Seizure reduction in TSC2-mutant mouse model by an mTOR catalytic inhibitor.

Objective: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by autosomal-dominant pathogenic variants in either the TSC1 or TSC2 gene, and it is characterized by hamartomas in multiple organs, such as skin, kidney, lung, and brain. These changes can result in epilepsy, learning disabilities, and behavioral complications, among others. The mechanistic link between TSC and the mechanistic target of the rapamycin (mTOR) pathway is well established, thus mTOR inhibitors can potentially be used to treat the clinical manifestations of the disorder, including epilepsy.

Blockade of IL-6 signaling alleviates atherosclerosis in -deficient clonal hematopoiesis.

Clonal hematopoiesis (CH) increases the risk of atherosclerotic cardiovascular disease possibly due to increased plaque inflammation. Human studies suggest that limitation of interleukin-6 (IL-6) signaling could be beneficial in people with large CH clones, particularly in CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression.

Functional ProTracer identifies patterns of cell proliferation in tissues and underlying regulatory mechanisms.

A genetic system, ProTracer, has been recently developed to record cell proliferation in vivo. However, the ProTracer is initiated by an infrequently used recombinase Dre, which limits its broad application for functional studies employing floxed gene alleles. Here we generated Cre-activated functional ProTracer (fProTracer) mice, which enable simultaneous recording of cell proliferation and tissue-specific gene deletion, facilitating broad functional analysis of cell proliferation by any Cre driver.

First-in-Human Study of the Safety, Pharmacokinetics, and Pharmacodynamics of MHV370, a Dual Inhibitor of Toll-Like Receptors 7 and 8, in Healthy Adults.

Background And Objective: MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and  has demonstrated efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370.

Methods: This was a phase 1, randomised, placebo-controlled study conducted in three parts.

kcnj13 regulates pigment cell shapes in zebrafish and has diverged by cis-regulatory evolution between Danio species.

Teleost fish of the genus Danio are excellent models to study the genetic and cellular bases of pigment pattern variation in vertebrates. The two sister species Danio rerio and Danio aesculapii show divergent patterns of horizontal stripes and vertical bars that are partly caused by the divergence of the potassium channel gene kcnj13. Here, we show that kcnj13 is required only in melanophores for interactions with xanthophores and iridophores, which cause location-specific pigment cell shapes and thereby influence colour pattern and contrast in D.

Investigating the human and nonobese diabetic mouse MHC class II immunopeptidome using protein language modeling.

Motivation: Identifying peptides associated with the major histocompability complex class II (MHCII) is a central task in the evaluation of the immunoregulatory function of therapeutics and drug prototypes. MHCII-peptide presentation prediction has multiple biopharmaceutical applications, including the safety assessment of biologics and engineered derivatives in silico, or the fast progression of antigen-specific immunomodulatory drug discovery programs in immune disease and cancer. This has resulted in the collection of large-scale datasets on adaptive immune receptor antigenic responses and MHC-associated peptide proteomics.

Integrated analysis of the transcriptome and its interaction with the metabolome in metabolic associated fatty liver disease: Gut microbiome signatures, correlation networks, and effect of PNPLA3 genotype.

Interactions between communities of the gut microbiome and with the host could affect the onset and progression of metabolic associated fatty liver disease (MAFLD), and can be useful as new diagnostic and prognostic biomarkers. In this study, we performed a multi-omics approach to unravel gut microbiome signatures from 32 biopsy-proven patients (10 simple steatosis -SS- and 22 steatohepatitis -SH-) and 19 healthy volunteers (HV). Human and microbial transcripts were differentially identified between groups (MAFLD vs.

Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma.

Recent studies suggest that BRAF-mutated melanomas in particular respond to dual anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibition (ICI). Here we identified an over-representation of interleukin (IL)-17-type 17 helper T (T17) gene expression signatures (GES) in BRAF-mutated tumors. Moreover, high baseline IL-17 GES consistently predicted clinical responses in dual-ICI-treated patient cohorts but not in mono anti-CTLA-4 or anti-PD-1 ICI cohorts.

Liver injury in cynomolgus monkeys following intravenous and intrathecal scAAV9 gene therapy delivery.

Hepatotoxicity associated with intravenous/intrathecal adeno-associated virus (AAV) gene therapy has been observed in preclinical species and patients. In nonhuman primates, hepatotoxicity following self-complementary AAV9 administration varies from asymptomatic transaminase elevation with minimal to mild microscopic changes to symptomatic elevations of liver function and thromboinflammatory markers with microscopic changes consistent with marked hepatocellular necrosis and deteriorating clinical condition. These transient acute liver injury marker elevations occur from 3-4 days post intravenous administration to ∼2 weeks post intrathecal administration.

Advances in Chemical Probing Concepts for Chemical Biology Applications.

Chemical probes allow us to identify, validate and confirm novel targets for therapeutic applications, enable the development of drug candidates, and open the way to new therapeutic strategies, vaccines and diagnostic tools.

