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Myeloid cell recruitment propels right ventricular dysfunction in HFpEF via sterile inflammation
Get PDFBACKGROUND: In contrast to what has already been shown in HFpEF associated left ventricular (LV) diastolic dysfunction, leukocytes’ role in frequently occurring right ventricular dysfunction (RVD) secondary to HFpEF are so far missing, partially due to the lack of suitable small animal models. Here, we follow a translational research approach by establishing a murine HFpEF model developing manifest RVD and analyzed human HFpEF cohorts to study the mechanistic link between leukocytes and RVD in HFpEF. METHODS: 8-week-old male and female C57BL/6J or Cx3cr1(CreER)/+R26(tdTomato/+) mice were divided into four experimental groups: i) chow, ii) HFpEF (N[ω]-nitro-l-arginine methyl ester (L-NAME), 60% highfat diet), iii) chronic hypoxia (10% O2) and iv) HFpEF and hypoxia (RV-HFpEF) to assess bi-ventricular function and myeloid cell dynamics. To test whether myeloid cells are causally involved in the development of RV remodeling in HFpEF, we additionally treated RV-HFpEF mice with the colony stimulating factor 1 receptor inhibitor PLX-5622 (PLX) to deplete myeloid cells. After 12 weeks, all experimental groups were subjected to transthoracic echocardiography, invasive hemodynamics or flow cytometry. RESULTS: RV-HFpEF resulted in LV diastolic dysfunction indicated by increased E/E’ ratio, reduced global longitudinal peak strain, smaller end-diastolic diameters and increased isovolumetric relaxation time compared to chow. RV-HFpEF animals developed RV hypertrophy and RVD evident as increased Fulton’s index and collagen content as well as elevated RV systolic pressures (RVSPs) and reduced tricuspid annular plane systolic excursion, respectively. Flow cytometric analyses revealed elevated total leukocyte, monocyte, and macrophage counts in RV tissue of RV-HFpEF compared to chow or LV tissue from RV-HFpEF animals. These data were confirmed by unbiased proteomic analyses of RV tissue from RV-HFpEF mice, demonstrating increased abundance of proteins involved in activation of the innate immune system, macrophage chemotaxis, cell adhesion and extracellular matrix organization when compared to LV tissue or other experimental groups. Fate mapping experiments revealed that recruited monocyte-derived macrophages became the main source of total cardiac macrophages in RV tissue from RV-HFpEF mice. Depletion of myeloid cells was associated with rescued RVSP profiles compared to RVHFpEF control mice. In HFpEF patients, RV dilation was associated with an increased percentage of circulating monocytes. In RV biopsies from HFpEF patients, we found increased expression of adhesion molecules, fibrotic markers and inflammatory transcripts. CONCLUSION: We demonstrate that dysregulated myeloid cell dynamics are associated with, and directly contribute to, the pathogenesis of HFpEF-associated RVD in humans and mice
TAAR9 knockout increases hippocampal serotonin and alters grooming behavior in rats
Get PDFINTRODUCTION: Despite their association with brain disorders, the neurophysiological roles of the trace amine-associated receptors remain poorly understood. In humans, the genomic trace amine-associated receptor cluster comprises nine consecutive genes, six of which code for functional proteins (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9). While homologues of the former three are known to regulate classical monoamines and neurogenesis, the functions of the latter three remain largely unknown. In this exploratory study, we demonstrate for the first time that TAAR9 plays a significant regulatory role in the monoaminergic systems of the rat. METHODS: We used qPCR to measure TAAR9 mRNA expression throughout the rat brain. Serotonin, dopamine, and their metabolite levels were assessed by HPLC in brain tissues from TAAR9-KO and wild-type littermates. We applied fast-scan cyclic voltammetry to measure mesolimbic dopamine release. Behavioral analysis included assessment of grooming, anxiety-like, and sexual behaviors. A battery of hematological/hormone assays was also applied. RESULTS AND DISCUSSION: We detected TAAR9 mRNA in the brainstem and midbrain–regions that include key monoaminergic nuclei such as the locus coeruleus, raphe nuclei, and the ventral tegmental area. The TAAR9-KO rats exhibited increased hippocampal serotonin levels and a slight shift in dopamine turnover, but not mesolimbic dopamine release. Although hippocampal serotonin is commonly implicated in mood and anxiety regulation, behaviorally, no genotype differences were detected in the elevated plus maze, suggesting that basal anxiety-like behavior remained unaffected under the test conditions. However, changes in grooming microstructure indicated subtle alterations in behavioral organization, which may reflect the neurochemical changes observed in the hippocampus. No changes were evident in a battery of hematological assays. CONCLUSION: Together, these findings suggest that TAAR9 deletion selectively modulates central monoaminergic systems and related behavioral patterns, without altering systemic physiological parameters
Contextualizing models: deriving a kinetic model of cancer metabolism including growth via stoichiometric reduction
Get PDFGenome-scale metabolic models (GEMs) offer unprecedented possibilities to study human metabolism, including alterations in cancers. Yet, analyses of GEMs still entail several disadvantages. In particular, constraint-based methods, such as flux balance analysis, are typically restricted to analyse steady-state flux distributions. In contrast, kinetic models based on ordinary differential equations allow assessment of regulatory properties and dynamics. Building kinetic models, however, is still hampered by the lack of knowledge about kinetic parameters and is typically focused on individual pathways. Here, we present an approach to derive kinetic models of metabolism augmented by coarse-grained overall reactions that represent the remaining cellular metabolism and biosynthetic processes. Using algorithmic network reduction, we derive coarse-grained reactions that preserve the correct stoichiometry of precursors, energy, and redox equivalents required for cellular growth. Analysis of the GEM-embedded kinetic model uses Monte Carlo sampling to address parameter uncertainty. We exemplify our approach by constructing a kinetic model of cancer metabolism that includes an explicit description of cellular growth. We show that the GEM-embedded kinetic model differs in its control properties from the corresponding model without growth, with implications for understanding regulatory hotspots and drug target identification
Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming [04scRNA_seq_D10]
No full textSpatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here, we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naïve mouse pluripotent stem cells leads to upregulation of the cysteine generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naïve to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature aging, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Importantly, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity, and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases
Socioeconomic characteristics and the home food environment are associated with feeding healthful and discretionary foods during the first year of life in the Pregnancy Eating Attributes Study
No full textBACKGROUND: Feeding of nutrient-poor foods begins in infancy and may adversely affect long-term food preferences. OBJECTIVE: To examine associations of socioeconomic characteristics, childbearing parent eating behaviors, and home food environment with infant feeding characteristics. DESIGN: Secondary analysis of a prospective cohort study from first trimester of pregnancy through 12-months postpartum. PARTICIPANTS/SETTING: Participants with uncomplicated singleton pregnancies and no major chronic illness were enrolled from November 2014 through October 2016 from two university-based obstetrics clinics in Chapel Hill, NC. Of 458 enrolled, 321 were retained through 12 months postpartum. MAIN OUTCOME MEASURES: Participants completed infant food frequency questionnaires indicating age at introduction and frequency of consuming multiple food groups. Exposures included childbearing parent socioeconomic characteristics, hedonic hunger, addictive-like eating, Healthy Eating Index-2015 (HEI) calculated from three 24-hour diet recalls, and home food environment fruit/vegetable and obesogenic scores. STATISTICAL ANALYSES PERFORMED: Multiple imputation using Heckman selection model; linear and logistic regressions examining associations with infant feeding characteristics. RESULTS: Lower education and income were associated with later infant age at introduction to, and lower frequency of consuming fruits and vegetables at age 12 months. Socioeconomic characteristics were not associated with age at introduction to discretionary solid foods; however, lower education and income were associated with greater infant frequency of intake of discretionary foods and greater odds of introducing fruit juice and sweetened beverages by age 12 months. Childbearing parent HEI, hedonic hunger, and addictive-like eating were not consistently associated with infant feeding characteristics. A more obesogenic food environment was associated with greater frequency of intake of discretionary foods, lower frequency of intake of fruit, and greater odds of fruit juice introduction by age 12 months. CONCLUSIONS: Infant feeding characteristics may be important intervention targets for addressing socioeconomic disparities in child diet quality. Efforts to reduce routine feeding of discretionary foods across socioeconomic groups are needed; modifying the home food environment may promote healthful infant feeding
Simplified preanalytical laboratory procedures for therapeutic drug monitoring (TDM) in patients treated with high-dose methotrexate (HD-MTX) and glucarpidase
Get PDFDistinguishing transient from persistent brain structural changes in pediatric patients with acute disseminated encephalomyelitis
