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Protein–protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic potential in the development of small molecules that modulate these interactions; however, rational design of small molecule enhancers of PPIs remains elusive. Herein, we report the prospective identification and rational design of potent small molecules that enhance the interaction between an oncogenic transcription factor, β-Catenin, and its cognate E3 ligase, SCF β-TrCP . These enhancers potentiate the ubiquitylation of mutant β-Catenin by β-TrCP in vitro and induce the degradation of an engineered mutant β-Catenin in a cellular system. Distinct from PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, with contacts optimized for both the substrate and ligase within the same small molecule entity. The prospective discovery of ‘molecular glue’ presented here provides a paradigm for the development of small molecule degraders targeting hard-to-drug proteins. Directed protein degradation to target hard-to-drug proteins is a promising therapeutic approach. Here, the authors report the prospective discovery of small molecule “molecular glue” that inserts into a naturally occurring E3 ligase-substrate interface leading to degradation of substrate protein.

Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and antiinflammatory phenotypes. Targeting FAAH activity, therefore, presents a promising new therapeutic strategy for the treatment of pain and other neurological-related or inflammatory disorders. Nearly all FAAH inhibitors known to date attain their binding potency through a reversible or irreversible covalent modification of the nucleophile Ser241 in the unusual Ser-Ser-Lys catalytic triad. Here, we report the discovery and mechanism of action of a series of ketobenzimidazoles as unique and potent noncovalent FAAH inhibitors. Compound 2, a representative of these ketobenzimidazoles, was designed from a series of ureas that were identified from high-throughput screening. While urea compound 1 is characterized as an irreversible covalent inhibitor, the cocrystal structure of FAAH complexed with compound 2 reveals that these ketobenzimidazoles, though containing a carbonyl moiety, do not covalently modify Ser241. These inhibitors achieve potent inhibition of FAAH activity primarily from shape complementarity to the active site and through numerous hydrophobic interactions. These noncovalent compounds exhibit excellent selectivity and good pharmacokinetic properties. The discovery of this distinctive class of inhibitors opens a new avenue for modulating FAAH activity through nonmechanism-based inhibition.

Abstract 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. We tested the hypothesis that direct GIRK activation promotes sleep without inducing SWD using ML297, a potent and selective GIRK activator. Methods Whole-cell patch-clamp recordings from hypocretin/orexin or hippocampal neurons in mouse brain slices were made to study neuronal excitability and synaptic activity; spontaneous activity, locomotion, contextual and tone-conditioned memory, and novel object recognition were assessed. Electroencephalogram/electromyogram (EEG/EMG) recordings were used to study GIRK modulation of sleep. Results ML297, like baclofen, caused membrane hyperpolarization, decreased input resistance, and blockade of spontaneous action potentials. Unlike baclofen, ML297 (5–10 µM) did not cause significant depression of postsynaptic excitatory and inhibitory currents (EPSCs–IPSCs), indicating preferential postsynaptic inhibition. ML297 (30 mg/kg, i.p.) inhibited wake activity and locomotion, and preferentially increased NREM sleep without altering EEG delta power, REM sleep, inducing SWDs, or impairing conditioned memory and novel object recognition. Conclusions This study finds that direct activation of neuronal GIRK channels modulates postsynaptic membrane excitability and prolongs NREM sleep without changing sleep intensity, inducing SWDs, or impairing memory in rodents. These results suggest that direct GIRK activation with a selective compound may present an innovative approach for the treatment of chronic insomnia.

Whether to continue to exploit a source of reward, or to search for a new one of potentially greater value, is a fundamental and underconstrained decision. Recent computational studies of this exploration-exploitation tradeoff have found that variability in exploration across individuals is influenced by a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene, whose protein product degrades synaptically released dopamine. However, these and other genotype-phenotype associations have rarely been causally tested. To directly test this association and to evaluate additional behavioral characteristics, including perceived locus of control (LOC), here we used the COMT inhibitor tolcapone in a randomized, double-blind, counterbalanced, within-subject study of 66 subjects genotyped for the Val158Met allele to assess the hypothesis that reducing COMT enzymatic activity interacts with genotype to increase uncertainty-driven exploration. In keeping with our initial hypothesis, tolcapone led to an increase in exploratory, but not exploitative, behavior in Met/Met rather than Val/Val subjects. Independent of genotype, those subjects with a more external LOC also showed increases in uncertainty-driven exploration on tolcapone relative to placebo. However, we did not replicate our previous finding that Met/Met subjects show greater exploration at baseline. Together these findings support a model in which exploration is hypothesized to have a dopaminergic basis. Moreover, in keeping with findings in other behavioral and cognitive domains, the response to an increase in presumptively frontal dopamine is dependent upon baseline dopamine tone.

Surface microstructures of bitumen are key sites in atmospheric photo-oxidation leading to changes in the mechanical properties and finally resulting in cracking and rutting of the material. Investigations at the nanoscale remain challenging. Conventional combination of optical microscopy and spectroscopy cannot resolve the submicrostructures due to the Abbe restriction. For the first time, we report here respective surface domains, namely catana, peri and para phases, correlated to distinct molecules using combinations of atomic force microscopy with infrared spectroscopy and with correlative time of flight—secondary ion mass spectrometry. Chemical heterogeneities on the surface lead to selective oxidation due to their varying susceptibility to photo-oxidation. It was found, that highly oxidized compounds, are preferentially situated in the para phase, which are mainly asphaltenes, emphasising their high oxidizability. This is an impressive example how chemical visualization allows elucidation of the submicrostructures and explains their response to reactive oxygen species from the atmosphere.

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.

One of the most widely used systems for wind speed and direction observations at meteorological sites is based on Doppler wind lidar (DWL) technology. The wind vector derivation strategies of these instruments rely on the assumption of stationary and homogeneous horizontal wind, which is often not the case over heterogeneous terrain. This study focuses on the validation of two DWL systems, operated by the German Weather Service [Deutscher Wetterdienst (DWD)] and installed at the boundary layer field site Falkenberg (Lindenberg, Germany), with respect to measurements from a small, fixed-wing uncrewed aircraft system (UAS) of the type Multi-Purpose Airborne Sensor Carrier (MASC-3). A wind vector intercomparison at an altitude range from 100 to 500 m between DWL and UAS is performed, after a quality control of the aircraft’s data accuracy against a cup anemometer and wind vane mounted on a meteorological mast also operating at the location. Both DWL systems exhibit an overall root-mean-square difference in the wind vector retrieval of less than 22% for wind speed and lower than 18° for wind direction. The enhancement or deterioration of these statistics is analyzed with respect to scanning height and atmospheric stability. The limitations of this type of validation approach are highlighted and accounted for in the analysis.

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

Automotive radar sensors play a vital role in the current development of autonomous driving. Their ability to detect objects even under adverse conditions makes them indispensable for environment-sensing tasks in autonomous vehicles. As their functional operation must be validated in-place, a fully integrated test system is required. Radar Target Simulators (RTS) are capable of executing end-of-line, over-the-air validation tests by looping back a received and afterward modified radar signal and have been incorporated into existing Vehicle-in-the-Loop (ViL) test beds before. However, the currently available ViL test beds and the RTS systems that they consist of lack the ability to generate authentic radar echoes with respect to their complexity. The paper at hand reviews the current development stage of the research as well as commercial ViL and RTS systems. Furthermore, the concept and implementation of a new test setup for the rapid prototyping and validation of ADAS functions is presented. This represents the first-ever integrated radar validation test system to comprise multiple angle-resolved radar target channels, each capable of generating multiple radar echoes. A measurement campaign that supports this claim has been conducted.