Biology subjects

Cook, T.

Publications and source records attributed to Cook, T..

5 recordsLinked to original sources

bioRxiv2026

Midbrain Tet1 dosage defines inter-individual binge-eating susceptibility

Binge-eating disorder (BED) is the most common eating disorder worldwide and carries life-altering comorbidities. While genetic and environmental risk factors have been identified, the mechanisms that determine inter-individual susceptibility to BED remain largely unknown. Here, we demonstrate that developmental dosage of the DNA hydroxymethylase Tet1 defines stable inter-individual differences in binge-eating susceptibility. In mice, midbrain dopaminergic neurons of the ventral tegmental area (VTADA) are essential for the induction of addictive binge-eating behavior, express high levels of Tet1, and undergo rapid and widespread DNA hydroxymethylation remodeling upon experimental binge eating. Strikingly, Tet1 haploinsufficiency creates pronounced inter-individual variation in binge-eating susceptibility even among genetically identical mice, which we trace to reduced connectivity between the prelimbic medial prefrontal cortex (mPFCPL) and the VTA. Chemogenetic inhibition of mPFCPL[->]VTA projections reduces binge-eating susceptibility, whereas EGR1-guided re-activation of TET1 in VTA dopaminergic neurons restores susceptibility, supporting a causal role for this axis. Importantly, TET1 promoter methylation in patients associates with binge-eating behavior and reward-circuit function, suggesting conservation of this regulatory network in humans. Collectively, these findings identify Tet1 dosage as a novel regulator of binge-eating susceptibility and provide a mechanistic basis for how inter-individual differences in behavior are established.

neuroscience↗

bioRxiv2025

The mitochondrial unfolded protein response and metabolic reprogramming promote PASMC proliferation in response to sphingosine kinase-1/sphingosine-1-phosphate signaling

Proliferation and vasoconstriction of the intimal smooth muscle layer of the pulmonary artery are pathogenic characteristics of pulmonary arterial hypertension (PAH). Altered mitochondrial function, i.e. glycolysis, ROS generation and fission, are known potentiators of vascular remodeling. However, most current therapeutic interventions fail to effectively address the proliferation of the pulmonary artery smooth muscle cells (PASMCSs) lining the pulmonary vasculature and highlight the importance of identifying novel pathways to target for intervention. The Sphk1/S1P/S1P2 signaling axis is upregulated in PAH patients and is known to induce PASMC proliferation during hypoxia-mediated pulmonary hypertension (HPH). Interestingly, Sphk1 modulates mitochondrial function in that it regulates dynamics, cell growth and survival and in C. elegans, it induces activation of the unfolded protein response (UPRmt). We aimed to investigate if the Sphk1/S1P/S1P2 signaling axis promotes vascular remodeling in PAH via activation of the UPRmt. PASMCs isolated from IPAH patients were subjected to RNAseq analysis. The effect of Sphk1 or S1P was interrogated in hPASMC cell lines and the HPH model was used to assess the effect of the UPRmt on PAH pathogenesis. RNAseq analysis revealed that pathways involved in mitochondrial respiration were among the top 20 most significantly regulated pathways. Furthermore, ATF-5, the transcription factor that mediates the UPRmt was significantly upregulated. In hPASMCs, Sphk1/S1P lead to decreased respiration, increased glycolysis, fission, ROS and UPRmt activation. Pharmacological inhibition of the UPRmt mediator, mtHSP70, mitigated the Sphk1 induced increase in hPASMC proliferation. Furthermore, mtHSP70 inhibition was protective in hypoxia-mediated pulmonary hypertension (HPH) as we observed a decrease in right ventricular systolic pressure, right ventricular hypertrophy and vascular remodeling. These data suggest that the UPRmt promotes vascular remodeling in PAH and may present a novel pathway to target for pharmaceutical intervention.

cell biology↗

bioRxiv2025

Partial Wwox Loss of Function Increases Severity of Murine Sepsis and Neuroinflammation

RationaleWW domain-containing oxidoreductase (WWOX) is a gene associated implicated in both neurologic and inflammatory diseases and is susceptible to environmental stressors. We hypothesize partial loss of Wwox function will result in increased sepsis severity and neuroinflammation. MethodsWwox WT/P47T mice, generated by CRISPR/Cas9, and Wwox WT/WT mice were treated with intraperitoneal PBS vs LPS (10mg/kg) and euthanized 12 hours post-injection. Open Field Testing (OFT) and Murine Sepsis Severity Scores (MSS) were utilized to measure sickness behavior and sepsis severity, respectively. Brain tissue was analyzed using immunohistochemistry and PCR to measure neuroinflammation and apoptosis. ResultsWwox WT/P47T LPS mice demonstrated a more significant response to sepsis with an increase in sickness behavior, sepsis severity, gliosis, and apoptosis compared to Wwow WT/WT LPS littermates. ConclusionsPartial loss of Wwox function increases risk for severe sepsis and neuroinflammation. Given the susceptibility of WWOX to environmental stressors, this may be a target for future therapeutic interventions.

neuroscience↗

bioRxiv2024

ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism

Fatty acid {beta}-oxidation (FAO) is a central catabolic pathway with broad implications for organismal health. However, various fatty acids are largely incompatible with standard FAO machinery until they are modified by other enzymes. Included among these are the 4-hydroxy acids (4-HAs)--fatty acids hydroxylated at the 4 ({gamma}) position--which can be provided from dietary intake, lipid peroxidation, and certain drugs of abuse. Here, we reveal that two atypical and poorly characterized acyl-CoA dehydrogenases (ACADs), ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains N-terminal to their ACAD domains that phosphorylate the 4-OH position as a requisite step in the conversion of 4-hydroxyacyl-CoAs into 2-enoyl-CoAs--conventional FAO intermediates. Our ACAD11 cryo-EM structure and molecular modeling reveal a unique binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma while comparable 3- and 5-hydroxy acids remain unchanged. Collectively, this work defines ACAD10 and ACAD11 as the primary gatekeepers of mammalian 4-HA catabolism and sets the stage for broader investigations into the ramifications of aberrant 4-HA metabolism in human health and disease.

biochemistry↗

bioRxiv2020

SARS-CoV2 (COVID-19) Structural/Evolution Dynamicome: Insights into functional evolution and human genomics.

The SARS-CoV-2 pandemic, starting in 2019, has challenged the speed at which labs perform science, ranging from discoveries of the viral composition to handling health outcomes in humans. The small ~30kb single-stranded RNA genome of Coronaviruses makes them adept at cross species spread and drift, increasing their probability to cause pandemics. However, this small genome also allows for a robust understanding of all proteins coded by the virus. We employed protein modeling, molecular dynamic simulations, evolutionary mapping, and 3D printing to gain a full proteome and dynamicome understanding of SARS-CoV-2. The Viral Integrated Structural Evolution Dynamic Database (VIStEDD) has been established (prokoplab.com/vistedd), opening future discoveries and educational usage. In this paper, we highlight VIStEDD usage for nsp6, Nucleocapsid (N), and Spike (S) surface glycoprotein. For both nsp6 and N we reveal highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we have developed a quantitative dynamics cross correlation matrix insight into interaction with the ACE2/SLC6A19 dimer complex. From this quantitative matrix, we elucidated 47 potential functional missense variants from population genomic databases within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Moreover, these variants have ultralow frequency, but can exist as hemizygous in males for ACE2, which falls on the X-chromosome. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2. This powerful database of SARS-CoV-2 can aid in research progress in the ongoing pandemic.

genetics↗