The Innovation最新文献

Solid surfaces usually reach thermodynamic equilibrium through particle exchange with their environment under reactive conditions. A prerequisite for understanding their functionalities is detailed knowledge of the surface composition and atomistic geometry under working conditions. Owing to the large number of possible Miller indices and terminations involved in multielement solids, extensive sampling of the compositional and conformational space needed for reliable surface energy estimation is beyond the scope of ab initio calculations. Here, we demonstrate, using the case of iron carbides in environments with varied carbon chemical potentials, that the stable surface composition and geometry of multielement solids under reactive conditions, which involve large compositional and conformational spaces, can be predicted at ab initio accuracy using an approach that combines the bond valence model, Gaussian process regression, and ab initio thermodynamics. Determining the atomistic structure of surfaces under working conditions paves the way toward identifying the true active sites of multielement catalysts in heterogeneous catalysis.

Partial endothelial-to-mesenchymal transition (EndMT) is an intermediate phenotype observed in endothelial cells (ECs) undergoing a transition toward a mesenchymal state to support neovascularization during (patho)physiological angiogenesis. Here, we investigated the occurrence of partial EndMT in ECs under hypoxic/ischemic conditions and identified general transcription factor IIH subunit 4 (GTF2H4) as a positive regulator of this process. Additionally, we discovered that GTF2H4 collaborates with its target protein excision repair cross-complementation group 3 (ERCC3) to coregulate partial EndMT. Furthermore, by using phosphorylation proteomics and site-directed mutagenesis, we demonstrated that GTF2H4 was involved in the phosphorylation of receptor coactivator 3 (NCOA3) at serine 1330, which promoted the interaction between NCOA3 and p65, resulting in the transcriptional activation of NF-κB and the NF-κB/Snail signaling axis during partial EndMT. In vivo experiments confirmed that GTF2H4 significantly promoted partial EndMT and angiogenesis after ischemic injury. Collectively, our findings reveal that targeting GTF2H4 is promising for tissue repair and offers potential opportunities for treating hypoxic/ischemic diseases.

The type V-I CRISPR-Cas system is becoming increasingly more attractive for genome editing. However, natural nucleases of this system often exhibit low efficiency, limiting their application. Here, we utilized structure-guided rational design and protein engineering to optimize an uncharacterized Cas12i nuclease, Cas12i3. As a result, we developed Cas-SF01, a Cas12i3 variant that exhibits significantly improved gene-editing activity in mammalian cells. Cas-SF01 shows comparable or superior editing performance compared to SpCas9 and other Cas12 nucleases. Compared to natural Cas12i3, Cas-SF01 has an expanded PAM range and effectively recognizes NTTN and noncanonical NATN and TTVN PAMs. Additionally, we identified an amino acid substitution, D876R, that markedly reduced the off-target effect while maintaining high on-target activity, leading to the development of Cas-SF01^HiFi (high-fidelity Cas-SF01). Finally, we show that Cas-SF01 has high gene-editing activities in mice and plants. Our results suggest that Cas-SF01 can serve as a robust gene-editing platform with high efficiency and specificity for genome editing applications in various organisms.

Helicobacter pylori infection is associated with the risk of gastrointestinal (GI) cancers; however, its impact on immunotherapy for GI cancers remains uncertain. In this study, we included 10,122 patients who underwent ¹³C-urea breath tests. Among 636 patients with Epstein-Barr virus-negative microsatellite-stable gastric cancer (GC) who were treated with anti-PD-1/PD-L1 therapy, H. pylori-positive patients exhibited significantly longer immune-related progression-free survival (irPFS) compared with H. pylori-negative patients (6.97 months vs. 5.03 months, P<0.001; hazards ratio [HR], 0.76; 95% confidence interval [CI], 0.62–0.95; P=0.015). Moreover, the H. pylori-positive group demonstrated a trend of 4-months longer median immune-related overall survival (irOS) than the H. pylori-negative group. H. pylori-positive GC displayed higher densities of PD-L1⁺ cells and non-exhausted CD8⁺ T cells, indicative of a "hot" tumor microenvironment. Transcriptomic analysis revealed that H. pylori-positive GC shared similar molecular characteristics to immunotherapy-sensitive GC. However, H. pylori-positive patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal adenocarcinoma and esophageal squamous cell carcinoma (ESCC) had shorter irPFS compared with H. pylori-negative patients (16.13 months vs. not reached, P=0.042; HR, 2.26; 95% CI, 1.13–4.50; P=0.021 and 5.57 months vs. 6.97 months, P=0.029; HR, 1.59; 95% CI, 1.14–2.23; P=0.006, respectively). The difference of irOS between H. pylori-positive and negative patients had the same trend to that between dMMR/MSI-H colorectal adenocarcinoma and ESCC patients. We also identified a trend of shorter irPFS and irOS in H. pylori-positive liver cancer and pancreatic cancer patients. In summary, our findings supported that H. pylori infection is a beneficial factor for GC immunotherapy by shaping "hot" tumor microenvironment. However, in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients, H. pylori adversely affects the efficacy of immunotherapy.