Explaining compound activity predictions with a substructure-aware loss for graph neural networks.

Explainable machine learning is increasingly used in drug discovery to help rationalize compound property predictions. Feature attribution techniques are popular choices to identify which molecular substructures are responsible for a predicted property change. However, established molecular feature attribution methods have so far displayed low performance for popular deep learning algorithms such as graph neural networks (GNNs), especially when compared with simpler modeling alternatives such as random forests coupled with atom masking.

PREFER: A New Predictive Modeling Framework for Molecular Discovery.

Machine-learning and deep-learning models have been extensively used in cheminformatics to predict molecular properties, to reduce the need for direct measurements, and to accelerate compound prioritization. However, different setups and frameworks and the large number of molecular representations make it difficult to properly evaluate, reproduce, and compare them. Here we present a new PREdictive modeling FramEwoRk for molecular discovery (PREFER), written in Python (version 3.

The application of organ-on-chip models for the prediction of human pharmacokinetic profiles during drug development.

Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential of OoC models to improve the prediction of human oral bioavailability and intrinsic clearance is discussed, with a focus on the functionality of the models and the application in current drug development practice. Multi-OoC models demonstrating the application for pharmacokinetic (PK) studies are summarized and existing challenges are identified.

A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs.

In vitro secondary pharmacology assays are an important tool for predicting clinical adverse drug reactions (ADRs) of investigational drugs. We created the Secondary Pharmacology Database (SPD) by testing 1958 drugs using 200 assays to validate target-ADR associations. Compared to public and subscription resources, 95% of all and 36% of active (AC50 < 1 µM) results are unique to SPD, with bias towards higher activity in public resources.

Discovery of New Binders for DCAF1, an Emerging Ligase Target in the Targeted Protein Degradation Field.

In this study, we describe the rapid identification of potent binders for the WD40 repeat domain (WDR) of DCAF1. This was achieved by two rounds of iterative focused screening of a small set of compounds selected on the basis of internal WDR domain knowledge followed by hit expansion. Subsequent structure-based design led to nanomolar potency binders with a clear exit vector enabling DCAF1-based bifunctional degrader exploration.

In vaccinated individuals serum bactericidal activity against B meningococci is abrogated by C5 inhibition but not by inhibition of the alternative complement pathway.

Introduction: Several diseases caused by the dysregulation of complement activation can be treated with inhibitors of the complement components C5 and/or C3. However, complement is required for serum bactericidal activity (SBA) against encapsulated Gram-negative bacteria. Therefore, C3 and C5 inhibition increases the risk of invasive disease, in particular by As inhibitors against complement components other than C3 and C5 may carry a reduced risk of infection, we compared the effect of inhibitors targeting the terminal pathway (C5), the central complement component C3, the alternative pathway (FB and FD), and the lectin pathway (MASP-2) on SBA against serogroup B meningococci.

Distinct hepatocyte identities in liver homeostasis and regeneration.

The process of metabolic liver zonation is spontaneously established by assigning distributed tasks to hepatocytes along the porto-central blood flow. Hepatocytes fulfil critical metabolic functions, while also maintaining hepatocyte mass by replication when needed. Recent technological advances have enabled us to fine-tune our understanding of hepatocyte identity during homeostasis and regeneration.

Phototoxicity─Medicinal Chemistry Strategies for Risk Mitigation in Drug Discovery.

Phototoxicity is a common safety concern encountered by project teams in pharmaceutical research and has the potential to stop progression of an otherwise promising candidate molecule. This perspective aims to provide an overview of the approaches toward mitigation of phototoxicity that medicinal chemists have taken during the lead optimization phase in the context of regulatory standards for photosafety evaluation. Various strategies are laid out based on available literature examples in order to highlight how structural modification can be utilized toward successful mitigation of a phototoxicity liability.

European Society of Toxicologic Pathology (Pathology 2.0 Molecular Pathology Special Interest Group): Review of In Situ Hybridization Techniques for Drug Research and Development.

In situ hybridization (ISH) is used for the localization of specific nucleic acid sequences in cells or tissues by complementary binding of a nucleotide probe to a specific target nucleic acid sequence. In the last years, the specificity and sensitivity of ISH assays were improved by innovative techniques like synthetic nucleic acids and tandem oligonucleotide probes combined with signal amplification methods like branched DNA, hybridization chain reaction and tyramide signal amplification. These improvements increased the application spectrum for ISH on formalin-fixed paraffin-embedded tissues.

Magnetic resonance imaging and ultrasound elastography in the context of preclinical pharmacological research: significance for the 3R principles.

The 3Rs principles-reduction, refinement, replacement-are at the core of preclinical research within drug discovery, which still relies to a great extent on the availability of models of disease in animals. Minimizing their distress, reducing their number as well as searching for means to replace them in experimental studies are constant objectives in this area. Due to its non-invasive character imaging supports these efforts by enabling repeated longitudinal assessments in each animal which serves as its own control, thereby enabling to reduce considerably the animal utilization in the experiments.