Structural roles of Ump1 and β-subunit propeptides in proteasome biogenesis.

The yeast (β4-S142F) mutant accumulates late 20S proteasome core particle precursor complexes (late-PCs). We report a 2.1 Å cryo-EM structure of this intermediate with full-length Ump1 trapped inside, and Pba1-Pba2 attached to the α-ring surfaces.

SurLym trial: study protocol for a multicentre pragmatic randomised controlled trial on the added value of reconstructive lymphatic surgery to decongestive lymphatic therapy for the treatment of lymphoedema.

Introduction: Lymphoedema is a chronic condition caused by lymphatic insufficiency. It leads to swelling of the limb/midline region and an increased risk of infection. Lymphoedema is often associated with mental and physical problems limiting quality of life.

Ex vivo study correlating the stiffness of the ovine patellar tendon to age and weight.

Tendons play a crucial role in the musculoskeletal system. In humans, tendon injuries, especially chronic tendinopathy, are very common and the patellar tendon is a frequent location for tendinopathy or injuries. The biomechanical characteristics of the patellar tendon, such as elasticity and stiffness, are of paramount importance and constitute major outcome measures in research studies.

Delineation guidelines for the lymphatic target volumes in 'prone crawl' radiotherapy treatment position for breast cancer patients.

Our recently developed prone crawl position (PCP) for radiotherapy of breast cancer patients with lymphatic involvement showed promising preliminary data and it is being optimized for clinical use. An important aspect in this process is making new, position specific delineation guidelines to ensure delineation (for treatment planning) is uniform across different centers. The existing ESTRO and PROCAB guidelines for supine position (SP) were adapted for PCP.

Semiquantitative Solid-State NMR Study of the Adsorption of Soybean Oils on Silica and Its Significance for Rubber Processing.

Soybean oil (SBO) is a renewable material used as an alternative to conventional petroleum-derived oils in the processing of rubber composites. Upon chemical modifications, such as epoxidation, its performance in the processing of rubber can be significantly improved, as indicated by a considerable reduction of the mixing energy. Although it has been hypothesized that hydrogen bonding between functional groups (e.

Breast implant seroma: A SARS-CoV-2 mRNA vaccine side effect.

Fluid collection surrounding breast implants, called seroma, is a frequent issue that has diverse etiologies. We describe a 48-year-old woman with an acute onset of bilateral breast swelling occurring 5 years after aesthetic surgery and 10 days after a second SARS-CoV-2 mRNA vaccine dose. At breast ultrasound, we found an abundant bilateral peri-implant seroma.

Subgaleal Lipoma: Imaging Findings.

Unlabelled: Subgaleal lipoma is a benign tumor of adipose tissue. It should be suspected when a semi-spherical avascular mass with well-defined margins, iso- or hyperechoic in most cases, with thin internal echogenic lines parallel to the long axis of the tumor, is observed between the galea aponeurosis and periosteum of the cranial bone. We report a series of cases of three patients who underwent surgical lesion excision and whose histopathological examination findings confirmed the diagnosis of lipoma.

Sensitivity enhancement multiple contacts in the {H-Si}-H cross polarization experiment: a case study of modified silica nanoparticle surfaces.

{H-Si}-H double cross polarization inverse detection (DCPi) solid-state NMR, has recently been shown to be a powerful tool for studying molecules adsorbed on the silica surface. In this contribution, we develop an improved version (MCPi) which incorporates a block of multiple contact pulses, and quantitatively compare the sensitivities of MCPi and DCPi over a typical range of experimental parameters. The MCPi pulse sequence aims at higher sensitivity and robustness for studying samples with various relaxation characteristics.

Organocatalytic sequential ring-opening polymerization of a cyclic ester and anionic polymerization of a vinyl monomer.

Organocatalysis has provided new tools for making block copolymers, in particular active species able to polymerize monomers of different chemical nature such as cyclic esters, cyclic carbonates and epoxides. We report herein the first example of an organocatalytic active species able to polymerize sequentially a cyclic ester, ε-decalactone, and a vinyl monomer, methyl methacrylate. The resulting block copolymer shows the properties of thermoplastic elastomers.

Ultrasound anatomy of the normal stifle in the sheep.

