7196 research outputs found
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Bridging the Gap to Translating Genomewide Discoveries into Therapies to Prevent and Treat Atherosclerotic Cardiovascular Disease
No full textThe authors provide a review article that comments on a peer-reviewed article to be published in the journal Circulation:
"Solomon CU, McVey DG, Andreadi C, Gong P, Turner L, Stanczyk PJ, Khemiri S, Chamberlain JC, Yang W, Webb TR, Nelson CP, Samani NJ, Ye S. Effects of coronary artery disease-associated variants on vascular smooth muscle cells."
Comments include a brief overiview of the field of genomics (genomewide association studies=GWAS) of CAD, summary of the "Solomon et al" study findings, strengths and limitations of the "Solomon et al" study, and opportunities and gaps for drug development for prevention and treatment of CAD
Advances toward transformative therapies for tendon diseases.
No full textApproved therapies for tendon diseases have not yet changed the clinical practice of symptomatic pain treatment and physiotherapy. This review article summarizes advances in the development of novel drugs, biologic products, and biomaterial therapies for tendon diseases with perspectives for translation of integrated therapies. Shifting from targeting symptom relief toward disease modification and prevention of disease progression may open new avenues for therapies. Deep evidence-based clinical, cellular, and molecular characterization of the underlying pathology of tendon diseases, as well as therapeutic delivery optimization and establishment of multidiscipline interorganizational collaboration platforms, may accelerate the discovery and translation of transformative therapies for tendon diseases
Evaluation of drug-drug interactions between midostaurin and strong CYP3A4 inhibitors in patients with FLT-3-mutated acute myeloid leukemia (AML).
No full textMidostaurin, approved for the treatment of newly diagnosed, FLT3-mutated acute myeloid leukemia (AML), is metabolized by cytochrome P450 3A4 (CYP3A4). Midostaurin with concomitant strong CYP3A4 inhibitors use (e.g., antifungal azoles) may result in drug-drug interactions. This post hoc analysis of RATIFY phase 3 study data evaluated effects of strong CYP3A4 inhibitor use on the exposure and safety of midostaurin.Trough concentrations were used to assess midostaurin and metabolite exposure in the presence and absence of strong CYP3A4 inhibitors. Adverse event (AE) frequency was assessed in patients who received concomitant strong CYP3A4 inhibitors vs those who did not. Time to first clinically notable AE (CNAE) was also assessed in patients with high midostaurin plasma exposure vs those of matched placebo controls.Use of concomitant strong CYP3A4 inhibitors was most frequent during the induction phase (60.8%). A 1.44-fold increase in midostaurin plasma exposure was observed in patients with concomitant strong CYP3A4 inhibitor use vs those without. Midostaurin-treated patients who received concomitant strong CYP3A4 inhibitors experienced grade 3/4 infection-related AEs more frequently vs those who did not. Patients with high levels of midostaurin exposure had a shorter median time to first grade 3/4 CNAE vs placebo controls (36 vs 41 days, respectively; P = .012).Although concomitantly administered strong CYP3A4 inhibitors increased midostaurin exposure 1.44-fold, no clinically relevant differences in safety were noted. Midostaurin dose adjustment is not necessary with concomitant strong CYP3A4 inhibitors in patients with FLT3-mutated AML; however, caution is advised, and patients should be closely monitored
Thermal Safety and Structure-Related Reactivity Investigation of Five-Membered Cyclic Sulfamidates
No full textFive-membered cyclic sulfamidates are very valuable electrophiles in organic synthesis and readily used on a multikilogram scale. However, their thermal degradation is underreported and might lead to unforeseen and undesirable safety events. In addition, ring or nitrogen substitution can have a tremendous influence on cyclic sulfamidate reactivity toward bases and therefore impact the overall safety assessment of a process. An understanding of such behavior is therefore of high importance in the industry while designing a synthetic route, as a change of, e.g., a protecting group can increase the thermal safety of a step on scale. We report herein the thermal degradation investigation as well as the structure-related reactivity exploration of cyclic sulfamidates, including their use in combination with strong bases. The design of a predictive model to rapidly assess the thermal hazard based on collected data and selected molecular descriptors is also presented
Efficient Screening of Target-Specific Selected Compounds in Mixtures by 19F NMR Binding Assay with Predicted 19F NMR Chemical Shifts
No full textLigand-based 19F NMR screening is a highly effective and well-established hit-finding approach. The high sensitivity to protein binding makes it particularly suitable for fragment screening. Different criteria can be considered for generating fluorinated fragment libraries. One common strategy is to assemble a large, diverse, well-designed and characterized fragment library which is screened in mixtures, generated based on experimental 19F NMR chemical shifts. Here, we introduce a complementary knowledge-based 19F NMR screening approach, named 19Focused screening, enabling the efficient screening of putative active molecules selected by computational hit finding methodologies, in mixtures assembled and on-the-fly deconvoluted based on predicted 19F NMR chemical shifts. In this study, we developed a novel approach, named LEFshift, for 19F NMR chemical shift prediction using rooted topological fluorine torsion fingerprints in combination with a random forest machine learning method. A demonstration of this approach to a real test case is reported
The Catalytic Formation of Atropisomers and New Stereocenters via Asymmetric Suzuki-Miyaura Couplings
No full textAlthough Suzuki-Miyaura cross-coupling is one of the most convenient and well-developed cross-coupling reactions, its applications to the asymmetric version to deliver highly functionalized atropisomers or non-racemic coupling products have been less explored. Besides some excellent work reported intermittently, the asymmetric Suzuki-Miyaura reaction remains a significant challenge, particularly for preparing highly functionalized heterocyclic atropisomers. A concise but critical knowledge on this topic may further inspire researchers across various subdisciplines to develop innovative and sustainable solutions to tackle this problem. Therefore, this concise review aims to summarize the pioneering work on asymmetric Suzuki-Miyaura cross-couplings and cover the new implementations via homogeneous or heterogeneous catalysis reported during recent years. Most notably, the use of transition-metals other than palladium is also described
Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants.
