Chemoselective, regioselective, and positionally selective fluorogenic stapling of unprotected peptides for cellular uptake and direct cell imaging.

Peptide stapling reactions represent powerful methods for structuring native α-helices to improve their bioactivity in targeting protein-protein interactions (PPIs). In light of a growing need for regio- and positionally selective stapling methods involving natural amino acid residues in their unprotected states, we report a rapid, mild, and highly chemoselective three-component stapling reation using a class of molecular linchpins based on 2-arylketobenzaldehydes (ArKBCHOs) that create a fluorescent staple, hereafter referred to as a Fluorescent Isoindole Crosslink (FlICk). This methodology offers positional selectivity favouring , + 4 helical staples comprising a lysine and cysteine, in the presence of competing nucleophiles on unprotected peptides.

AAPM task group report 314: Fault recovery in external beam radiation therapy.

Task Group (TG) 314 of the American Association of Physicists in Medicine (AAPM) was charged to develop guidance for recovering from fault states in radiation therapy, specifically regarding the delivery of photon or electron beams using a linear accelerator (linac) including ancillary systems. The fault conditions addressed may involve software, hardware, or a combination of causes. The report provides detailed recommendations for the proactive steps to be taken before a fault, the actions to be taken at the time of a fault, and the safety steps before returning a linac to clinical service, as well as the activities that device manufacturers and standard organizations can do to prevent and resolve the faults.

Pyruvate dehydrogenase kinase 1 controls triacylglycerol hydrolysis in cardiomyocytes.

Pyruvate dehydrogenase kinase (PDK) 1 is one of four isozymes that inhibit the oxidative decarboxylation of pyruvate to acetyl-CoA via pyruvate dehydrogenase. PDK activity is elevated in fasting or starvation conditions to conserve carbohydrate reserves. PDK has also been shown to increase mitochondrial fatty acid utilization.

Image-based simulation of mitral valve dynamic closure including anisotropy.

Simulation of the dynamic behavior of mitral valve closure could improve clinical treatment by predicting surgical procedures outcome. We propose here a method to achieve this goal by using the immersed boundary method. In order to go towards patient-based simulation, we tailor our method to be adapted to a valve extracted from medical image data.

Synthesis of (2,3,4)-Dihydroxyisoleucine for Use in Amatoxin Synthesis.

We report a streamlined synthesis of (2,3,4)-4,5-dihydroxy isoleucine (DHIle), an amino acid found in α-amanitin, which appears to be critical for toxicity. This synthetic route is transition metal-free and enables the production of significant quantities of DHIle with suitable protection for use in peptide synthesis. Its incorporation into a cytotoxic amatoxin analog is reported.

An Immersive Virtual Reality Intervention for Preoperative Anxiety and Distress Among Adults Undergoing Oncological Surgery: Protocol for a 3-Phase Development and Feasibility Trial.

Background: Preoperative state anxiety (PSA) is distress and anxiety directly associated with perioperative events. PSA is associated with negative postoperative outcomes such as longer hospital length of stay, increased pain and opioid use, and higher rates of rehospitalization. Psychological prehabilitation, such as education, exposure to hospital environments, and relaxation strategies, has been shown to mitigate PSA; however, there are limited skilled personnel to deliver such interventions in clinical practice.

Tibial osteochondroma with thick cartilage which mimicked a chondrosarcoma: A case report.

We report a case of tibial osteochondroma in a 25-year-old female who presented with a palpable calf mass. This mass was associated with a thick cartilaginous cap on cross-sectional imaging, suggesting chondrosarcoma. A CT-guided biopsy was performed, and histology, however, was consistent with osteochondroma.

A Humeral Osteosarcoma Mimicking Osseous Leiomyosarcoma: A Case Report.

Osteosarcoma stands as one of the primary mesenchymal bone neoplasms commonly encountered in clinical practice. This malignancy often presents with a wide range of distinctive imaging characteristics. Here, we present a unique case wherein a delayed diagnosis of high-grade osteosarcoma occurred due to the absence of an osteoid matrix in the initial imaging studies.

Diphenylphosphinylhydroxylamine (DPPH) Affords Late-Stage S-imination to access free-NH Sulfilimines and Sulfoximines.