Though the ovine stifle is commonly used as a model in research, there is no description of its anatomy at ultrasonography (US). The objective of this study was to provide reference US images of the ovine stifle that are relevant in musculoskeletal research. Four pairs of hindlimbs were scanned, whilst four other pairs were frozen and cut in different planes to compare gross anatomy to US scans.

Direct activation of G-protein-gated inward rectifying K+ channels promotes nonrapid eye movement sleep.

Study Objectives: A major challenge in treating insomnia is to find effective medicines with fewer side effects. Activation of G-protein-gated inward rectifying K+ channels (GIRKs) by GABAB agonists baclofen or γ-hydroxybutyric acid (GHB) promotes nonrapid eye movement (NREM) sleep and consolidates sleep. However, baclofen has poor brain penetration, GHB possesses abuse liability, and in rodents both drugs cause spike-wave discharges (SWDs), an absence seizure activity.

At-home tDCS of the left dorsolateral prefrontal cortex improves visual short-term memory in mild vascular dementia.

Objectives: Previous studies have shown that anodal transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex (DLPFC) led to an improvement of various cognitive functions in patients with Alzheimer dementia, early affected by short-term memory deficits. Since this approach has not been evaluated in the context of vascular dementia, which rather affects the velocity of cognitive responses, we aimed at improving these functions by applying repetitive sessions of anodal tDCS.

Methods: Four 20-minute sessions of 2mA anodal or sham at-home tDCS were applied to the left DLPFC in a single-blinded randomised study of 21 patients with mild vascular dementia, with parallel-group design.

A selective prostaglandin E2 receptor subtype 2 (EP2) antagonist increases the macrophage-mediated clearance of amyloid-beta plaques.

A high-throughput screen resulted in the discovery of benzoxazepine 1, an EP2 antagonist possessing low microsomal stability and potent CYP3A4 inhibition. Modular optimization of lead compound 1 resulted in the discovery of benzoxazepine 52, a molecule with single-digit nM binding affinity for the EP2 receptor and significantly improved microsomal stability. It was devoid of CYP inhibition and was ∼4000-fold selective against the other EP receptors.

Optimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction.

We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.

Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4.

Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach.

Discovery of 6-phenylpyrimido[4,5-b][1,4]oxazines as potent and selective acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors with in vivo efficacy in rodents.

The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST.

Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development.

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer.

Discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel gpr119 agonists.

We describe the discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel agonists of GPR119. Previously described aniline 2 had suboptimal efficacy in signaling assays using cynomolgus monkey (cyno) GPR119 making evaluation of the target in preclinical models difficult. Replacement of the aniline ring with a tetrahydroquinoline ring constrained the rotation of the aniline C-N bond and gave compounds with increased efficacy on human and cyno receptors.

Discovery and optimization of N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamides as novel GPR119 agonists.

The discovery and optimization of novel N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamide GPR119 agonists is described. Modification of the pyridylphthalimide motif of the molecule with R(1)=-Me and R(2)=-(i)Pr substituents, incorporated with a 6-fluoro substitution on the central phenyl ring offered a potent and metabolically stable tool compound 22.

Effects of corticotropin-releasing hormone on proopiomelanocortin derivatives and monocytic HLA-DR expression in patients with septic shock.

Little is known about interactions between immune and neuro-endocrine systems in patients with septic shock. We therefore evaluated whether the corticotropin-releasing hormone (CRH) and/or proopiomelanocortin (POMC) derivatives [ACTH, β-endorphin (β-END), β-lipotropin (β-LPH), α-melanocyte stimulating hormone (α-MSH) or N-acetyl-β-END (Nac-β-END)] have any influences on monocyte deactivation as a major factor of immunosuppression under septic shock conditions. Sixteen patients with septic shock were enrolled in a double-blind, cross-over and placebo controlled clinical study; 0.

Structure guided design of a series of sphingosine kinase (SphK) inhibitors.

Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other's loss.

Discovery and optimization of arylsulfonyl 3-(pyridin-2-yloxy)anilines as novel GPR119 agonists.

We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties.

Rational design and binding mode duality of MDM2-p53 inhibitors.

Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes.