Active Learning the High-Dimensional Transferable Hubbard U and V Parameters in the DFT + U + V Scheme.

Density functional theory (DFT) is a powerful quantum mechanical computational tool to perform electronic structure calculations for materials. Few DFT methods can ensure accuracy and efficiency simultaneously. DFT + U + V is an alternative effective approach to overcome this drawback. However, the accuracy sensitively depends on the self-consistent estimation of the high-dimensional onsite and intersite Hubbard interaction U and V terms. We propose Bayesian optimization using a dropout (BOD) algorithm, one type of active learning method, to optimize U and V terms. The DFT + U + V with U/V obtained by BOD can produce improved electronic properties for diverse bulk materials of comparable quality to the hybrid functionals with lower computational cost compared to the linear response approach. Note that the band gaps calculated by BOD are somewhat different from that of hybrid functionals by simply applying the same U/V parameters as in the case of surface slabs and interfaces, which suggests that the transferability of U/V from the bulk models to slabs and interfaces is not as well as expected. BOD is extended to calculate the U/V parameters for slabs and interfaces and reach similar results as bulk solids. Moreover, we find that the U/V are reasonably transferable between surface slabs and interfaces with different thicknesses under various effects of quantum confinement, which contributes to fast access to the electronic properties of large-scale systems with higher accuracy.

Glioblastoma stem cell-specific histamine secretion drives pro-angiogenic tumor microenvironment remodeling.

The communication between glioblastoma stem cells (GSCs) and the surrounding microenvironment is a prominent feature accounting for the aggressive biology of glioblastoma multiforme (GBM). However, the mechanisms by which GSCs proactively drive interactions with microenvironment is not well understood. In this study, we interrogated metabolites that are preferentially secreted from GSCs and found that GSCs produce and secrete histamine to shape a pro-angiogenic tumor microenvironment. This histamine-producing ability is attributed to H3K4me3 modification-activated histidine decarboxylase (HDC) transcription via MYC. Notably, HDC is highly expressed in GBM, which is associated with poor survival of these patients. GSC-secreted histamine activates endothelial cells by triggering a histamine H1 receptor (H1R)-Ca2+-NF-κB axis, thereby promoting angiogenesis and GBM progression. Importantly, pharmacological blockage of H1R using antihistamines impedes the growth of GBM xenografts in mice. Our findings establish that GSC-specific metabolite secretion remodels the tumor microenvironment and highlight histamine targeting as a potential strategy for GBM therapy.

Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice.

Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1+/- mice exhibit impairment in the autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species, thereby resulting in defective neuronal and cardiac functions. Moreover, we discovered that the FDA-approved drug 13-cis retinoic acid can reverse these mitophagic defects and neurobehavioral abnormalities in Kansl1+/- mice by promoting autophagosome-lysosome fusion. Hence, these findings demonstrate a critical role for KANSL1 in autophagy and indicate a potentially viable therapeutic strategy for KdVS.