Get PDFBACKGROUND AND OBJECTIVES: Pediatric patients with acute disseminated encephalomyelitis (ADEM) are at risk of impaired brain growth, with long-term neuropsychiatric consequences. We previously reported transient expansions of cerebral ventricle volume (VV) in experimental autoimmune encephalomyelitis, which subsequently normalized. In this study, we investigated changes in VV in ADEM in relation to other brain structures and clinical outcomes. METHODS: We investigated brain MRI scans acquired in routine clinical practice from a multicenter cohort of 61 pediatric patients with ADEM, of whom 39 were myelin oligodendrocyte glycoprotein (MOG) antibody-positive. Patients were compared with 1,219 pediatric healthy controls (HCs). Volumes of multiple brain structures were computed using a contrast-agnostic machine learning–based tool and analyzed with mixed-effect models regarding other clinical parameters. RESULTS: Patients with ADEM had larger VV than HCs at initial clinical presentation, before immune therapy. Most of the patients showed further VV increases within 2 months after disease onset. Patients had smaller brain volumes than HCs, with specific reductions in deep gray matter structures. These changes were more pronounced in MOG antibody-negative patients. Of the patients with more than 2 MRI scans, 12 of 22 resolved their VV expansion back to within 15% of baseline values while 10 of 22 had persistently increased VV at the last available MRI within 1 year from onset. Patients with persistent VV expansion had greater reductions in volumes of other brain structures at the last MRI than patients whose VV resolved and were more likely to have residual neurologic signs. The VV resolving and nonresolving patients did not differ regarding age, sex, elevated CSF cell counts at baseline, or occurrence of relapses. However, patients with a larger magnitude of VV expansion—≥90% of baseline volume—were more likely to be in the nonresolving group. DISCUSSION: We could distinguish between 2 outcomes of VV changes in ADEM: one in which the VV expanded but ultimately returned to normal and one in which the expansions continued after disease onset and treatment but failed to resolve. The latter was associated with reduced brain volume, particularly in deep gray matter structures. This highlights the necessity for patients with ADEM to undergo regular MRI scans to assess whether developing VV expansions indicate a greater risk of permanent brain atrophy
The role of Neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in MS and AQP4-NMOSD: advancing clinical applications
Get PDFFluid biomarkers such as Glial Fibrillary Acidic Protein (GFAP) and Neurofilament Light (NfL) play important roles in the diagnosis, monitoring, and evaluation of therapeutic responses in conditions such as Multiple Sclerosis (MS) and Aquaporin-4 Neuromyelitis Optica Spectrum Disorder (AQP4-NMOSD). These biomarkers offer key insights into the underlying pathophysiological mechanisms of these diseases, enabling effective follow-up and personalized treatment approaches, which are essential for improving patient outcomes. Herein, we synthesize the structural attributes, functional roles, and clinical significance of GFAP and NfL in the context of MS and AQP4-NMOSD. We explore the critical implications of these biomarkers in disease manifestation and progression, emphasizing the necessity to develop standardized methodologies and multicentric studies to confirm their clinical applicability
Effect of siponimod on retinal thickness, a marker of neurodegeneration, in participants with SPMS: Findings from the EXPAND OCT substudy
Get PDFBACKGROUND: People with MS show abnormal thinning of the retinal layers, which is associated with clinical disability and brain atrophy, and is a potential surrogate marker of neurodegeneration and treatment effects. OBJECTIVE: To evaluate the utility of retinal thickness as a surrogate marker of neurodegeneration and treatment effect in participants with secondary progressive MS (SPMS) from the optical coherence tomography (OCT) substudy of the EXPAND Phase 3 clinical trial (siponimod versus placebo). METHODS: In the OCT substudy population (n=159), treatment effects on change in the average thickness of the retinal layer, peripapillary retinal nerve fiber layer (pRNFL), and combined macular ganglion cell and inner plexiform layers (GCIPL) were analyzed by high-definition spectral domain OCT at months 3, 12, and 24. RESULTS: Thinning from baseline was observed across all retinal layers and time points in the placebo group. Siponimod significantly reduced GCIPL thinning versus placebo at month 24 (adjusted mean [SE] [µm]: −0.47 [0.81] vs. −4.29 [1.23]; p=0.01), and overall retinal thinning at months 12 (+0.66 [0.54] vs. −1.86 [0.75]; p=0.006) and 24 (−0.05 [0.59] vs. −2.30 [0.88]; p=0.033). Although not significant, results for pRNFL consistently followed the same trends. CONCLUSION: This exploratory substudy supports further investigation of OCT measurement of retinal atrophy as a non-invasive potential biomarker of treatment effects on neurodegeneration in SPMS