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Yavari, A.

Publications and source records attributed to Yavari, A..

3 recordsLinked to original sources

Dissociable Spatial and Feature Tuning of Gamma and Alpha Rhythms in Human Visual Cortex

Visual stimulation in humans reliably induces narrowband gamma (40-80 Hz) increases and alpha (8-12 Hz) suppression in EEG, but the relationship between these rhythms is not fixed. Using high-density EEG, we mapped gamma and alpha responses across a broad set of retinotopic, orientation, and motion conditions. Gamma was strongly retinotopically tuned, with linear summation of subfield responses accurately predicting full-field responses. In contrast, alpha showed little spatial tuning, substantial responses even in the absence of visual input (anticipatory suppression), and subadditive summation consistent with divisive normalization. Across most retinotopic configurations, higher gamma coincided with stronger alpha suppression, yet systematic dissociations emerged, with full-field and foveal-centered gratings evoking stronger than expected gamma relative to alpha suppression. Orientation tuning was robust for gamma but weak for alpha, with oblique gratings producing high gamma yet weak alpha suppression, reversing the usual inverse relationship. These patterns indicate that EEG gamma power primarily reflects large-scale synchronous activity that matches the global LFP observed in macaque V1, whose spatial and feature tuning properties are independent of both single-neuron selectivity and feedback-driven alpha dynamics. The results establish a mechanistic dissociation between gamma and alpha rhythms, highlighting distinct circuit origins and tuning principles for these canonical visual responses.

neuroscience↗

Modulating Cardiac Energetics in Cardio-Metabolic Syndromes: A mechanistic, hyperpolarized MR Trial of Ninerafaxstat Treatment

BackgroundType 2 diabetes (T2D) and obesity are key contributors for heart failure (HF)- development, especially for HF with a preserved ejection fraction (HFpEF). On a molecular basis, excessive use of fatty acids (FA) induces lipotoxicity which in turn promotes inflammation, reduces mitochondrial pyruvate dehydrogenase (PDH) activity and impairs myocardial energetics and -function. Harnessing in-vivo, real time measurement of cellular metabolism via hyperpolarized pyruvate MR, we aimed to assess the effects of ninerafaxstat, a selective FA oxidation inhibitor, on cardiac energetics, metabolism & diastolic function in patients with cardio-metabolic syndromes. MethodsIMPROVE-DiCE was an open-label, mechanistic phase 2a trial. 21 participants received 200mg ninerafaxstat twice daily for four (n=5) or eight weeks (n=16). Myocardial energetics (phosphocreatine to adenosine triphosphate ratio, PCr/ATP), metabolism and function were assessed pre-& post-treatment using magnetic resonance imaging (MRI), 31P- and 1H-MR spectroscopy (MRS). We utilised hyperpolarized [1-13C]pyruvate MRS to assess in-vivo PDH-flux (n=9) and plasma metabolomics and proteomics to assess whole body metabolism. ResultsPatients presented with impaired PCr/ATP, (median 1.6 [IQR 1.4, 2.1]), myocardial steatosis (2.2 % [IQR 1.5, 3.2]) and LV diastolic dysfunction (peak circumferential diastolic strain rate 0.86/s [IQR 0.82, 1.06]) at baseline. Ninerafaxstat treatment improved myocardial energetics by 32% (p<0.01), reduced myocardial triglyceride content by 34% (p=0.03) and showed a trend towards improved PDH-flux (mean 45% increase, p=0.08). Diastolic function was significantly improved post-treatment (peak diastolic strain rate by 10%, peak LV filling rate by 11%, both p<0.05). ConclusionsMetabolic modulation with ninerafaxstat significantly improved myocardial energetics, reduced myocardial steatosis and improved LV diastolic filling. Combining hyperpolarized MRS and metabolomics, is a powerful approach to examine the mechanism of action of novel metabolic modulators. REGISTRATIONURL: https://clinicaltrials.gov; Unique identifier: NCT04826159 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/591019v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@86fae1org.highwire.dtl.DTLVardef@1c1037eorg.highwire.dtl.DTLVardef@cc5ca9org.highwire.dtl.DTLVardef@d789d1_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

Metabolic Profiling of Aortic Stenosis and Hypertrophic Cardiomyopathy Identifies Mechanistic Contrasts in Substrate Utilisation

BackgroundAortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are highly distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated.\n\nMethodWe undertook a detailed invasive (aortic root and coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison to non-LVH controls, to investigate cardiac fuel selection and metabolic remodelling. These patients were assessed under different physiological states (at rest and during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts.\n\nResultsWe identified a highly discriminant metabolomic signature in severe AS characterised by striking accumulation of long-chain acylcarnitines, intermediates of long-chain transport and fatty acid metabolism, and validated this in a separate cohort. Mechanistically, we identify a down-regulation in the PPAR- transcriptional network, including expression of genes regulating FAO.\n\nConclusionsWe present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate fundamental distinctions in substrate preference between AS and HCM, highlighting insufficient long-chain FAO, and the PPAR- signalling network as a specific metabolic therapeutic target in AS.

systems biology↗