Climate impacts of critical mineral supply chain bottlenecks for electric vehicle deployment.

New tailpipe emissions standards aim to increase electric vehicle (EV) sales in the United States. Here, we analyze the associated critical mineral supply chain constraints and enumerate the climate consequences of these constraints. Our work yields five findings.

Asymmetric Engagement of Dimeric CRL3 by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes.

UM171 is a potent small molecule agonist of ex vivo human hematopoietic stem cell (HSC) self-renewal, a process that is tightly controlled by epigenetic regulation. By co-opting KBTBD4, a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, UM171 promotes the degradation of members of the CoREST transcriptional corepressor complex, thereby limiting HSC attrition. However, the direct target and mechanism of action of UM171 remain unclear.

KBTBD4 Cancer Hotspot Mutations Drive Neomorphic Degradation of HDAC1/2 Corepressor Complexes.

Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB) , the most common embryonal brain tumor in children, and pineoblastoma . These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST .

A Facile Platform to Engineer Tyrosyl-tRNA Synthetase Adds New Chemistries to the Eukaryotic Genetic Code, Including a Phosphotyrosine Mimic.

The tyrosyl-tRNA synthetase (EcTyrRS)/tRNA pair offers an attractive platform for genetically encoding new noncanonical amino acids (ncAA) in eukaryotes. However, challenges associated with a eukaryotic selection system, which is needed to engineer the platform, have impeded its success in the past. Recently, using a facile -based selection system, we showed that EcTyrRS could be engineered in a strain where the endogenous tyrosyl pair was substituted with an archaeal counterpart.

Profiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders.

Targeted protein degradation (TPD) holds immense promise for drug discovery, but mechanisms of acquired resistance to degraders remain to be fully identified. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)-suppressor scanning to identify mechanistic classes of drug resistance mutations to molecular glue degraders in GSPT1 and RBM39, neosubstrates targeted by E3 ligase substrate receptors cereblon and DCAF15, respectively. While many mutations directly alter the ternary complex heterodimerization surface, distal resistance sites were also identified.

Structural Robustness Affects the Engineerability of Aminoacyl-tRNA Synthetases for Genetic Code Expansion.

The ability to engineer the substrate specificity of natural aminoacyl-tRNA synthetase/tRNA pairs facilitates the site-specific incorporation of noncanonical amino acids (ncAAs) into proteins. The -derived tyrosyl-tRNA synthetase (MjTyrRS)/tRNA pair has been engineered to incorporate numerous ncAAs into protein expressed in bacteria. However, it cannot be used in eukaryotic cells due to cross-reactivity with its host counterparts.

A pilot study to investigate the feasibility of the modified Blaylock Tool for Occupational Therapy Referral (MBTOTR) for use by nurses in acute care.

Purpose: Patients in acute care settings may have limitations in their functional capacity associated with multiple morbidities. Occupational therapy can address factors affecting functional decline, and early and accurate identification of patients requiring occupational therapy referral can facilitate safe discharge. This study aimed to investigate the feasibility of the Modified Blaylock Tool for Occupational Therapy Referral to identify the characteristics of patients who would potentially require occupational therapy referral, for use by acute care nurses.

The development of the modified blaylock tool for occupational therapy referral (MBTOTR): a preliminary evaluation of its utility in acute care.

Purpose: Acute hospitals are facing more complex admissions with older people at increased risk of functional decline. This study aimed to create and trial the feasibility of a new screening tool designed to identify patients at risk of functional decline who need an occupational therapy referral within acute care.

Method: Ten screening tools were reviewed and the Modified Blaylock Tool for Occupational Therapy Referral (MBTOTR) was developed.