Evaluation of Cereblon-Directing Warheads for the Development of Orally Bioavailable PROTACs.

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (), and results of a comprehensive comparative study with analogues containing alternative CRBN-directing warheads.

Service evaluation of 'GP at Door' of accident and emergency services in Eastern England.

Aim: We describe activity, outcomes, and benefits after streaming low urgency attenders to eneral practice services at oor of ccident and mergency departments (GDAE).

Background: Many attendances to A&Es are for non-urgent health problems that could be better met by primary care rather than urgent care clinicians. It is valuable to monitor service activity, outcomes, service user demographics, and potential benefits when primary care is co-located with A&E departments.

Mosquitoes Reared in Nearby Insectaries at the Same Institution Have Significantly Divergent Microbiomes.

The microbiome influences critical aspects of mosquito biology and variations in microbial composition can impact the outcomes of laboratory studies. To investigate how biotic and abiotic conditions in an insectary affect the composition of the mosquito microbiome, a single cohort of Aedes aegypti eggs was divided into three batches and transferred to three different climate-controlled insectaries within the Liverpool School of Tropical Medicine. The bacterial microbiome composition was compared as mosquitoes developed, the microbiome of the mosquitoes' food sources was characterised, environmental conditions over time in each insectary were measured, and mosquito development and survival were recorded.

Decoding Deception: The binding affinity of cuttlefish ink on shark smell receptors.

Chemical signaling can play a crucial role in predator-prey dynamics. Here, we present evidence that ink from the common cuttlefish (Sepia officinalis) targets olfactory receptor proteins in shark, potentially acting as a predator deterrence. We apply in silico 3D docking analysis to investigate the binding affinity of various odorant molecules to shark olfactory receptors of two shark species: cloudy catshark (Scyliorhinus torazame) and white shark (Carcharodon carcharias).

Intraprocedural transthoracic echocardiography to facilitate left bundle branch pacing: EC-LBBP.

Background: Left bundle branch (LBB) pacing (LBBP) has gained rapid adoption. Evidence for direct LBB capture has varied from 30%-95% depending on the criteria.

Objective: The purpose of this study was to assess the feasibility and efficacy of intraprocedural transthoracic echocardiographic guidance to achieve LBB capture.