Anion–π Enzymes

In this report, we introduce artificial enzymes that operate with anion-π interactions, an interaction that is essentially new to nature. The possibility to stabilize anionic intermediates and transition states on an π-acidic surface has been recently demonstrated, using the addition of malonate half thioesters to enolate acceptors as a biologically relevant example. The best chiral anion-π catalysts operate with an addition/decarboxylation ratio of 4:1, but without any stereoselectivity. To catalyze this important but intrinsically disfavored reaction stereoselectively, a series of anion-π catalysts was equipped with biotin and screened against a collection of streptavidin mutants. With the best hit, the S112Y mutant, the reaction occurred with 95% ee and complete suppression of the intrinsically favored side product from decarboxylation. This performance of anion-π enzymes rivals, if not exceeds, that of the best conventional organocatalysts. Inhibition of the S112Y mutant by nitrate but not by bulky anions supports that contributions from anion-π interactions exist and matter, also within proteins. In agreement with docking results, K121 is shown to be essential, presumably to lower the p K a of the tertiary amine catalyst to operate at the optimum pH around 3, that is below the p K a of the substrate. Most importantly, increasing enantioselectivity with different mutants always coincides with increasing rates and conversion, i.e., selective transition-state stabilization

Anion-π catalysis: Bicyclic products with four contiguous stereogenic centers from otherwise elusive diastereospecific domino reactions on π-acidic surfaces

Anion–π interactions have been introduced recently to catalysis. The idea of stabilizing anionic intermediates and transition states on π-acidic surfaces is a new fundamental concept. By now, examples exist for asymmetric enolate, enamine, iminium and transamination chemistry, and the first anion–π enzyme has been created. Delocalized over large aromatic planes, anion–π interactions appear particularly attractive to stabilize extensive long-distance charge displacements during domino processes. Moving on from the formation of cyclohexane rings with five stereogenic centers in one step on a π-acidic surface, we here focus on asymmetric anion–π catalysis of domino reactions that afford bicyclic products with quaternary stereogenic centers. Catalyst screening includes a newly synthesized, better performing anion–π version of classical organocatalysts from cinchona alkaloids, and anion–π enzymes. We find stereoselectivities that are clearly better than the best ones reported with conventional catalysts, culminating in unprecedented diastereospecificity. Moreover, we describe achiral salts as supramolecular chirality enhancers and report the first artificial enzyme that operates in neutral water with anion–π interactions, i.e., interactions that are essentially new to enzymes. Evidence in support of contributions of anion–π interactions to asymmetric catalysis include increasing diastereo- and enantioselectivity with increasing rates, i.e., asymmetric transition-state stabilization in the presence of π-acidic surfaces and inhibition with the anion selectivity sequence NO3− > Br− > BF4− > PF6−

Pharmacists' clinical roles and activities in inpatient hospice and palliative care: a scoping review.

BACKGROUND Pharmacists contribute to medication safety by providing their services in various settings. However, standardized definitions of the role of pharmacists in hospice and palliative care (HPC) are lacking. AIM The purpose of this scoping review was to provide an overview of the evidence on the role of pharmacists and to map clinical activities in inpatient HPC. METHOD We performed a scoping review according to the PRISMA-ScR extension in CINAHL, Embase, and PubMed. We used the American Society of Hospital Pharmacists (ASHP) Guidelines on the Pharmacist's Role in Palliative and Hospice Care as a framework for standardized categorization of the identified roles and clinical activities. RESULTS After screening 635 records (published after January 1st, 2000), the scoping review yielded 23 publications reporting various pharmacy services in HPC. The articles addressed the five main categories in the following descending order: 'Medication order review and reconciliation', 'Medication counseling, education and training', 'Administrative Roles', 'Direct patient care', and 'Education and scholarship'. A total of 172 entries were mapped to the subcategories that were added to the main categories. CONCLUSION This scoping review identified a variety of pharmacists' roles and clinical activities. The gathered evidence will help to establish and define the role of pharmacists in inpatient hospice and palliative care

Prescription Trends in Hospice Care: A Longitudinal Retrospective and Descriptive Medication Analysis.

