Al-Saleh, Stuart Silverman, Nicola Veronese, René Rizzoli, Cyrus Cooper, Jean-Yves Reginster, Nicholas C. Harvey
Journal: Nature Reviews Rheumatology (2024)
Focused ultrasound-mediated cerium-based nanoreactor against Parkinson's disease via ROS regulation and microglia polarization
Authors: Yifei Gao, Limin Zhai, Jiapeng Chen, Danmin Lin, Ling-Kun Zhang, Hao Yang, Runcai Yang, LinJing Mi, Yan-Qing Guan
Journal: Journal of Controlled Release (2024)
Iron-carbohydrate complexes treating iron anaemia: Understanding the nano-structure and interactions with proteins through orthogonal characterisation
Authors: Leonard Krupnik, Jonathan Avaro, Marianne Liebi, Neda Iranpour Anaraki, Joachim Kohlbrecher, Alla Sologubenko, Stephan Handschin, Andrzej J. Rzepiela, Christian Appel, Tiberiu Totu, Clement E. Blanchet, Amy E. Barton Alston, Reinaldo Digigow, Erik Philipp, Beat Flühmann, Bruno F.B. Silva, Antonia Neels, Peter Wick
Journal: Journal of Controlled Release (2024)

Intravenous (IV) iron-carbohydrate complexes are widely used nanoparticles (NPs) to treat iron deficiency anaemia, often associated with medical conditions such as chronic kidney disease, heart failure and various inflammatory conditions. Even though a plethora of physicochemical characterisation data and clinical studies are available for these products, evidence-based correlation between physicochemical properties of iron-carbohydrate complexes and clinical outcome has not fully been elucidated yet. Studies on other metal oxide NPs suggest that early interactions between NPs and blood upon IV injection are key to understanding how differences in physicochemical characteristics of iron-carbohydrate complexes cause variance in clinical outcomes. We therefore investigated the core-ligand structure of two clinically relevant iron-carbohydrate complexes, iron sucrose (IS) and ferric carboxymaltose (FCM), and their interactions with two structurally different human plasma proteins, human serum albumin (HSA) and fibrinogen, using a combination of cryo-scanning transmission electron microscopy (cryo-STEM), x-ray diffraction (XRD), small-angle x-ray scattering (SAXS) and small-angle neutron scattering (SANS). Using this orthogonal approach, we defined the nano-structure, individual building blocks and surface morphology for IS and FCM. Importantly, we revealed significant differences in the surface morphology of the iron-carbohydrate complexes. FCM shows a localised carbohydrate shell around its core, in contrast to IS, which is characterised by a diffuse and dynamic layer of carbohydrate ligand surrounding its core. We hypothesised that such differences in carbohydrate morphology determine the interaction between iron-carbohydrate complexes and proteins and therefore investigated the NPs in the presence of HSA and fibrinogen. Intriguingly, IS showed significant interaction with HSA and fibrinogen, forming NP-protein clusters, while FCM only showed significant interaction with fibrinogen. We postulate that these differences could influence bio-response of the two formulations and their clinical outcome. In conclusion, our study provides orthogonal characterisation of two clinically relevant iron-carbohydrate complexes and first hints at their interaction behaviour with proteins in the human bloodstream, setting a prerequisite towards complete understanding of the correlation between physicochemical properties and clinical outcome.
B-cells in pulmonary arterial hypertension: friend, foe or bystander?
Authors: Sébastien Sanges, Wen Tian, Sylvain Dubucquoi, Jason L. Chang, Aurore Collet, David Launay, Mark R. Nicolls
Journal: European Respiratory Journal (2024)

