162 research outputs found
The Formation of [TiO(H2O)n]+ Cluster Ions
Gas phase [TiO(H2O)n]+ clusters are produced by laser induced plasma reactions of titanium and water, and studied using a triple quadrupole mass spectrometer. More than 60 water molecules cluster onto TiO+; but, no [Ti(H2O)n]+ clusters are observed. The cluster size distributions of [TiO(H2O)n]+ can be fit to log-normal curves. Considered in the context of other data reported herein for cluster distributions of [NbO(H2O)n]+, it is concluded that the cluster formation and growth proceed via a coalescence mechanism between [TiO(H2O)n]+ and water molecule(s), which may lead to the formation of solvation shells. Ab initio calculations were employed to gain insight into the structures and energetics of small [TiO(H2O)n]+ clusters with n = 1–3. A charge donation from the water ligand to the TiO+ ion is found, which indicates the existence of high binding energies between water and TiO+. These experimental and theoretical results further contribute to an understanding of ion-induced nucleation in general, and hydration of TiO+, in particular
Aurora B Regulates Formin mDia3 in Achieving Metaphase Chromosome Alignment
SummaryProper bipolar attachment of sister kinetochores to the mitotic spindle is critical for accurate chromosome segregation in mitosis. Here we show an essential role of the formin mDia3 in achieving metaphase chromosome alignment. This function is independent of mDia3 actin nucleation activity, but is attributable to EB1-binding by mDia3. Furthermore, the microtubule binding FH2 domain of mDia3 is phosphorylated by Aurora B kinase in vitro, and cells expressing the nonphosphorylatable mDia3 mutant cannot position chromosomes at the metaphase plate. Purified recombinant mDia3 phosphorylated by Aurora B exhibits reduced ability to bind microtubules and stabilize microtubules against cold-induced disassembly in vitro. Cells expressing the phosphomimetic mDia3 mutant do not form stable kinetochore microtubule fibers; despite they are able to congress chromosomes to the metaphase plate. These findings reveal a key role for mDia3 and its regulation by Aurora B phosphorylation in achieving proper stable kinetochore microtubule attachment
GIMLET: A Unified Graph-Text Model for Instruction-Based Molecule Zero-Shot Learning
Molecule property prediction has gained significant attention in recent
years. The main bottleneck is the label insufficiency caused by expensive lab
experiments. In order to alleviate this issue and to better leverage textual
knowledge for tasks, this study investigates the feasibility of employing
natural language instructions to accomplish molecule-related tasks in a
zero-shot setting. We discover that existing molecule-text models perform
poorly in this setting due to inadequate treatment of instructions and limited
capacity for graphs. To overcome these issues, we propose GIMLET, which unifies
language models for both graph and text data. By adopting generalized position
embedding, our model is extended to encode both graph structures and
instruction text without additional graph encoding modules. GIMLET also
decouples encoding of the graph from tasks instructions in the attention
mechanism, enhancing the generalization of graph features across novel tasks.
We construct a dataset consisting of more than two thousand molecule tasks with
corresponding instructions derived from task descriptions. We pretrain GIMLET
on the molecule tasks along with instructions, enabling the model to transfer
effectively to a broad range of tasks. Experimental results demonstrate that
GIMLET significantly outperforms molecule-text baselines in instruction-based
zero-shot learning, even achieving closed results to supervised GNN models on
tasks such as toxcast and muv
Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers
Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibits T cell activation, leading to reduced interleukin 2 (IL2) production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescues IL2 production. In the mouse model of castration-resistant prostate cancer (CRPC) by prostate-specific deletion of Pten, p53, and Smad4, CRPC is resistant to an ICB therapy composed of antiprogrammed cell death 1 (PD1) and anticytotoxic-T lymphocyte-associated protein 4 (CTLA4) antibodies. However, we showed that ICB elicits strong anti-CRPC efficacy when combined with an RNS neutralizing agent. Together, these data identify a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of CRPC
Acetylation-defective mutant of Pparγ is associated with decreased lipid synthesis in breast cancer cells.
In our prior publications we characterized a conserved acetylation motif (K(R)xxKK) of evolutionarily related nuclear receptors. Recent reports showed that peroxisome proliferator activated receptor gamma (PPARγ) deacetylation by SIRT1 is involved in delaying cellular senescence and maintaining the brown remodeling of white adipose tissue. However, it still remains unknown whether lysyl residues 154 and 155 (K154/155) of the conserved acetylation motif (RIHKK) in Pparγ1 are acetylated. Herein, we demonstrate that Pparγ1 is acetylated and regulated by both endogenous TSA-sensitive and NAD-dependent deacetylases. Acetylation of lysine 154 was identified by mass spectrometry (MS) while deacetylation of lysine 155 by SIRT1 was confirmed by in vitro deacetylation assay. An in vivo labeling assay revealed K154/K155 as bona fide acetylation sites. The conserved acetylation sites of Pparγ1 and the catalytic domain of SIRT1 are both required for the interaction between Pparγ1 and SIRT1. Sirt1 and Pparγ1 converge to govern lipid metabolism in vivo. Acetylation-defective mutants of Pparγ1 were associated with reduced lipid synthesis in ErbB2 overexpressing breast cancer cells. Together, these results suggest that the conserved lysyl residues K154/K155 of Pparγ1 are acetylated and play an important role in lipid synthesis in ErbB2-positive breast cancer cells
Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing
RBM15, an RNA binding protein, determines cell-fate specification of many tissues including blood. We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578 leading to its degradation via ubiquitylation by an E3 ligase (CNOT4). Overexpression of PRMT1 in acute megakaryocytic leukemia cell lines blocks megakaryocyte terminal differentiation by downregulation of RBM15 protein level. Restoring RBM15 protein level rescues megakaryocyte terminal differentiation blocked by PRMT1 overexpression. At the molecular level, RBM15 binds to pre-mRNA intronic regions of genes important for megakaryopoiesis such as GATA1, RUNX1, TAL1 and c-MPL. Furthermore, preferential binding of RBM15 to specific intronic regions recruits the splicing factor SF3B1 to the same sites for alternative splicing. Therefore, PRMT1 regulates alternative RNA splicing via reducing RBM15 protein concentration. Targeting PRMT1 may be a curative therapy to restore megakaryocyte differentiation for acute megakaryocytic leukemia
Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein
The Beclin 1 gene is a haplo-insufficient tumor suppressor and plays an
essential role in autophagy. However, the molecular mechanism by which Beclin 1
functions remains largely unknown. Here we report the crystal structure of the
evolutionarily conserved domain (ECD) of Beclin 1 at 1.6 Å
resolution. Beclin 1 ECD exhibits a previously unreported fold, with three
structural repeats arranged symmetrically around a central axis. Beclin 1 ECD
defines a novel class of membrane-binding domain, with a strong preference for
lipid membrane enriched with cardiolipin. The tip of a surface loop in Beclin 1
ECD, comprising three aromatic amino acids, acts as a hydrophobic finger to
associate with lipid membrane, consequently resulting in the deformation of
membrane and liposomes. Mutation of these aromatic residues rendered Beclin 1
unable to stably associate with lipid membrane in vitro and unable to
fully rescue autophagy in Beclin 1-knockdown cells in vivo. These
observations form an important framework for deciphering the biological
functions of Beclin 1
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