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Endoplasmic reticulum aminopeptidases ERAP1 and 2 are intracellular aminopeptidases that trim antigenic precursors and generate antigens presented by major histocompatibility complex class I (MHC-I) molecules. They thus modulate the antigenic repertoire and drive the adaptive immune response. ERAPs are considered as emerging targets for precision immuno-oncology or for the treatment of autoimmune diseases, in particular MHC-I-opathies. This perspective covers the structural and biological characterization of ERAP, their relevance to these diseases and the ongoing research on small-molecule inhibitors. We describe the chemical and pharmacological space explored by medicinal chemists to exploit the potential of these targets given their localization, biological functions, and family depth. Specific emphasis is put on the binding mode, potency, selectivity, and physchem properties of inhibitors featuring diverse scaffolds. The discussion provides valuable insights for the future development of ERAP inhibitors and analysis of persisting challenges for the translation for clinical applications.

Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents.

A novel series of potent agonists of the bile acid receptor TGR5 bearing a dihydropyridone scaffold was developed from a high-throughput screen. Starting from a micromolar hit compound, we implemented an extensive structure–activity-relationship (SAR) study with the synthesis and biological evaluation of 83 analogues. The project culminated with the identification of the potent nanomolar TGR5 agonist 77A. We report the GLP-1 secretagogue effect of our lead compound ex vivo in mouse colonoids and in vivo. In addition, to identify specific features favorable for TGR5 activation, we generated and optimized a three-dimensional quantitative SAR model that contributed to our understanding of our activity profile and could guide further development of this dihydropyridone series.

Introduction: On-site milling with mobile machine tools is a popular solution for the modification of large or immobile metal parts. For such operations the transportation and setup of the machine constitutes a delicate process. Hence, mobile machine designs must find a good compromise between power, structural rigidity, and adaptability. However, this compromise can lead to flexible structures which are susceptible to chatter. Materials and methods: The present article is dedicated to chatter identification in a numerically controlled mobile milling machine using low-frequency internal sensors. This solution is low-cost and removes the need for further sensor installation during on-site operations. Milling operations are carried out for a wide range of parameters and chatter is diagnosed using a high-frequency accelerometer. Then, time domain statistical features on the internal sensor signals are computed to evaluate their potential for chatter identification. Two strategies for chatter classification are tested: firstly, using an empirically determined threshold on the features, and, secondly, using Support Vector Machine (SVM). Results: Using the linear thresholding technique, maximum agreement between the accelerometer classification and the internal sensor classification is 91 % for chatter and non chatter data. However, using the C-SVM method, classification was improved up to a 98 % agreement for the chatter cases and a 95 % agreement for the non-chatter cases. Conclusion: Thus the authors conclude that using a C-SVM classification method allows accurate chatter detection in the mobile milling machine using internal sensor data.

There has been an increasing interest in fraud detection methods, driven by new regulations and by the financial losses linked to fraud. One of the state-of-the-art methods to fight fraud is network analytics. Network analytics leverages the interactions between different entities to detect complex patterns that are indicative of fraud. However, network analytics has only recently been applied to fraud detection in the actuarial literature. Although it shows much potential, many network methods are not yet applied. This paper extends the literature in two main ways. First, we review and apply multiple methods in the context of insurance fraud and assess their predictive power against each other. Second, we analyse the added value of network features over intrinsic features to detect fraud. We conclude that (1) complex methods do not necessarily outperform basic network features, and that (2) network analytics helps to detect different fraud patterns, compared to models trained on claim-specific features alone.

MYH7variants cause hypertrophic cardiomyopathy (HCM), noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM). Screening of relatives of patients with genetic cardiomyopathy is recommended from 10 to 12 years of age onward, irrespective of the affected gene.

Computer-aided detection (CADe) systems could assist endoscopists in detecting early neoplasia in Barrett's oesophagus, which could be difficult to detect in endoscopic images. The aim of this study was to develop, test, and benchmark a CADe system for early neoplasia in Barrett's oesophagus.