There is an unmet need for new therapeutic strategies that target alternative pathways to improve the prognosis of patients with pulmonary arterial hypertension (PAH). As immunity has been involved in the development and progression of vascular lesions in PAH, we review the potential contribution of B-cells in its pathogenesis and evaluate the relevance of B-cell-targeted therapies. Circulating B-cell homeostasis is altered in PAH patients, with total B-cell lymphopenia, abnormal subset distribution (expansion of naïve and antibody-secreting cells, reduction of memory B-cells) and chronic activation. B-cells are recruited to the lungs through local chemokine secretion, and activated by several mechanisms: 1) interaction with lung vascular autoantigens through cognate B-cell receptors; 2) costimulatory signals provided by T follicular helper cells (interleukin (IL)-21), type 2 T helper cells and mast cells (IL-4, IL-6 and IL-13); and 3) increased survival signals provided by B-cell activating factor pathways. This activity results in the formation of germinal centres within perivascular tertiary lymphoid organs and in the local production of pathogenic autoantibodies that target the pulmonary vasculature and vascular stabilisation factors (including angiotensin-II/endothelin-1 receptors and bone morphogenetic protein receptors). B-cells also mediate their effects through enhanced production of pro-inflammatory cytokines, reduced anti-inflammatory properties by regulatory B-cells, immunoglobulin (Ig)G-induced complement activation, and IgE-induced mast cell activation. Precision-medicine approaches targeting B-cell immunity are a promising direction for select PAH conditions, as suggested by the efficacy of anti-CD20 therapy in experimental models and a trial of rituximab in systemic sclerosis-associated PAH.
FEV<sub>1</sub>Q: a race-neutral approach to assessing lung function
Authors: Aparna Balasubramanian, Robert A. Wise, Sanja Stanojevic, Martin R. Miller, Meredith C. McCormack
Journal: European Respiratory Journal (2024)

Background Forced expiratory volume in 1 s quotient (FEV 1 Q) is a simple approach to spirometry interpretation that compares measured lung function to a lower boundary. This study evaluated how well FEV 1 Q predicts survival compared with current interpretation methods and whether race impacts FEV 1 Q. Methods White and Black adults with complete spirometry and mortality data from the National Health and Nutrition Examination Survey (NHANES) III and the United Network for Organ Sharing (UNOS) database for lung transplant referrals were included. FEV 1 Q was calculated as FEV 1 divided by 0.4 L for females or 0.5 L for males. Cumulative distributions of FEV 1 were compared across races. Cox proportional hazards models tested mortality risk from FEV 1 Q adjusting for age, sex, height, smoking, income and among UNOS individuals, referral diagnosis. Harrell's C-statistics were compared between absolute FEV 1 , FEV 1 Q, FEV 1 /height 2 , FEV 1 z-scores and FEV 1 % predicted. Analyses were stratified by race. Results Among 7182 individuals from NHANES III and 7149 from UNOS, 1907 (27%) and 991 (14%), respectively, were Black. The lower boundary FEV 1 values did not differ between Black and White individuals in either population (FEV 1 first percentile difference ≤0.01 L; p&gt;0.05). Decreasing FEV 1 Q was associated with increasing hazard ratio (HR) for mortality (NHANES III HR 1.33 (95% CI 1.28–1.39) and UNOS HR 1.18 (95% CI 1.12–1.23)). The associations were not confounded nor modified by race. Discriminative power was highest for FEV 1 Q compared with alternative FEV 1 approaches in both Black and White individuals. Conclusions FEV 1 Q is an intuitive and simple race-neutral approach to interpreting FEV 1 that predicts survival better than current alternative methods.
The longitudinal microbial and metabolic landscape of infant cystic fibrosis: the gut–lung axis
Authors: Katherine B. Frayman, Matthew Macowan, Jose Caparros-Martin, Sarath C. Ranganathan, Benjamin J. Marsland
Journal: European Respiratory Journal (2024)

Background and aim In cystic fibrosis, gastrointestinal dysfunction and lower airway infection occur early and are independently associated with poorer outcomes in childhood. This study aimed to define the relationship between the microbiota at each niche during the first 2 years of life, its association with growth and airway inflammation, and explanatory features in the metabolome. Materials and methods 67 bronchoalveolar lavage fluid (BALF), 62 plasma and 105 stool samples were collected from 39 infants with cystic fibrosis between 0 and 24 months who were treated with prophylactic antibiotics. 16S rRNA amplicon and shotgun metagenomic sequencing were performed on BALF and stool samples, respectively; metabolomic analyses were performed on all sample types. Sequencing data from healthy age-matched infants were used as controls. Results Bacterial diversity increased over the first 2 years in both BALF and stool, and microbial maturation was delayed in comparison to healthy controls from the RESONANCE cohort. Correlations between their respective abundance in both sites suggest stool may serve as a noninvasive alternative for detecting BALF Pseudomonas and Veillonella . Multisite metabolomic analyses revealed age- and growth-related changes, associations with neutrophilic airway inflammation, and a set of core systemic metabolites. BALF Pseudomonas abundance was correlated with altered stool microbiome composition and systemic metabolite alterations, highlighting a complex gut–plasma–lung interplay and new targets with therapeutic potential. Conclusion Exploration of the gut–lung microbiome and metabolome reveals diverse multisite interactions in cystic fibrosis that emerge in early life. Gut–lung metabolomic links with airway inflammation and Pseudomonas abundance warrant further investigation for clinical utility, particularly in non-expectorating patients.
Even short periods of diabetes remission are linked to lower risk of heart attack and stroke
Authors: Helen Saul, Brendan Deeney, Laura Swaithes, Hilda Hounkpatin, Hajira Dambha-Miller
Journal: BMJ (2024)

