Ag(I)-promoted fragment coupling of peptide thioamides.

Despite advances in solid phase peptide synthesis and peptide ligation, challenges remain in the assembly of polypeptides through coupling of peptide fragments. Herein we describe a new method for peptide fragment coupling employing the Ag(I)-promoted transformation of peptide thioamides. This process proceeds an isoimide-tethered intermediate, which undergoes an O-N acyl transfer to generate the polypeptide.

Late-Stage Pd(II)-Catalyzed C(sp)-H Functionalization of Peptides Directed by a Removable, Backbone-Inserted Amidoxime Ether.

Palladium(II)-catalyzed C-H functionalization has attracted considerable attention as a pathway to late-stage modification of peptides. Herein, we report the Pd-catalyzed C(sp)-H arylation of peptides directed by an amidoxime ether, which can be easily incorporated into peptides at any amide bond. Site- and stereoselective arylation of peptides has been achieved, including unprecedented functionalization of internal residues of native peptides.

A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo.

The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent reaction hijacking inhibitor of PfTyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity.

"Do they think I'm good enough?": General practitioners' experiences when treating doctor-patients.

Background: When doctors seek medical care, there is evidence that the treating doctor can struggle to provide optimal treatment. Guidelines state that doctor-patients should be treated like any other patient, but this is challenging for the treating doctor. This study set out to explore both the positive experiences general practitioners (GPs) have when caring for doctor-patients, and the challenges they confront.

Transient Elastography and Video Recovery Narrative Access to Support Recovery From Alcohol Misuse: Development of a Novel Intervention for Use in Community Alcohol Treatment Services.

Background: Mortality from alcohol-related liver disease has risen significantly for 3 decades. Transient elastography (TE) is a noninvasive test providing a numerical marker of liver disease. Preliminary evidence suggests that TE can reduce alcohol consumption.

Development of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin-2 Receptor Positive Cancers.

Peptide receptor radionuclide therapy (PRRT) is a promising form of systemic radiation therapy designed to eradicate cancer. Cholecystokinin-2 receptor (CCKR) is an important molecular target that is highly expressed in a range of cancers. This study describes the synthesis and characterization of a novel series of Lu-labeled peptides ([Lu]Lu--) in comparison with the reference CCKR-targeting peptide CP04 ([Lu]Lu-).

Doctors' experiences when treating doctor-patients: a scoping review.

Background: To work effectively, doctors need to look after themselves. They often delay seeking medical care for a range of reasons. Once they do, there is evidence that the doctors treating them ('treating doctors') can struggle to provide optimal care.

Does knowledge of liver fibrosis affect high-risk drinking behaviour (KLIFAD): an open-label pragmatic feasibility randomised controlled trial.

Background: Early identification followed by effective behaviour interventions is pivotal to changing the natural history of alcohol-related liver disease. We examined the feasibility of using transient elastography based advice and alcohol recovery video stories (ARVS) to change drinking behaviour in community alcohol services.

Methods: A feasibility randomised control trial (RCT) was conducted in three community alcohol services.

Incidence of Symptomatic Venous Thromboembolism (VTE) in 8,885 Elective Total Hip Arthroplasty Patients Receiving Post-operative Aspirin VTE Prophylaxis.

Background: Venous thromboembolism (VTE) is a potentially reducible cause of morbidity and mortality in patients undergoing elective hip arthroplasty surgery. The balance of post-operative VTE prophylaxis and risk of post-operative haemorrhage remains at the forefront of surgeon's mind. The National Institute for Health and Care Excellence (NICE) published updated guidelines in 2018 which recommend the use of both mechanical and pharmacological methods in patients undergoing elective total hip arthroplasty (THA).

USP7 inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development.

Adenomatous polyposis coli (APC) mutation is the hallmark of colorectal cancer (CRC), resulting in constitutive WNT activation. Despite decades of research, targeting WNT signaling in cancer remains challenging due to its on-target toxicity. We have previously shown that the deubiquitinating enzyme USP7 is a tumor-specific WNT activator in APC-truncated cells by deubiquitinating and stabilizing β-catenin, but its role in gut tumorigenesis is unknown.

Estimation of field inhomogeneity map following magnitude-based ambiguity-resolved water-fat separation.

