Biology subjects

Edalati, M.

Publications and source records attributed to Edalati, M..

3 recordsLinked to original sources

bioRxiv2026

Effect of tempo on newborns' neural processing of auditory rhythm: Emergence of sensitivity to metrical structure

Rhythm perception ability underpins music and language processing, and its developmental origins trace back to the earliest periods of life. While most rhythm patterns contain a variety of inter-onset intervals, listeners typically extract a steady underlying beat periodicity, as well as beat grouping periodicities (groups of two or three beats will be at frequencies 1/2 or 1/3, respectively, of that of the primary beat), forming a metrical hierarchy. While the developing brain can track auditory rhythm before birth, a previous study found that neural sensitivity to faster beat-related periodicities emerges early in third trimester of gestation, whereas encoding of slower metrical structure periodicities only appears closer to term birth. However, as rhythm patterns were only presented at one tempo, neural sensitivity to metrical structure could not be disentangled from sensitivity to tempo during early development. Thus, here we presented auditory rhythmic sequences at two different tempi and used high-resolution electroencephalography to measure neural sensitivity to their encoding in full-term newborns and young adults. Adults demonstrated a similar sensitivity to metrical structure across tempi, with greatest response at the duple metrical frequency regardless of tempo. Newborn neural responses, by contrast, were tempo-dependent, displaying markedly different response patterns across beat and meter frequencies at the different tempi. Together, these results reveal that tempo and metrical structure interact in shaping how the neonatal brain encodes auditory rhythm, suggesting that early neural processing may be constrained in its ability to track slower periodicities, and highlighting a developmental shift in the relative contributions of tempo and metrical structure to rhythmic processing. Research HighlightsO_LIAdults show stable sensitivity to metrical structure across tempi, with peak responses at the duple level. C_LIO_LINewborns neural responses are tempo-dependent, showing distinct patterns across beat and metrical frequencies. C_LIO_LITempo and metrical structure jointly shape neural encoding of rhythm in the brain, revealing a developmental shift in their relative contributions. C_LI

neuroscience↗

bioRxiv2025

Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas

Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using luciferase-labeled JeKo-1 and Maver mantle cell lymphoma xenografts demonstrate that ACSS1 knockdown significantly suppresses tumor growth. NSG mice injected with ACSS1-silenced cells exhibit a marked reduction in tumor burden, as measured by bioluminescence imaging and total photon flux, with significant differences observed at days 14 and 21 post-injection. These findings establish that ACSS1 is required not only for metabolic adaptation in vitro but also for lymphoma progression in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability. Statement of SignificanceThis study identifies ACSS1 as a critical metabolic vulnerability in mantle cell lymphoma (MCL), linking mitochondrial acetate metabolism to de novo pyrimidine biosynthesis and tumor progression. We demonstrate that ACSS1 is frequently overexpressed in MCL and is essential for converting acetate into mitochondrial acetyl-CoA, thereby sustaining TCA cycle activity, nucleotide production, and cell survival under nutrient stress. Loss of ACSS1 disrupts this acetate-pyrimidine axis, impairing oxidative metabolism and reducing lymphoma cell viability in vitro. Importantly, ACSS1 silencing significantly suppresses tumor growth in vivo, establishing its requirement for lymphoma progression. The ability of acetate or uridine supplementation to rescue ACSS1-deficient cells further highlights the functional coupling between mitochondrial acetate utilization and nucleotide synthesis. Together, these findings reveal a previously unrecognized mechanism of metabolic adaptation in aggressive lymphomas and offer ACSS1-mediated acetate metabolism as a promising therapeutic target.

cancer biology↗

bioRxiv2024

Mitochondrial ACSS1 regulates the oncometabolite 2-hydroxyglutarate and De Novo Pyrimidine biosynthesis under nutrient-deprived conditions in lymphoma

The mitochondrial Acetyl-CoA synthetase short-chain family member 1 (ACSS1) converts acetate, an energy source in nutrient-deprived conditions, to mitochondrial acetyl-CoA. However, the specific mechanism behind this process remains unknown. Here, we show that ACSS1 is overexpressed in patients with mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and Ibrutinib (IBR)-resistant cell lines. The mitochondrial stress test showed reduced oxygen consumption in ACSS1 knockdown (KD) cell lines. 13C-acetate stable isotope tracing revealed that ACSS1 knockdown (KD) in MCL cell lines attenuates the flux of mitochondrial acetate to acetyl-CoA, acetylcarnitine, and TCA cycle intermediates, including glutamine and aspartate, which are precursors for de novo pyrimidine synthesis. Consistently, there was a decrease in the labeling of glutamate, aspartate, dihydroorotate, and orotate pools in KD cell lines. Pathway analysis revealed the enrichment of de novo pyrimidine synthesis metabolites and depleting ACSS1 impaired cell growth and potential vulnerability of IBR-resistant MCL cells. Further, we discovered that acetate is used to synthesize 2-hydroxyglutarate in an ACSS1-dependent manner, and it is involved in histone methylation. These results highlight a metabolic phenotype in MCL cells, showing their ability to metabolize acetate in nutrient-deprived conditions and provide new insights into the role of ACSS1 in cancer metabolism. SignificanceThe enzyme ACSS1 catalyzes the conversion of acetate, an energy source in nutrient-deprived conditions, to mitochondrial acetyl-CoA. Our results show that ACSS1 may affect cancer metabolism, particularly in MCL. Studies using MCL cell lines showed that reducing ACSS1 activity affects acetate utilization for various metabolic pathways and influences the production of oncometabolite D-2-hydroxyglutarate. Additionally, reducing ACSS1 activity affects the expression of cyclin D1 and inhibits cell growth, highlighting the potential significance of ACSS1 in cancer metabolism.

cancer biology↗