Ni-Catalyzed Enantioselective C-Acylation of α-Substituted Lactams

A new strategy for catalytic enantioselective C-acylation to generate α-quaternary-substituted lactams is reported. Ni-catalyzed three-component coupling of lactam enolates, benzonitriles, and aryl halides produces β-imino lactams that then afford β-keto lactams by acid hydrolysis. Use of a readily available Mandyphos-type ligand and addition of LiBr enable the construction of quaternary stereocenters on α-substituted lactams to form β-keto lactams in up to 94% ee

Ni-Catalyzed Enantioselective C-Acylation of α-Substituted Lactams

A new strategy for catalytic enantioselective C-acylation to generate α-quaternary-substituted lactams is reported. Ni-catalyzed three-component coupling of lactam enolates, benzonitriles, and aryl halides produces β-imino lactams that then afford β-keto lactams by acid hydrolysis. Use of a readily available Mandyphos-type ligand and addition of LiBr enable the construction of quaternary stereocenters on α-substituted lactams to form β-keto lactams in up to 94% ee

Palladium-Catalyzed Construction of Quaternary Stereocenters by Enantioselective Arylation of γ-Lactams with Aryl Chlorides and Bromides

Herein, we report the first Pd‐catalyzed enantioselective arylation of α‐substituted γ‐lactams. Two sets of conditions were developed for this transformation, allowing for the use of either aryl chlorides or bromides as electrophiles. Utilizing a highly electron‐rich, dialkylphosphine ligand, we have been able to construct α‐quaternary centers in good yields (up to 91% yield) and high enantioselectivities (up to 97% ee)

CaMKII binds both substrates and activators at the active site [preprint]

Ca2+/calmodulin dependent protein kinase II (CaMKII) is a signaling protein that is required for long-term memory formation. Ca2+/CaM activates CaMKII by binding to its regulatory segment, thereby freeing the substrate binding site. Despite having a large variety of interaction partners, the specificity of CaMKII interactions have not been structurally well-characterized. One exceptional feature of this kinase is that interaction with specific binding partners persistently activates CaMKII. To address the molecular details of this, we solved X-ray crystal structures of the CaMKII kinase domain bound to four different binding partners that modulate CaMKII activity in different ways. We show that all four partners bind in the same manner across the substrate binding site. We generated a sequence alignment based on our structural observations, which revealed conserved interactions. Using biochemistry and molecular dynamics simulations, we propose a mechanistic model that persistent CaMKII activity is facilitated by high affinity binding partners, which compete with the regulatory segment to allow substrate phosphorylation

Palladium-Catalyzed Construction of Quaternary Stereocenters by Enantioselective Arylation of γ-Lactams with Aryl Chlorides and Bromides

Herein, we report the first Pd‐catalyzed enantioselective arylation of α‐substituted γ‐lactams. Two sets of conditions were developed for this transformation, allowing for the use of either aryl chlorides or bromides as electrophiles. Utilizing a highly electron‐rich, dialkylphosphine ligand, we have been able to construct α‐quaternary centers in good yields (up to 91% yield) and high enantioselectivities (up to 97% ee)

Labelling and optical erasure of synaptic memory traces in the motor cortex

Dendritic spines are the major loci of synaptic plasticity and are considered as possible structural correlates of memory. Nonetheless, systematic manipulation of specific subsets of spines in the cortex has been unattainable, and thus, the link between spines and memory has been correlational. We developed a novel synaptic optoprobe, AS-PaRac1 (activated synapse targeting photoactivatable Rac1), which can label recently potentiated spines specifically, and induce the selective shrinkage of AS-PaRac1-containing spines. In vivo imaging of AS-PaRac1 revealed that a motor learning induced substantial synaptic remodelling in a small subset of neurons. The acquired motor learning was disrupted by the optical shrinkage of the potentiated spines, whereas it was not affected by the identical manipulation of spines evoked by a distinct motor task in the same cortical region. Taken together, our results demonstrate that a newly acquired motor skill depends on the formation of a task-specific dense synaptic ensemble

The Complete Genome Sequence of Escherichia coli EC958: A High Quality Reference Sequence for the Globally Disseminated Multidrug Resistant E. coli O25b:H4-ST131 Clone

Escherichia coli ST131 is now recognised as a leading contributor to urinary tract and bloodstream infections in both community and clinical settings. Here we present the complete, annotated genome of E. coli EC958, which was isolated from the urine of a patient presenting with a urinary tract infection in the Northwest region of England and represents the most well characterised ST131 strain. Sequencing was carried out using the Pacific Biosciences platform, which provided sufficient depth and read-length to produce a complete genome without the need for other technologies. The discovery of spurious contigs within the assembly that correspond to site-specific inversions in the tail fibre regions of prophages demonstrates the potential for this technology to reveal dynamic evolutionary mechanisms. E. coli EC958 belongs to the major subgroup of ST131 strains that produce the CTX-M-15 extended spectrum β-lactamase, are fluoroquinolone resistant and encode the fimH30 type 1 fimbrial adhesin. This subgroup includes the Indian strain NA114 and the North American strain JJ1886. A comparison of the genomes of EC958, JJ1886 and NA114 revealed that differences in the arrangement of genomic islands, prophages and other repetitive elements in the NA114 genome are not biologically relevant and are due to misassembly. The availability of a high quality uropathogenic E. coli ST131 genome provides a reference for understanding this multidrug resistant pathogen and will facilitate novel functional, comparative and clinical studies of the E. coli ST131 clonal lineage