Liquid–liquid extraction (LLE) screening can be a very labor-intensive exercise during commercial process development, particularly when workup challenges such as poor partitioning or emulsion formation arise. An automated platform for LLE has the potential to both accelerate process development and deliver a more optimized process, thereby reducing the burden on downstream purification requirements. To address this need, a fully automated liquid–liquid extraction workflow was designed and implemented to optimize extraction unit operations during process development. This workflow leverages commercially available hardware and software to perform extractions, identify phase boundaries, and prepare samples for analysis. A data visualization tool was also developed to streamline the processing of visual and quantitative data. Application of the automated LLE workflow on two case studies will be presented: one highlighting the development of an effective enzyme removal strategy for a biocatalytic cascade reaction and the other demonstrating the identification of operating parameters for workup of an intermediate with a tendency to partition into an oil layer.

MK-1026, also known as nemtabrutinib (1), has been developed as a reversible Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of chronic lymphocytic leukemia. This article describes the two-step manufacturing synthesis and subsequent isolation of biaryl ether (4) en route to MK-1026. First, the esterification step employs unique conditions leveraging dimethyl carbonate as a dual-function reagent, acting as both the solvent and the desiccant to drive the reaction forward. Second, the heterogeneous etherification step requires water content control to achieve acceptable reaction rates and minimize undesired impurities. Finally, isolation from water was developed that addressed oiling issues while also affording effective drying, despite the low melting point (as low as 28 °C) of the biaryl ether.

The therapeutic potential of liposomes to deliver drugs into inflamed tissue is well documented. Liposomes are believed to largely transport drugs into inflamed joints by selective extravasation through endothelial gaps at the inflammatory sites, known as the enhanced permeation and retention effect. However, the potential of blood-circulating myeloid cells for the uptake and delivery of liposomes has been largely overlooked. Here we show that myeloid cells can transport liposomes to inflammatory sites in a collagen-induced arthritis model. It is shown that the selective depletion of the circulating myeloid cells reduces the accumulation of liposomes up to 50–60%, suggesting that myeloid-cell-mediated transport accounts for more than half of liposomal accumulation in inflamed regions. Although it is widely believed that PEGylation inhibits premature liposome clearance by the mononuclear phagocytic system, our data show that the long blood circulation times of PEGylated liposomes rather favours uptake by myeloid cells. This challenges the prevailing theory that synovial liposomal accumulation is primarily due to the enhanced permeation and retention effect and highlights the potential for other pathways of delivery in inflammatory diseases.

Electronic boluses with biotelemetry capabilities enable wireless monitoring of animals’ physiological data (e.g., temperature, pH). The aim of this study was to design and experimentally validate a novel multiband (434, 868, and 1400)-MHz conformal patch antenna for in-body biotelemetry applications for cows. The optimal frequency band was studied prior to the design of the antenna, based on the dielectric measurements of the antenna environment (i.e., rumen). The antenna was integrated in a 13.5- $\times {\varnothing }3$ -cm bolus and simulated in a ${\varnothing }300$ -mm spherical phantom with electromagnetic properties of cows’ rumen fluid. The proposed antenna presented a high performance with a realized gain of (−38.5, −41.2, and −45.7) dBi and a radiation efficiency of (0.012%, 0.0045%, and 0.001%) at 434, 868, and 1400 MHz, respectively. Following the numerical analysis and optimization, a prototype was manufactured to experimentally evaluate the antenna performance. Good agreement was obtained between the measurements and simulations both for reflection coefficients and radiation performance. The measured gain was −36.3, −40.4, and −43.6 dBi, at 434, 868, and 1400 MHz, respectively. The proposed multiband antenna will enable the development of a new generation of boluses for animal biotelemetry applications to enhance the performance of the animal monitoring systems.

Provision of feeds containing hydrolysed, peptide-based proteins and medium-chain triglycerides (MCT), can help mitigate gastrointestinal (GI) intolerance in adults with impaired GI function, maldigestion and/or malabsorption.

Metallo-β-lactamases (MBLs) contribute to the resistance of Gram-negative bacteria to carbapenems, last-resort antibiotics at hospital, and MBL inhibitors are urgently needed to preserve these important antibacterial drugs. Here, we describe a series of 1,2,4-triazole-3-thione-based inhibitors displaying an α-amino acid substituent, which amine was mono- or disubstituted by (hetero)aryl groups. Compounds disubstituted by certain nitrogen-containing heterocycles showed submicromolar activities against VIM-type enzymes and strong NDM-1 inhibition (Ki= 10–30 nM). Equilibrium dialysis, native mass spectrometry, isothermal calorimetry (ITC), and X-ray crystallography showed that the compounds inhibited both VIM-2 and NDM-1 at least partially by stripping the catalytic zinc ions. These inhibitors also displayed a very potent synergistic activity with meropenem (16- to 1000-fold minimum inhibitory concentration (MIC) reduction) against VIM-type- and NDM-1-producing ultraresistant clinical isolates, including Enterobacteralesand Pseudomonas aeruginosa. Furthermore, selected compounds exhibited no or moderate toxicity toward HeLa cells, favorable absorption, distribution, metabolism, excretion (ADME) properties, and no or modest inhibition of several mammalian metalloenzymes.

