资源环境科技发展态势分析平台

The cyclin-dependent kinase inhibitor CR8 acts as a molecular glue compound by inducing the formation of a complex between CDK12-cyclin K and DDB1, which results in the ubiquitination and degradation of cyclin K.

Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation(1). Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets(2). They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines(3-5), we identify CR8-a cyclin-dependent kinase (CDK) inhibitor(6)-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.

After taking up tumour-associated antigens, dendritic cells in mouse and human tumours upregulate a regulatory gene program that limits dendritic cell immunostimulatory function, and modulating this program can rescue antitumor immunity in mice.

The ability to communicate quantum information over long distances is of central importance in quantum science and engineering(1). Although some applications of quantum communication such as secure quantum key distribution(2,3) are already being successfully deployed(4-7), their range is currently limited by photon losses and cannot be extended using straightforward measure-and-repeat strategies without compromising unconditional security(8). Alternatively, quantum repeaters(9), which utilize intermediate quantum memory nodes and error correction techniques, can extend the range of quantum channels. However, their implementation remains an outstanding challenge(10-16), requiring a combination of efficient and high-fidelity quantum memories, gate operations, and measurements. Here we use a single solid-state spin memory integrated in a nanophotonic diamond resonator(17-19) to implement asynchronous photonic Bell-state measurements, which are a key component of quantum repeaters. In a proof-of-principle experiment, we demonstrate high-fidelity operation that effectively enables quantum communication at a rate that surpasses the ideal loss-equivalent direct-transmission method while operating at megahertz clock speeds. These results represent a crucial step towards practical quantum repeaters and large-scale quantum networks(20,21).

A solid-state spin memory is used to demonstrate quantum repeater functionality, which has the potential to overcome photon losses involved in long-distance transmission of quantum information.

The biology of haematopoietic stem cells (HSCs) has predominantly been studied under transplantation conditions(1,2). It has been particularly challenging to study dynamic HSC behaviour, given that the visualization of HSCs in the native niche in live animals has not, to our knowledge, been achieved. Here we describe a dual genetic strategy in mice that restricts reporter labelling to a subset of the most quiescent long-term HSCs (LT-HSCs) and that is compatible with current intravital imaging approaches in the calvarial bone marrow(3-5). We show that this subset of LT-HSCs resides close to both sinusoidal blood vessels and the endosteal surface. By contrast, multipotent progenitor cells (MPPs) show greater variation in distance from the endosteum and are more likely to be associated with transition zone vessels. LT-HSCs are not found in bone marrow niches with the deepest hypoxia and instead are found in hypoxic environments similar to those of MPPs. In vivo time-lapse imaging revealed that LT-HSCs at steady-state show limited motility. Activated LT-HSCs show heterogeneous responses, with some cells becoming highly motile and a fraction of HSCs expanding clonally within spatially restricted domains. These domains have defined characteristics, as HSC expansion is found almost exclusively in a subset of bone marrow cavities with bone-remodelling activity. By contrast, cavities with low bone-resorbing activity do not harbour expanding HSCs. These findings point to previously unknown heterogeneity within the bone marrow microenvironment, imposed by the stages of bone turnover. Our approach enables the direct visualization of HSC behaviours and dissection of heterogeneity in HSC niches.

A dual genetic strategy enables the labelling and in vivo imaging of native long-term haematopoietic stem cells in the mouse calvarial bone marrow.