Magnitude-based PDFF (Proton Density Fat Fraction) and R mapping with resolved water-fat ambiguity is extended to calculate field inhomogeneity (field map) using the phase images. The estimation is formulated in matrix form, resolving the field map in a least-squares sense. PDFF and R from magnitude fitting may be updated using the estimated field maps.

HiHi fMRI: a data-reordering method for measuring the hemodynamic response of the brain with high temporal resolution and high SNR.

There is emerging evidence that sampling the blood-oxygen-level-dependent (BOLD) response with high temporal resolution opens up new avenues to study the in vivo functioning of the human brain with functional magnetic resonance imaging. Because the speed of sampling and the signal level are intrinsically connected in magnetic resonance imaging via the T1 relaxation time, optimization efforts usually must make a trade-off to increase the temporal sampling rate at the cost of the signal level. We present a method, which combines a sparse event-related stimulus paradigm with subsequent data reshuffling to achieve high temporal resolution while maintaining high signal levels (HiHi).

Effective Preparation of [F]Flumazenil Using Copper-Mediated Late-Stage Radiofluorination of a Stannyl Precursor.

(1) Background: [18F]Flumazenil 1 ([18F]FMZ) is an established positron emission tomography (PET) radiotracer for the imaging of the gamma-aminobutyric acid (GABA) receptor subtype, GABAA in the brain. The production of [18F]FMZ 1 for its clinical use has proven to be challenging, requiring harsh radiochemical conditions, while affording low radiochemical yields. Fully characterized, new methods for the improved production of [18F]FMZ 1 are needed.

Site Specific Preparation of N-Glycosylated Peptides: Thioamide-Directed Activation of Aspartate.

A site-specific method for the preparation of N-glycosylated peptides is described. Incorporation of a peptide backbone thioamide linkage adjacent to an Asp residue facilitates a Ag -promoted, site-specific conversion to N-glycosylated Asn residues in peptides.

Earth observation and geospatial data can predict the relative distribution of village level poverty in the Sundarban Biosphere Reserve, India.

There is increasing interest in leveraging Earth Observation (EO) and geospatial data to predict and map aspects of socioeconomic conditions to support survey and census activities. This is particularly relevant for the frequent monitoring required to assess progress towards the UNs' Sustainable Development Goals (SDGs). The Sundarban Biosphere Reserve (SBR) is a region of international ecological importance, containing the Indian portion of the world's largest mangrove forest.

Backbone thioamide directed macrocyclisation: lactam stapling of peptides.

A novel method for lactam stapling of Asp/Lys-containing peptides has been developed that does not require coupling agents. A backbone thioamide is incorporated at the N-terminal side of the aspartate residue. Ag(I)-promoted activation of the thioamide in the vicinity of the Asp carboxylate generates a cyclic isoimide intermediate that is trapped by the Lys amine to generate the macrolactam.

Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however the effects of individual stromal subsets remain incompletely characterised. Here, we describe how heterocellular Oncostatin M (OSM) - Oncostatin M Receptor (OSMR) signalling reprograms fibroblasts, regulates tumour growth and metastasis.

The management of the shoulder skin microbiome ( in the context of shoulder surgery: a review of the current literature.

Background: This review aims to establish current knowledge of the shoulder skin microbiome and how to manage the bacteria that reside within it.

Methods: A review was undertaken of the current literature through OvidSP. All abstracts were reviewed by three independent researchers.

Developing socio-ecological scenarios: A participatory process for engaging stakeholders.

Deltas are experiencing profound demographic, economic and land use changes and human-induced catchment and climate change. Bangladesh exemplifies these difficulties through multiple climate risks including subsidence/sea-level rise, temperature rise, and changing precipitation patterns, as well as changing management of the Ganges and Brahmaputra catchments. There is a growing population and economy driving numerous more local changes, while dense rural population and poverty remain significant.

Comparisons of disease cluster patterns, prevalence and health factors in the USA, Canada, England and Ireland.

Background: Identification of those who are most at risk of developing specific patterns of disease across different populations is required for directing public health policy. Here, we contrast prevalence and patterns of cross-national disease incidence, co-occurrence and related risk factors across population samples from the U.S.

A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.

Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin-integrin α/α signalling in establishment and survival of pancreatic organoids.