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Papillary renal cell carcinoma (pRCC) is the most heterogenous renal cell carcinoma. Patient survival varies and no effective therapies for advanced pRCC exist. Histological and molecular characterization studies have highlighted the heterogeneity of pRCC tumours. Recent studies identified the proximal tubule (PT) cell as a cell-of-origin for pRCC. However, it remains elusive whether other pRCC subtypes have different cell-of-origin. Here, by obtaining genome-wide chromatin accessibility profiles of normal human kidney cells using single-cell transposase-accessible chromatin-sequencing and comparing the profiles with pRCC samples, we discover that besides PT cells, pRCC can also originate from kidney collecting duct principal cells. We show pRCCs with different cell-of-origin exhibit different molecular characteristics and clinical behaviors. Further, metabolic reprogramming appears to mediate the progression of pRCC to the advanced state. Here, our results suggest that determining cell-of-origin and monitoring origin-dependent metabolism could potentially be useful for early diagnosis and treatment of pRCC.

Reproducible resting-state functional connectivity (rsFC) patterns and their alterations play an increasing role in neuropsychiatric research. Studies that limit the analysis of metabolites and rsFC strengths to a predefined canonical network suggest that the rsFC strength positively correlates with the local glutamate (Glu) levels and negatively correlates with the gamma-aminobutyric acid (GABA) levels. The contribution of regional neurotransmitter activity to rsFC strengths from a given seed to the whole-brain remains unclear. In this study, 121 healthy participants (50 female/71 male) underwent multimodal resting-state functional magnetic resonance imaging (rsfMRI) and magnetic resonance spectroscopy (MRS) at 7 T, allowing for acquisition of multiple, neuroanatomically well-defined MRS voxels in the same session. We examined the association between rsFC and local neurotransmitter levels in the

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