The study Dambha-Miller H, Hounkpatin HO, Stuart B, Farmer A, Griffin S. Type 2 diabetes remission trajectories and variation in risk of diabetes complications: a population-based cohort study. PLoS ONE 2023;18. doi: 10.1371/journal.pone.0290791 . To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/even-short-periods-of-diabetes-remission-are-linked-to-lower-risk-of-heart-attack-and-stroke/
ERS/EBMT clinical practice guidelines on treatment of pulmonary chronic graft-<i>versus</i>-host disease in adults
Authors: Saskia Bos, John Murray, Monia Marchetti, Guang-Shing Cheng, Anne Bergeron, Daniel Wolff, Clare Sander, Akshay Sharma, Sherif M. Badawy, Zinaida Peric, Agnieszka Piekarska, Joseph Pidala, Kavita Raj, Olaf Penack, Samar Kulkarni, Molly Beestrum, Andrea Linke, Matthew Rutter, Courtney Coleman, Thomy Tonia, Hélène Schoemans, Daiana Stolz, Robin Vos
Journal: European Respiratory Journal (2024)

Chronic graft- versus -host disease (cGvHD) is a common complication after allogeneic haematopoietic stem cell transplantation, characterised by a broad disease spectrum that can affect virtually any organ. Although pulmonary cGvHD is a less common manifestation, it is of great concern due to its severity and poor prognosis. Optimal management of patients with pulmonary cGvHD is complicated and no standardised approach is available. The purpose of this joint European Respiratory Society (ERS) and European Society for Blood and Marrow Transplantation task force was to develop evidence-based recommendations regarding the treatment of pulmonary cGvHD phenotype bronchiolitis obliterans syndrome in adults. A multidisciplinary group representing specialists in haematology, respiratory medicine and methodology, as well as patient advocates, formulated eight PICO (patient, intervention, comparison, outcome) and two narrative questions. Following the ERS standardised methodology, we conducted systematic reviews to address these questions and used the Grading of Recommendations Assessment, Development and Evaluation approach to develop recommendations. The resulting guideline addresses common therapeutic options (inhalation therapy, fluticasone-azithromycin-montelukast, imatinib, ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis and lung transplantation), as well as other aspects of general management, such as lung functional and radiological follow-up and pulmonary rehabilitation, for adults with pulmonary cGvHD phenotype bronchiolitis obliterans syndrome. These recommendations include important advancements that could be incorporated in the management of adults with pulmonary cGvHD, primarily aimed at improving and standardising treatment and improving outcomes.
Type 2 airway inflammation in COPD
Authors: Francesca Polverino, Don D. Sin
Journal: European Respiratory Journal (2024)

Globally, nearly 400 million persons have COPD, and COPD is one of the leading causes of hospitalisation and mortality across the world. While it has been long-recognised that COPD is an inflammatory lung disease, dissimilar to asthma, type 2 inflammation was thought to play a minor role. However, recent studies suggest that in approximately one third of patients with COPD, type 2 inflammation may be an important driver of disease and a potential therapeutic target. Importantly, the immune cells and molecules involved in COPD-related type 2 immunity may be significantly different from those observed in severe asthma. Here, we identify the important molecules and effector immune cells involved in type 2 airway inflammation in COPD, discuss the recent therapeutic trial results of biologicals that have targeted these pathways and explore the future of therapeutic development of type 2 immune modulators in COPD.
Precision medicine in cystic fibrosis: predictive role of forskolin-induced swelling assay
Authors: Eva Furstova, Pavel Drevinek, Stepanka Novotna, Malgorzata Libik, Klara Benesova, Lucie Borek-Dohalska, Kristina Sakmarova, Martin Modrak, Milan Macek, Tereza Dousova
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>The FIS assay generally indicates responsiveness to CFTR modulators, but it cannot discriminate between high and low responders within the F508del homozygous subjects. Higher FIS response in intestinal organoids did not predict better clinical outcomes.</b>https://bit.ly/3VgaHSj