SUMMARY The genetic dependencies of human cancers widely vary. Here, we catalog this heterogeneity and use it to identify functional gene interactions and genotype-dependent liabilities in cancer. By using genome-wide CRISPR-based screens, we generate a gene essentiality dataset across 14 human acute myeloid leukemia (AML) cell lines. Sets of genes with correlated patterns of essentiality across the lines reveal new gene relationships, the essential substrates of enzymes, and the molecular functions of uncharacterized proteins. Comparisons of differentially essential genes between Ras-dependent and -independent lines uncover synthetic lethal partners of oncogenic Ras. Screens in both human AML and engineered mouse pro-B cells converge on a surprisingly small number of genes in the Ras processing and MAPK pathways and pinpoint PREX1 as an AML-specific activator of MAPK signaling. Our findings suggest general strategies for defining mammalian gene networks and synthetic lethal interactions by exploiting the natural genetic and epigenetic diversity of human cancer cells.

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Colloidal carbon quantum dots (C-dots) have attracted a lot of attentions because of their excellent optical properties for various types of applications. While due to the complicated structure in C-dots,...

Stimulator of interferon genes (STING) is an intracellular sensor of cyclic di-nucleotides involved in the innate immune response against pathogen- or self-derived DNA. STING trafficking is tightly linked to its function, and its dysregulation can lead to disease. Here, we systematically characterize genes regulating STING trafficking and examine their impact on STING-mediated responses. Using proximity-ligation proteomics and genetic screens, we demonstrate that an endosomal sorting complex required for transport (ESCRT) complex containing HGS, VPS37A and UBAP1 promotes STING degradation, thereby terminating STING-mediated signaling. Mechanistically, STING oligomerization increases its ubiquitination by UBE2N, forming a platform for ESCRT recruitment at the endosome that terminates STING signaling via sorting in the lysosome. Finally, we show that expression of a UBAP1 mutant identified in patients with hereditary spastic paraplegia and associated with disrupted ESCRT function, increases steady-state STING-dependent type I IFN responses in healthy primary monocyte-derived dendritic cells and fibroblasts. Based on these findings, we propose that STING is subject to a tonic degradative flux and that the ESCRT complex acts as a homeostatic regulator of STING signaling.

Microglia, the macrophages of the brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer’s disease. These cells adopt distinct transcriptional subtypes known as states. Understanding state function, especially in human microglia, has been elusive owing to a lack of tools to model and manipulate these cells. Here, we developed a platform for modeling human microglia transcriptional states in vitro. We found that exposure of human stem-cell-differentiated microglia to synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated transcriptional diversity that mapped to gene signatures identified in human brain microglia, including disease-associated microglia, a state enriched in neurodegenerative diseases. Using a new lentiviral approach, we demonstrated that the transcription factor MITF drives a disease-associated transcriptional signature and a highly phagocytic state. Together, these tools enable the manipulation and functional interrogation of human microglial states in both homeostatic and disease-relevant contexts.

Among various types of clean energy sources, hydrogen is considered promising due to its high energy density, zero carbon emission during combustion. [4][5][6] To fully deploy technologies for hydrogen production, there is a critical need for the selection of efficient hydrogen evolution reaction (HER) catalysts. [7][8][9] Many researchers focus on producing cost-effective Pt-based catalysts by enhancing the active sites of the Pt (e.g., single atom-based catalysts) and distribution of the Pt in the supports, which can largely decrease the amount of Pt. [10][11][12][13] However, up to date, it is still a major challenge to stabilize Pt nanoclusters during the HER. [14,15] 1D or 2D nanostructures can have large surface energy, spatial confinement, and tunable imperfections, which endow them with unique properties, such as increased catalytic activity, enhanced mechanical strength, and chemical stability. [16][17][18][19] Combining 0D Pt nanocluster with 1D/2D nanostructures can prevent their aggregation and mass loss in catalytic recycling. [20] Until now, considerable efforts have focused on developing low-dimensional heterostructures. [21,22] Carbon nanofibers (CNFs) possess unique mechanical, thermal, and Large scale solar-driven hydrogen production is a crucial step toward decarbonizing society. However, the solar-to-hydrogen (STH) conversion efficiency, long-term stability, and cost-effectiveness in hydrogen evolution reaction (HER) still need to be improved. Herein, an efficient approach is demonstrated to produce low-dimensional Pt/graphene-carbon nanofibers (CNFs)-based heterostructures for bias-free, highly efficient, and durable HER. Carbon dots are used as efficient building blocks for the in situ formation of graphene along the CNFs surface. The presence of graphene enhances the electronic conductivity of CNFs to ≈3013.5 S m −1 and simultaneously supports the uniform Pt clusters growth and efficient electron transport during HER. The electrode with a low Pt loading amount (3.4 µg cm −2 ) exhibits a remarkable mass activity of HER in both acidic and alkaline media, which is significantly better than that of commercial Pt/C (31 µg cm −2 of Pt loading). In addition, using a luminescent solar concentrator-coupled solar cell to provide voltage, the bias-free water splitting system exhibits an STH efficiency of 0.22% upon one-sun illumination. These results are promising toward using low-dimensional heterostructured catalysts for future energy storage and conversion applications.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/smtd.202101470.

SUMMARY The activities of frontal thrusts in the northern Qilian Shan are critical for understanding the deformation of the Qilian Shan and the northeastern Tibetan Plateau. In this study, we estimate the slip rate of the active Fodongmiao–Hongyazi thrust along the northern margin of the Qilian Shan. High-resolution satellite imagery interpretations and detailed field investigations suggest that the fault displaced late Pleistocene terraces and formed fresh prominent north-facing fault scarps. To quantify the slip rate of the fault, we measured the displacements along the fault scarps using an unmanned aerial vehicle system and dated the displaced geomorphic surfaces using optically stimulated luminescence (OSL) and 14C methods. The vertical slip rate of the fault is estimated at 1.0 ± 0.3 mm yr−1 for the western segment. The slip rates for two branches in the eastern segment are 0.3 ± 0.1 and 0.6 ± 0.1 mm yr−1. Using a fault dip of 40 ± 10°, we constrain the corresponding shortening rates to 1.4 ± 0.5 and 1.2 ± 0.4 mm yr−1, respectively. The rates are consistent with values over different timescales, which suggests steady rock uplift and northeastward growth of the western Qilian Shan. Crustal shortening occurs mainly on the range-bounding frontal thrust.

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