The rise of multidrug-resistant bacterial infections is a cause of global concern. There is an urgent need to both revitalize antibacterial agents that are ineffective due to resistance while concurrently developing new antibiotics with novel targets and mechanisms of action. Pathogen associated resistance-conferring ribosomal RNA (rRNA) methyltransferases are a growing threat that, as a group, collectively render a total of seven clinically-relevant ribosome-targeting antibiotic classes ineffective. Increasing frequency of identification and their growing prevalence relative to other resistance mechanisms suggests that these resistance determinants are rapidly spreading among human pathogens and could contribute significantly to the increased likelihood of a post-antibiotic era. Herein, with a view toward stimulating future studies to counter the effects of these rRNA methyltransferases, we summarize their prevalence, the fitness cost(s) to bacteria of their acquisition and expression, and current efforts toward targeting clinically relevant enzymes of this class.

Magnetic resonance imaging of whole fetal body and placenta is limited by different sources of motion affecting the womb. Usual scanning techniques employ single-shot multi-slice sequences where anatomical information in different slices may be subject to different deformations, contrast variations or artifacts. Volumetric reconstruction formulations have been proposed to correct for these factors, but they must accommodate a non-homogeneous and non-isotropic sampling, so regularization becomes necessary. Thus, in this paper we propose a deep generative prior for robust volumetric reconstructions integrated with a diffeomorphic volume to slice registration method. Experiments are performed to validate our contributions and compare with ifdefined tmiformat R2.5a state of the art method methods in the literature in a cohort of 72 fetal datasets in the range of 20-36 weeks gestational age. Results suggest improved image resolution Quantitative as well as radiological assessment suggest improved image quality and more accurate prediction of gestational age at scan is obtained when comparing to a state of the art reconstruction method methods. In addition, gestational age prediction results from our volumetric reconstructions compare favourably are competitive with existing brain-based approaches, with boosted accuracy when integrating information of organs other than the brain. Namely, a mean absolute error of ${0}.{618}$ weeks ( ${R}^{{2}}={0}.{958}$ ) is achieved when combining fetal brain and trunk information.

The Atlantic Monthly's January/February issue explores the potential consequences of Donald Trump winning another term as president. Contributors discuss various aspects, including the Republican Party's role in supporting Trump's agenda and the potential damage to the social safety net. The issue also features articles that attempt to understand Trump voters and the challenges of messaging for the Democratic Party. Additionally, the cover story highlights rising anti-Semitism and its threat to the safety and prosperity of Jewish Americans. [Extracted from the article]

Pathogenic variants in GABRB3have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3variants to deepen the phenotypic understanding and investigate genotype–phenotype correlations.

Kinetic target-guided synthesis (KTGS) is an original discovery strategy allowing a target to catalyze the irreversible synthesis of its own ligands from a pool of reagents. Although pioneered almost two decades ago, it only recently proved its usefulness in medicinal chemistry, as exemplified by the increasing number of protein targets used, the wider range of target and pocket types, and the diversity of therapeutic areas explored. In recent years, two new leads for in vivo studies were released. Amidations and multicomponent reactions expanded the armamentarium of reactions beyond triazole formation and two new examples of in cellulo KTGS were also disclosed. Herein, we analyze the origins and the chemical space of both KTGS ligands and warhead-bearing reagents. We review the KTGS timeline focusing on recent cases in order to give medicinal chemists the full scope of this strategy which has great potential for hit discovery and hit or lead optimization.