BACKGROUND In hospice and palliative care, drug therapy is essential for symptom control. However, drug regimens are complex and prone to drug-related problems. Drug regimens must be simplified to improve quality of life and reduce risks associated with drug-related problems, particularly at end-of-life. To support clinical guidance towards a safe and effective drug therapy in hospice care, it is important to understand prescription trends. OBJECTIVES To explore prescription trends and describe changes to drug regimens in inpatient hospice care. DESIGN We performed a retrospective longitudinal and descriptive analysis of prescriptions for regular and as-needed (PRN) medication at three timepoints in deceased patients of one Swiss hospice. SETTING/SUBJECTS Prescription records of all patients ( 18 years) with an inpatient stay of three days and longer (admission and time of death in 2020) were considered eligible for inclusion. RESULTS Prescription records of 58 inpatients (average age 71.7 ± 12.8 [37-95] years) were analyzed. The medication analysis showed that polypharmacy prevalence decreased from 74.1% at admission to 13.8% on the day of death. For regular medication, overall numbers of prescriptions decreased over the patient stay while PRN medication decreased after the first consultation by the attending physician and increased slightly towards death. CONCLUSIONS Prescription records at admission revealed high initial rates of polypharmacy that were reduced steadily until time of death. These findings emphasize the importance of deprescribing at end-of-life and suggest pursuing further research on the contribution of clinical guidance towards optimizing drug therapy and deprescribing in inpatient hospice care

PHOTOCHEMICAL RING-OPENING IN meso-CHLORINATED CHLOROPHYLLS

Irradiation of 20-chloro-chlorophylls of the a-type with visible light produces long-wavelength shifted photoproducts, which transform in the dark to linear tetrapyrroles (bile pigments). The possible significance for chlorophyll degradation is discussed

Chimeric streptavidins as host proteins for artificial metalloenzymes

The streptavidin scaffold was expanded with well-structured naturally occurring motifs. These chimeric scaffolds were tested as hosts for biotinylated catalysts as artificial metalloenzymes (ArM) for asymmetric transfer hydrogenation, ring-closing metathesis and anion−π catalysis. The additional second coordination sphere elements significantly influence both the activity and the selectivity of the resulting hybrid catalysts. These findings lead to the identification of propitious chimeric streptavidins for future directed evolution efforts of artificial metalloenzymes

Multimodal imaging of pancreatic beta cells in vivo by targeting transmembrane protein 27 (TMEM27)

Aims/hypothesis: Non-invasive diagnostic tools specific for pancreatic beta cells will have a profound impact on our understanding of the pathophysiology of metabolic diseases such as diabetes. The objective of this study was to use molecular imaging probes specifically targeting beta cells on human samples and animal models using state-of-the-art imaging modalities (fluorescence and PET) with preclinical and clinical perspective. Methods: We generated a monoclonal antibody, 8/9-mAb, targeting transmembrane protein 27 (TMEM27; a surface N-glycoprotein that is highly expressed on beta cells), compared its expression in human and mouse pancreas, and demonstrated beta cell-specific binding in both. In vivo imaging was performed in mice with subcutaneous insulinomas overexpressing the human TMEM27 gene, or transgenic mice with beta cell-specific hTMEM27 expression under the control of rat insulin promoter (RIP-hTMEM27-tg), using fluorescence and radioactively labelled antibody, followed by tissue ex vivo analysis and fluorescence microscopy. Results: Fluorescently labelled 8/9-mAb showed beta cell-specific staining on human and mouse pancreatic sections. Real-time PCR on islet cDNA indicated about tenfold higher expression of hTMEM27 in RIP-hTMEM27-tg mice than in humans. In vivo fluorescence and PET imaging in nude mice with insulinoma xenografts expressing hTMEM27 showed high 8/9-mAb uptake in tumours after 72h. Antibody homing was also observed in beta cells of RIP-hTMEM27-tg mice by in vivo fluorescence imaging. Ex vivo analysis of intact pancreas and fluorescence microscopy in beta cells confirmed these findings. Conclusions/interpretation: hTMEM27 constitutes an attractive target for in vivo visualisation of pancreatic beta cells. Studies in mouse insulinoma models and mice expressing hTMEM27 demonstrate the feasibility of beta cell-targeted in vivo imaging, which is attractive for preclinical investigations and holds potential in clinical diagnostic