Sulfilimines, as potential aza-isosteres of sulfoxides, are valued as building blocks, auxiliaries, ligands, bioconjugation handles, and as precursors to versatile S(VI) scaffolds including sulfoximines and sulfondiimines. Here, we report a thioether imination methodology that exploits O-(diphenylphosphinyl)hydroxyl amine (DPPH). Under mild, metal-free, and biomolecule-compatible conditions, DPPH enables late-stage S-imination on peptides, natural products, and a clinically trialled drug, and shows both excellent chemoselectivity and broad functional group tolerance.

5-Hydroxypyrroloindoline Affords Tryptathionine and 2,2'-bis-Indole Peptide Staples: Application to Melanotan-II.

With peptides increasingly favored as drugs, natural product motifs, namely the tryptathionine staple, found in amatoxins and phallotoxins, and the 2,2'-bis-indole found in staurosporine represent unexplored staples for unnatural peptide macrocycles. We disclose the efficient condensation of a 5-hydroxypyrroloindoline with either a cysteine-thiol or a tryptophan-indole to form a tryptathionine or 2-2'-bis-indole staple. Judicious use of protecting groups provides for chemoselective stapling using α-MSH, which provides a basis for investigating both chemoselectivity and affinity.

A Comparative Study on Crystallisation for Virgin and Recycled Polyethylene Terephthalate (PET): Multiscale Effects on Physico-Mechanical Properties.

Poly(Ethylene Terephthalate) (PET) is one of the most used polymers for packaging applications. Modifications induced by service conditions and the means to make this matter circular have to be understood to really close the loop (from bottle to bottle for example). Physico-chemical properties, crystalline organisation, and mechanical behaviour of virgin PET (vPET) are compared with those of recycled PET (rPET).

Computational prediction of proximal sealing in endovascular abdominal aortic aneurysm repair with unfavorable necks.

Background And Objective: Endovascular aortic aneurysm repair (EVAR) has become the standard treatment for abdominal aortic aneurysms in most centers. However, proximal sealing complications leading to endoleaks and migrations sometimes occur, particularly in unfavorable aortic anatomies and are strongly dependent on biomechanical interactions between the aortic wall and the endograft. The objective of the present work is to develop and validate a computational patient-specific model that can accurately predict these complications.

Accommodating the continuum hypothesis with the déjà vu/déjà vécu distinction.

On Barzykowski and Moulin's continuum hypothesis, déjà vu and involuntary autobiographical memories (IAMs) share their underpinning neurocognitive processes. A discontinuity issue for them is that familiarity and episodic recollection exhibit different neurocognitive signatures. This issue can be overcome, I say, provided the authors are ready to distinguish a déjà vécu/episodic IAM continuity and a déjà vu/semantic IAM continuity.

Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy.

Toward tryptathionine-stapled one-bead-one-compound (OBOC) libraries: solid phase synthesis of a bioactive octretoate analog.

New somatostatin analogs are highly desirable for diagnosing and treating neuroendocrine tumors (NETs). Here we describe the solid-phase synthesis of a new octreotate (TATE) analog where the disulfide bond is replaced with a tryptathionine (Ttn) staple as part of an effort to prototyping a one-bead-one-compound (OBOC) library of Ttn-stapled peptides. Library design provides the potential for on- and off-bead screening.

Circadian ribosome profiling reveals a role for the upstream open reading frame in sleep.

Many mammalian proteins have circadian cycles of production and degradation, and many of these rhythms are altered posttranscriptionally. We used ribosome profiling to examine posttranscriptional control of circadian rhythms by quantifying RNA translation in the liver over a 24-h period from circadian-entrained mice transferred to constant darkness conditions and by comparing ribosome binding levels to protein levels for 16 circadian proteins. We observed large differences in ribosome binding levels compared to protein levels, and we observed delays between peak ribosome binding and peak protein abundance.

Comparative analysis of YAP/TEAD inhibitors in 2D and 3D cultures of primary human hepatocytes reveals a novel non-canonical mechanism of CYP induction.

Induction of cytochrome P450 (CYP) genes constitutes an important cause of drug-drug interactions and preclinical evaluation of induction liability is mandatory for novel drug candidates. YAP/TEAD signaling has emerged as an attractive target for various oncological indications and multiple chemically distinct YAP/TEAD inhibitors are rapidly progressing towards clinical stages. Here, we tested the liability for CYP induction of a diverse set of YAP/TEAD inhibitors with different modes of action and TEAD isoform selectivity profiles in monolayers and 3D spheroids of primary human hepatocytes (PHH).

