Randomized Spectrum Transformations for Adapting Object Detector in Unseen Domains.

We propose a Meta Learning on Randomized Transformations (MLRT) to learn domain invariant object detectors. Domain generalization is a problem about learning an invariant model from multiple source domains which can generalize well on unseen target domains. This problem is overlooked in object detection field, which is formally named as domain generalizable object detection (DGOD).

Powerful Microbial Base-Editing Toolbox: From Optimization Strategies to Versatile Applications.

Base editors (BE) based on CRISPR systems are practical gene-editing tools which continue to drive frontier advances of life sciences. BEs are able to efficiently induce point mutations at target sites without double-stranded DNA cleavage. Hence, they are widely employed in the fields of microbial genome engineering.

Preferential Regulation of Transient Protein-Protein Interaction by the Macromolecular Crowders.

The environmental condition is a critical regulation factor for protein behavior in solution. Several studies have shown that macromolecular crowders can modulate protein structures, interactions, and functions. Recent publications described the regulation of specific interaction by macromolecular crowders.

Preferential Interactions of a Crowder Protein with the Specific Binding Site of a Native Protein Complex.

Nonspecific binding of crowder proteins with functional proteins is likely prevalent , yet direct quantitative evidence, let alone residue-specific information, is scarce. Here we present nuclear magnetic resonance (NMR) characterization showing that bovine serum albumin weakly but preferentially interacts with the histidine carrier protein (HPr). Notably, the binding interface overlaps with that for HPr's specific partner protein, EIN, leading to competition.

Kinetic Constraints in the Specific Interaction between Phosphorylated Ubiquitin and Proteasomal Shuttle Factors.

Ubiquitin (Ub) specifically interacts with the Ub-associating domain () in a proteasomal shuttle factor, while the latter is involved in either proteasomal targeting or self-assembly coacervation. PINK1 at S65 and makes Ub alternate between C-terminally relaxed () and retracted conformations (). Using NMR spectroscopy, we show that but not preferentially interacts with the from two proteasomal shuttle factors Ubqln2 and Rad23A.

Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress.

Autophagy receptor p62/SQSTM1 promotes the assembly and removal of ubiquitylated proteins by forming p62 bodies and mediating their encapsulation in autophagosomes. Here we show that under nutrient-deficient conditions, cellular p62 specifically undergoes acetylation, which is required for the formation and subsequent autophagic clearance of p62 bodies. We identify K420 and K435 in the UBA domain as the main acetylation sites, and TIP60 and HDAC6 as the acetyltransferase and deacetylase.

Solution structure of the RNA recognition domain of METTL3-METTL14 N-methyladenosine methyltransferase.

N-methyladenosine (mA), a ubiquitous RNA modification, is installed by METTL3-METTL14 complex. The structure of the heterodimeric complex between the methyltransferase domains (MTDs) of METTL3 and METTL14 has been previously determined. However, the MTDs alone possess no enzymatic activity.

Transplantation of bone marrow-derived endothelial progenitor cells and hepatocyte stem cells from liver fibrosis rats ameliorates liver fibrosis.

Aim: To explore the effectiveness for treating liver fibrosis by combined transplantation of bone marrow-derived endothelial progenitor cells (BM-EPCs) and bone marrow-derived hepatocyte stem cells (BDHSCs) from the liver fibrosis environment.

Methods: The liver fibrosis rat models were induced with carbon tetrachloride injections for 6 wk. BM-EPCs from rats with liver fibrosis were obtained by different rates of adherence and culture induction.

Effect of the Flexible Regions of the Oncoprotein Mouse Double Minute X on Inhibitor Binding Affinity.

The oncoprotein MdmX (mouse double minute X) is highly homologous to Mdm2 (mouse double minute 2) in terms of their amino acid sequences and three-dimensional conformations, but Mdm2 inhibitors exhibit very weak affinity for MdmX, providing an excellent model for exploring how protein conformation distinguishes and alters inhibitor binding. The intrinsic conformation flexibility of proteins plays pivotal roles in determining and predicting the binding properties and the design of inhibitors. Although the molecular dynamics simulation approach enables us to understand protein-ligand interactions, the mechanism underlying how a flexible binding pocket adapts an inhibitor has been less explored experimentally.

Ubiquitin S65 phosphorylation engenders a pH-sensitive conformational switch.

Ubiquitin (Ub) is an important signaling protein. Recent studies have shown that Ub can be enzymatically phosphorylated at S65, and that the resulting pUb exhibits two conformational states-a relaxed state and a retracted state. However, crystallization efforts have yielded only the structure for the relaxed state, which was found similar to that of unmodified Ub.

A Fusion Protein of the p53 Transaction Domain and the p53-Binding Domain of the Oncoprotein MdmX as an Efficient System for High-Throughput Screening of MdmX Inhibitors.

In nearly half of cancers, the anticancer activity of p53 protein is often impaired by the overexpressed oncoprotein Mdm2 and its homologue, MdmX, demanding efficient therapeutics to disrupt the aberrant p53-MdmX/Mdm2 interactions to restore the p53 activity. While many potent Mdm2-specific inhibitors have already undergone clinical investigations, searching for MdmX-specific inhibitors has become very attractive, requiring a more efficient screening strategy for evaluating potential scaffolds or leads. In this work, considering that the intrinsic fluorescence residue Trp23 in the p53 transaction domain (p53p) plays an important role in determining the p53-MdmX/Mdm2 interactions, we constructed a fusion protein to utilize this intrinsic fluorescence signal to monitor high-throughput screening of a compound library.

Efficient reactivation of p53 in cancer cells by a dual MdmX/Mdm2 inhibitor.

The aberrant interaction between p53 and Mdm2/MdmX is an attractive target for cancer drug discovery because the overexpression of Mdm2 and/or MdmX ultimately impairs the function of p53 in approximately half of all human cancers. Recent studies have shown that inhibition of both Mdm2 and MdmX is more efficient than that of a single target in promoting cellular apoptosis in cancers. In this study, we demonstrate that a dual small-molecule antagonist of Mdm2/MdmX can efficiently reactivate the p53 pathway in model cancer cells overexpressing MdmX and/or Mdm2.