Systematic profiling of peptide substrate specificity in N-terminal processing by methionine aminopeptidase using mRNA display and an unnatural methionine analogue.

Methionine aminopeptidase (MAP) is useful in chemical biology research for N-terminal processing of peptides and proteins and in medicine as a potential therapeutic target. These technologies can benefit from a precise understanding of the enzyme's substrate specificity profiled over a wide chemical space, including not just natural substrates, peptides containing N-terminal Met, but also unnatural peptide substrates containing N-terminal Met analogues that are also cleaved by MAP like homopropargylglycine (HPG) and azidohomoalanine (AHA). A few studies have profiled substrate specificity for cleavage of N-terminal Met, but none have systematically done so using N-terminal Met analogues.

Donanemab immunogenicity in participants with early symptomatic Alzheimer's disease.

Introduction: Donanemab is an immunoglobulin G1 antibody that targets an N-terminal truncated form of amyloid beta present in mature plaques. Treatment-emergent (TE) anti-drug antibodies (ADAs) were quantified in donanemab-treated participants from two pivotal clinical trials, and effects of TE ADAs on donanemab pharmacokinetics, efficacy, and safety were assessed.

Methods: Data were pooled from the phase 2 TRAILBLAZER-ALZ (NCT03367403) and phase 3 TRAILBLAZER-ALZ 2 trials (NCT04437511).

Delivering public health advice to sign language users: a qualitative study with key stakeholders.

Objectives: There are more than 10 million deaf or hard of hearing people in the UK. While the deaf and hard of hearing population is heterogeneous, many of those with profound hearing loss are part of deaf communities (UK estimate around 120 000) which are defined minority communities. Many members of deaf communities are sign language users.

Bidirectional Modification of a Alkaloid Identifies Selective Opioid Ligands.

We report a bidirectional diversification and optimization campaign of the newly identified - and -opioid receptor antagonist GB18, a naturally occurring alkaloid. First, we find that replacement of the GB18 piperidine with pyridine alters the pharmacology from antagonism to partial agonism, with reduced potency but markedly higher receptor selectivity for over . Second, we optimize this hit via development of a mutually chemoselective cross-coupling of an alkyl iodide/vinyl triflate pair that leads to a series of low- and sub-nanomolar KOR-selective full agonists, some of which demonstrate bias for G protein activation over β-arrestin2 recruitment.

Heavy metal carcinogenicity: a scoping review of observational & experimental evidence.

Environmental heavy metal pollutants are highly toxic and are usually of human origin. Studies have suggested a link between cadmium and arsenic carcinogenesis and geographical location. This review was conducted to explore the methodologies that have been used to determine the risk of carcinogenesis as it relates to cadmium & arsenic exposure as well as geographical location.