Assessment of the potential of the MET inhibitor tepotinib to affect the pharmacokinetics of CYP3A4 and P-gp substrates.

Tepotinib is a highly selective, potent, mesenchymal-epithelial transition factor (MET) inhibitor, approved for the treatment of non-small cell lung cancer harboring MET exon 14 skipping alterations. The aims of this work were to investigate the potential for drug-drug interactions via cytochrome P450 (CYP) 3A4/5 or P-glycoprotein (P-gp) inhibition. In vitro studies were conducted in human liver microsomes, human hepatocyte cultures and Caco-2 cell monolayers to investigate whether tepotinib or its major metabolite (MSC2571109A) inhibited or induced CYP3A4/5 or inhibited P-gp.

Predicting Carcass Weight of Grass-Fed Beef Cattle before Slaughter Using Statistical Modelling.

Gaining insights into the utilization of farm-level data for decision-making within the beef industry is vital for improving production and profitability. In this study, we present a statistical model to predict the carcass weight (CW) of grass-fed beef cattle at different stages before slaughter using historical cattle data. Models were developed using two approaches: boosted regression trees and multiple linear regression.

[Drugs: minors and harm reduction?].

The use of controlled substances (narcotics and psychotropic substances) poses increased risks for minors. However, minors are generally excluded from existing harm reduction services (e.g.

Role of the bicarbonate transporter SLC4γ in stony-coral skeleton formation and evolution.

Coral reefs are highly diverse ecosystems of immense ecological, economic, and aesthetic importance built on the calcium-carbonate-based skeletons of stony corals. The formation of these skeletons is threatened by increasing ocean temperatures and acidification, and a deeper understanding of the molecular mechanisms involved may assist efforts to mitigate the effects of such anthropogenic stressors. In this study, we focused on the role of the predicted bicarbonate transporter SLC4γ, which was suggested in previous studies to be a product of gene duplication and to have a role in coral-skeleton formation.

The "Ins and Outs" of Prostate Specific Membrane Antigen (PSMA) as Specific Target in Prostate Cancer Therapy.

Prostate-specific membrane antigen (PSMA) is expressed in epithelial cells of the prostate gland and is strongly upregulated in prostatic adenocarcinoma, with elevated expression correlating with metastasis, progression, and androgen independence. Because of its specificity, PSMA is a major target of prostate cancer therapy; however, detectable levels of PSMA are also found in other tissues, especially in salivary glands and kidney, generating bystander damage of these tissues. Antibody target therapy has been used with relative success in reducing tumor growth and prostate specific antigen (PSA) levels.

IOA-244 is a Non-ATP-competitive, Highly Selective, Tolerable PI3K Delta Inhibitor That Targets Solid Tumors and Breaks Immune Tolerance.

Unlabelled: PI3K delta (PI3Kδ) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3Kδ inhibition in solid tumors has recently emerged as a potential novel anticancer therapy through the modulation of T-cell responses and direct antitumor activity. Here we report the exploration of IOA-244/MSC2360844, a first-in-class non-ATP-competitive PI3Kδ inhibitor, for the treatment of solid tumors.

Machine learning and reduced order modelling for the simulation of braided stent deployment.

Endoluminal reconstruction using flow diverters represents a novel paradigm for the minimally invasive treatment of intracranial aneurysms. The configuration assumed by these very dense braided stents once deployed within the parent vessel is not easily predictable and medical volumetric images alone may be insufficient to plan the treatment satisfactorily. Therefore, here we propose a fast and accurate machine learning and reduced order modelling framework, based on finite element simulations, to assist practitioners in the planning and interventional stages.

Imidazolium-methylene-trifluoroborate: A novel radioprosthetic group validated with preclinical F-Positron Emission Tomography imaging of Prostate Specific Membrane Antigen in mice.

Organotrifluoroborates have gained acceptance as radioprosthetic groups for radiofluorination. Of these, the zwitterionic prosthetic group "AMBF " with a quaternary dimethylammonium ion dominates the trifluoroborate space. Herein, we report on imidazolium-methylene trifluoroborate (ImMBF ) as an alternative radioprosthetic group and report on its properties in the context of a PSMA-targeting EUK ligand that was previously been conjugated to AMBF .