Cui, S.-X. | bioRxiv Science

bioRxiv2023

The Complexity of Functional Connectivity Profiles of the Subgenual Anterior Cingulate Cortex and Dorsal Lateral Prefrontal Cortex in Major Depressive Disorder: a DIRECT Consortium Study

BackgroundThe subgenual anterior cingulate cortex (sgACC) plays a central role in the pathophysiology of major depressive disorder (MDD), and its functional interactive profile with the left dorsal lateral prefrontal cortex (DLPFC) is associated with transcranial magnetic stimulation (TMS) treatment outcomes. Nevertheless, previous research on sgACC functional connectivity (FC) in MDD has yielded inconsistent results, partly due to small sample sizes and limited statistical power. Furthermore, calculating sgACC-FC to target TMS individually is challenging. MethodsLeveraging a large multi-site cross-sectional sample (1660 MDD patients vs. 1341 healthy controls) from Phase II of the Depression Imaging REsearch ConsorTium (DIRECT), we systematically delineated case-control difference maps of sgACC-FC. Then, we explored the potential impact of such group-level abnormality profiles on the TMS target localization and clinical efficacy. Next, we developed an MDD big data-guided individualized TMS targeting algorithm to integrate group-level statistical maps with individual-level brain activity to localize TMS targets individually. ResultsWe found an enhanced sgACC-DLPFC FC in MDD patients compared to healthy controls (HC). Such group differences altered the position of the sgACC anti-correlation peak in the left DLPFC. In two independent clinical samples, we showed that the magnitude of TMS targets case-control differences in sgACC FC was related to clinical improvement. The MDD big data-guided individualized TMS targeting algorithm may generate individualized TMS targets that are clinically superior to group-level targets. InterpretationWe reliably delineated MDD-related abnormalities of sgACC-FC profiles in a large, independently ascertained sample and demonstrated the potential impact of such case-control differences on FC-guided localization of TMS targets. FundingMinistry of Science and Technology of the Peoples Republic of China, National Natural Science Foundation of China, and Chinese Academy of Sciences

neuroscience↗

bioRxiv2021

ACKR3 induces the perturbation of rRNA biogenesis: a novel mechanism of colorectal tumorigenesis

Atypical chemokine receptor 3 (ACKR3), previously known as C-X-C chemokine receptor type 7 (CXCR7), has emerged as a key player in several biologic processes. Its atypical "intercepting receptor" signaling properties have established ACKR3 as the main regulator in pathophysiological processes in many diseases. However, much less is known the underlying mechanisms of ACKR3 in promoting tumorigenesis. We found, in both human and animal model, that activation of ACKR3 promotes colorectal tumorigenesis through the NOLC1-induced perturbations of rRNA biogenesis. As compared with adjacent non-neoplastic tissue, human colonic cancer tissues demonstrated higher expression of ACKR3, and high ACKR3 expression was associated with increased severity of colonic cancer. Villin-ACKR3 transgenic mice demonstrated the characteristics of ACKR3-induced colorectal cancer, showing the nuclear {beta}-arrestin-1-activated perturbation of rRNA biogenesis. Activation of ACKR3 induced nuclear translocation of {beta}-arrestin-1 ({beta}-arr1), leading to the interaction of {beta}-arr1 with nucleolar and coiled-body phosphoprotein 1 (NOLC1). As the highly phosphorylated protein in the nucleolus, NOLC1 further interacted with Fibrillarin, a highly conserved nucleolar methyltransferase responsible for ribosomal RNA methylation, leading to the increase of methylation in Histone H2A, resulting in the promotion of rRNA transcription of ribosome biogenesis. Conclusion: ACKR3 promotes colorectal tumorigenesis through the perturbation of rRNA biogenesis by nuclear {beta}-arr1-induced interaction of NOLC1 with Fibrillarin. HIGH LIGHTSO_LIACKR3 is an atypical G protein-coupled receptor (GPCR) C_LIO_LIACKR3 promotes colorectal tumorigenesis C_LIO_LIACKR3 induces nuclear translocation of {beta}-arr1 C_LIO_LINuclear {beta}-arr1 interacts with NOLC1 to activate Fibrillarin C_LIO_LIInteraction of NOLC1 to Fibrillarin leads to perturbation of rRNA biogenesis C_LI

cancer biology↗