Expanding the reaction toolbox for nanoscale direct-to-biology PROTAC synthesis and biological evaluation.

High-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis and biological evaluation of crude mixtures in cellular assays. The rise of these workflows has rapidly accelerated drug-discovery programs in the field of targeted protein degradation (TPD) in recent years by removing a key bottleneck of compound purification. However, the number of chemical transformations amenable to this methodology remain minimal, leading to limitations in the exploration of chemical space using existing library-based approaches.

Biocatalytic synthesis of ribonucleoside analogues using nucleoside transglycosylase-2.

Ribonucleosides are essential building blocks used extensively in antiviral and oligonucleotide therapeutics. A major challenge in the further development of nucleoside analogues for therapeutic applications is access to scalable and environmentally sustainable synthetic strategies. This study uses the type II nucleoside 2'-deoxyribosyltransferase from (NDT-2) to prepare a suite of ribonucleoside analogues using naturally-occurring uridine and cytidine sugar donors.

S-MGBs bearing amidine tail groups are potent, selective antiplasmodial agents.

There were an estimated 249 million cases of malaria globally in 2022, causing approximately 608 000 deaths. Most of these are attributed to infection by . Strathclyde minor groove binders (S-MGBs) are a promising new class of anti-infective agent that have been shown to be effective against many infectious organisms, including .

Tailoring lipid nanoparticle dimensions through manufacturing processes.

Lipid nanoparticles (LNPs), most commonly recognised for their role in COVID-19 mRNA vaccines, are important delivery vehicles for nucleic acid (mRNA, siRNA) therapies. The physicochemical attributes, such as size, nucleic acid encapsulation and electric charge, may have a significant impact on the efficacy of these medicines. In this study, adjustments to aqueous to lipid phase ratios were assessed for their impact on LNP size and other critical quality attributes (CQAs).

Films of linear conjugated polymer as photoanodes for oxidation reactions.

Photoelectrochemical (PEC) devices hold huge potential to convert solar energy into chemical energy. However, the high cost of raw materials and film processing has hindered its practical use. In this study, we attempt to tackle this issue by fabricating straightforward semiconducting polymer films.

Quantitative analysis of protein lipidation and acyl-CoAs reveals substrate preferences of the -acylation machinery.

Protein palmitoylation or -acylation has emerged as a key regulator of cellular processes. Increasing evidence shows that this modification is not restricted to palmitate but it can include additional fatty acids, raising the possibility that differential -acylation contributes to the fine-tuning of protein activity. However, methods to profile the acyl moieties attached to proteins are scarce.

Amorphous aggregates with a very wide size distribution play a central role in crystal nucleation.

There is mounting evidence that crystal nucleation from supersaturated solution involves the formation and reorganization of prenucleation clusters, contradicting classical nucleation theory. One of the key unresolved issues pertains to the origin, composition, and structure of these clusters. Here, a range of amino acids and peptides is investigated using light scattering, mass spectrometry, and terahertz Raman spectroscopy, showing that the presence of amorphous aggregates is a general phenomenon in supersaturated solutions.

Assessing the Stability of Clusters of Neuropsychiatric Symptoms in Alzheimer's Disease and Mild Cognitive Impairment.

Aim: The aim of the study was to investigate the factors that underpin neuropsychiatric symptoms and how they might evolve over time in people with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD) dementia.

Background: Neuropsychiatric symptoms are psychiatric and behavioural manifestations that occur in people with AD. These are highly prevalent along the continuum of the disease, including at the stage of MCI, as well as before cognitive decline.

Subspace shrinkage in conjugate Bayesian vector autoregressions.

Macroeconomists using large datasets often face the choice of working with either a large vector autoregression (VAR) or a factor model. In this paper, we develop a conjugate Bayesian VAR with a subspace shrinkage prior that combines the two. This prior shrinks towards the subspace which is defined by a factor model.

Improving the gas sorption capacity in lantern-type metal-organic polyhedra by a scrambled cage method.

The synthesis of multivariate metal-organic frameworks (MOFs) is a well-known method for increasing the complexity of porous frameworks. In these materials, the structural differences of the ligands used in the synthesis are sufficiently subtle that they can each occupy the same site in the framework. However, multivariate or ligand scrambling approaches are rarely used in the synthesis of porous metal-organic polyhedra (MOPs) - the molecular equivalent of MOFs - despite the potential to retain a unique intrinsic pore from the individual cage while varying the extrinsic porosity of the material.

Decomposing diversity into measures of evenness, similarity, and richness.

It has long been recognized that diversity has many measurable aspects, such as richness, evenness, and similarity among species. However, given a diversity index, it is unclear whether it necessarily can be decomposed into components that reflect these different aspects. Here, we present a scheme to decompose the Leinster and Cobbold diversity index, which subsumes and generalizes many other indices, into the components of richness, evenness and taxonomic similarity.

Methylthioadenosine Phosphorylase Genomic Loss in Advanced Gastrointestinal Cancers.

Background: One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker.

Covalent targeting of non-cysteine residues in PI4KIIIβ.

The synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIIIβ is described. The conserved lysine residue located within the ATP binding site was targeted, and optimised compounds based upon reversible inhibitors with good activity and physicochemical profile showed strong reversible interactions and slow onset times for the covalent inhibition, resulting in an excellent selectivity profile for the lipid kinase target. X-Ray crystallography demonstrated a distal tyrosine residue could also be targeted using a fluorosulfate strategy.

Teaching old presumptive tests new digital tricks with computer vision for forensic applications.

Presumptive (or 'spot') tests have served forensic scientists, law enforcement, and legal practitioners for over a hundred years. Yet, the intended design of such tests, enabling quick identification of drugs by-eye, also hides their full potential. Here, we report the development and application of time-resolved imaging methods of reactions attending spot tests for amphetamines, barbiturates, and benzodiazepines.

Computer vision as a new paradigm for monitoring of solution and solid phase peptide synthesis.

We report a strategy for the camera-enabled non-contact colourimetric reaction monitoring and optimisation of amide bond formation, mediated by coupling reagents. For amide bond formation in solution phase, investigation of reactions mediated by HATU, PyAOP, and DIC/Oxyma evidenced correlations between colour parameters extracted from video data and conversion to amide product measured by off-line HPLC analysis of concentration. These correlations, supported by mutual information analysis, were further investigated using video recordings of solid phase peptide synthesis (SPPS), co-analysed by off-line HPLC to track remaining unreacted substrate in solution.

Modelling clinical narrative as computable knowledge: The NICE computable implementation guidance project.

Introduction: Translating narrative clinical guidelines to computable knowledge is a long-standing challenge that has seen a diverse range of approaches. The UK National Institute for Health and Care Excellence (NICE) Content Advisory Board (CAB) aims ultimately to (1) guide clinical decision support and other software developers to increase traceability, fidelity and consistency in supporting clinical use of NICE recommendations, (2) guide local practice audit and intervention to reduce unwarranted variation, (3) provide feedback to NICE on how future recommendations should be developed.

Objectives: The first phase of work was to explore a range of technical approaches to transition NICE toward the production of natively digital content.

Neurophysiological Assessment of An Innovative Maritime Safety System in Terms of Ship Operators' Mental Workload, Stress, and Attention in the Full Mission Bridge Simulator.

The current industrial environment relies heavily on maritime transportation. Despite the continuous technological advances for the development of innovative safety software and hardware systems, there is a consistent gap in the scientific literature regarding the objective evaluation of the performance of maritime operators. The human factor is profoundly affected by changes in human performance or psychological state.

Highlights from the 56th Bürgenstock Conference on Stereochemistry 2023.

Herein, we share an overview of the scientific highlights from speakers at the latest edition of the longstanding Bürgenstock Conference.

Harmonized multi-metric and multi-centric assessment of EEG source space connectivity for dementia characterization.

Introduction: Harmonization protocols that address batch effects and cross-site methodological differences in multi-center studies are critical for strengthening electroencephalography (EEG) signatures of functional connectivity (FC) as potential dementia biomarkers.

Methods: We implemented an automatic processing pipeline incorporating electrode layout integrations, patient-control normalizations, and multi-metric EEG source space connectomics analyses.

Results: Spline interpolations of EEG signals onto a head mesh model with 6067 virtual electrodes resulted in an effective method for integrating electrode layouts.

Computer vision for non-contact monitoring of catalyst degradation and product formation kinetics.

We report a computer vision strategy for the extraction and colorimetric analysis of catalyst degradation and product-formation kinetics from video footage. The degradation of palladium(ii) pre-catalyst systems to form 'Pd black' is investigated as a widely relevant case study for catalysis and materials chemistries. Beyond the study of catalysts in isolation, investigation of Pd-catalyzed Miyaura borylation reactions revealed informative correlations between colour parameters (most notably Δ, a colour-agnostic measure of contrast change) and the concentration of product measured by off-line analysis (NMR and LC-MS).

An Ultrasound Investigation of Tongue Dorsum Raising in Children with Cleft Palate +/- Cleft Lip.

Objective: This study aimed to determine whether increased raising of the back of the tongue is evident in children with repaired cleft palate with or without cleft lip (CP+/-CL). We hypothesized that children with CP+/-CL would show increased raising of the tongue dorsum, a compensatory pattern.

Method: Secondary data analysis of mid-sagittal ultrasound tongue imaging data from 31 children with CP+/-CL and 29 typically developing children were used.

Role of PARP and TRPM2 in VEGF Inhibitor-Induced Vascular Dysfunction.

Background Hypertension and vascular toxicity are major unwanted side effects of antiangiogenic drugs, such as vascular endothelial growth factor inhibitors (VEGFis), which are effective anticancer drugs but have unwanted side effects, including vascular toxicity and hypertension. Poly (ADP-ribose) polymerase (PARP) inhibitors, used to treat ovarian and other cancers, have also been associated with elevated blood pressure. However, when patients with cancer receive both olaparib, a PARP inhibitor, and VEGFi, the risk of blood pressure elevation is reduced.

Memory-driven eye movements prospectively predict dementia in people at risk of Alzheimer's disease.

Introduction: Oculomotor behaviors linked to cognitive performance revealed neurocognitive features of Alzheimer's disease (AD) that can enhance the accuracy of its assessment and diagnosis.

Methods: A sample of 107 participants (i.e.