In the last 5 years, cellular thermal shift assay (CETSA), a technology based on ligand-induced changes in protein thermal stability, has been increasingly used in drug discovery to address the fundamental question of whether drug candidates engage their intended target in a biologically relevant setting. To analyze lysates from cells submitted to increasing temperature, the detection and quantification of the remaining soluble protein can be achieved using quantitative mass spectrometry, Western blotting, or AlphaScreen techniques. Still, these approaches can be time- and cell-consuming. To cope with limitations of throughput and protein amount requirements, we developed a new coupled assay combining the advantages of a nanoacoustic transfer system and reverse-phase protein array technology within CETSA experiments. We validated the technology to assess engagement of inhibitors of insulin-degrading enzyme (IDE), an enzyme involved in diabetes and Alzheimer’s disease. CETSA—acoustic reverse-phase protein array (CETSA-aRPPA) allows simultaneous analysis of many conditions and drug–target engagement with a small sample size, in a rapid, cost-effective, and biological material-saving manner.

In the last 5 years, cellular thermal shift assay (CETSA), a technology based on ligand-induced changes in protein thermal stability, has been increasingly used in drug discovery to address the fundamental question of whether drug candidates engage their intended target in a biologically relevant setting. To analyze lysates from cells submitted to increasing temperature, the detection and quantification of the remaining soluble protein can be achieved using quantitative mass spectrometry, Western blotting, or AlphaScreen techniques. Still, these approaches can be time- and cell-consuming. To cope with limitations of throughput and protein amount requirements, we developed a new coupled assay combining the advantages of a nanoacoustic transfer system and reverse-phase protein array technology within CETSA experiments. We validated the technology to assess engagement of inhibitors of insulin-degrading enzyme (IDE), an enzyme involved in diabetes and Alzheimer’s disease. CETSA—acoustic reverse-phase protein array (CETSA-aRPPA) allows simultaneous analysis of many conditions and drug–target engagement with a small sample size, in a rapid, cost-effective, and biological material-saving manner.

ABSTRACTObjectives: Psoriasis is a chronic skin disease requiring a multidimensional approach, given its varying appearance, presence of comorbidities and complex treatment regimens. Psoriasis care is however often performed fragmented and, in case of flares, reactive with little integrated information on and for the patient. Literature suggests a multileveled approach of psoriasis, but the effects of its implementation have not yet been validated. The aim of this study is to analyze the impact of a multileveled psoriasis consultation format, named PsoPlus, which has been implemented since 2012 in the Department of Dermatology at Ghent University Hospital in Belgium.Methods: The patient population was divided into two groups: one following the regular consultation and one following the PsoPlus format. Demographic data, clinical outcome and treatment approach of psoriasis patients were compared.Results: Patients who opted for the specialized PsoPlus consultation were younger and had longer disease duration. Decision parameters such as disease severity and quality of life were reported more often in the PsoPlus group. In the latter, a higher rate of patients were started on systemic therapy compared to the regular consultation group, and reporting on adverse events was done more frequently.Conclusion: The implementation of a specialized consultation with comprehensive guidance facilitates documentation on disease-relevant parameters such as disease severity and quality of life. This format can be seen as a guidance for capturing data in a structured manner, with evidence showing that it significantly impacts treatment decision, treating not only psoriasis but the patient as a whole.

Hydroxamic acids are outstanding zinc chelating groups that can be used to design potent and selective metalloenzyme inhibitors in various therapeutic areas. Some hydroxamic acids display a high plasma clearance resulting in poor in vivo activity, though they may be very potent compounds in vitro. We designed a 57-member library of hydroxamic acids to explore the structure–plasma stability relationships in these series and to identify which enzyme(s) and which pharmacophores are critical for plasma stability. Arylesterases and carboxylesterases were identified as the main metabolic enzymes for hydroxamic acids. Finally, we suggest structural features to be introduced or removed to improve stability. This work thus provides the first medicinal chemistry toolbox (experimental procedures and structural guidance) to assess and control the plasma stability of hydroxamic acids and realize their full potential as in vivo pharmacological probes and therapeutic agents. This study is particularly relevant to preclinical development as it allows obtaining compounds equally stable in human and rodent models.

This Review depicts the evolving role of MRI in the diagnosis and prognostication of anomalies of the fetal body, here including head and neck, thorax, abdomen and spine. A review of the current literature on the latest developments in antenatal imaging for diagnosis and prognostication of congenital anomalies is coupled with illustrative cases in true radiological planes with viewable three-dimensional video models that show the potential of post-acquisition reconstruction protocols. We discuss the benefits and limitations of fetal MRI, from anomaly detection, to classification and prognostication, and defines the role of imaging in the decision to proceed to fetal intervention, across the breadth of included conditions. We also consider the current capabilities of ultrasound and explore how MRI and ultrasound can complement each other in the future of fetal imaging.