No full textIL-1 receptor-activated kinase 1 (IRAK1) is involved in signal transduction downstream of many TLRs and the IL-1R. Its potential as a drug target for chronic inflammatory diseases is underappreciated. To study its functional role in joint inflammation, we generated a mouse model expressing a functionally inactive IRAK1 (IRAK1 kinase deficient, IRAK1KD), which also displayed reduced IRAK1 protein expression and cell type-specific deficiencies of TLR signaling. The serum transfer model of arthritis revealed a potentially novel role of IRAK1 for disease development and neutrophil chemoattraction exclusively via its activity in nonhematopoietic cells. Consistently, IRAK1KD synovial fibroblasts showed reduced secretion of neutrophil chemoattractant chemokines following stimulation with IL-1β or human synovial fluids from patients with rheumatoid arthritis (RA) and gout. Together with patients with RA showing prominent IRAK1 expression in fibroblasts of the synovial lining, these data suggest that targeting IRAK1 may be therapeutically beneficial. As pharmacological inhibition of IRAK1 kinase activity had only mild effects on synovial fibroblasts from mice and patients with RA, targeted degradation of IRAK1 may be the preferred pharmacologic modality. Collectively, these data position IRAK1 as a central regulator of the IL-1β-dependent local inflammatory milieu of the joints and a potential therapeutic target for inflammatory arthritis
EdgeSHAPer: Bond-Centric Shapley Value-Based Explanation Method for Graph Neural Networks
No full textGraph neural networks (GNNs) are becoming increasingly popular for many deep machine learning (ML) applications in science. By recursively propagating neural signals along the edges of an input graph, GNNs integrate node feature information with graph structure. One of their attractions is the ability to learn object representations from graphs, hence alleviating the need for feature engineering. However, as is the case for other deep neural networks, GNN models are complex and have notorious black box character, which works against their acceptance for experimental design in interdisciplinary research settings. Hence, with the advent of deep learning in many scientific areas, increasing attention is also being paid to approaches explaining ML models and their predictions. However, for GNNs, only few approaches are currently available to rationalize model decisions. In this work, we introduce EdgeSHAPer, a generally applicable method for explaining any GNN-based model. The approach is specifically devised to assess edge importance for predictions, which is its characteristic feature. EdgeSHAPer makes use of the Shapley value concept from game theory to quantify feature importance for individual predictions. In our-proof-of-concept study, it is applied to compound activity prediction, a central task in computational medicinal chemistry and drug discovery. For chemical predictions, EdgeSHAPer’s edge centricity is particularly relevant because edges represent bonds in molecular graphs. In combination with feature mapping, we show that EdgeSHAPer produces meaningful explanations for accurate compound activity predictions, demonstrating that GNN decisions are often centered on bond information. Compared to a popular node-centric and the only other currently available edge-centric explanation method, EdgeSHAPer reveals higher resolution in differentiating features determining predictions and identifies minimal pertinent positive feature sets
Protein profiles from used nesting material, saliva, and urine correspond with social behavior in group housed male mice, Mus musculus
No full textCurrent understanding of how odors impact intra-sex social behavior is based on those that increase intermale aggression. Yet, odors are often promoted to reduce
fighting among male laboratory mice. It has been shown that a cage of male mice contains many proteins used for identification purposes. However, it is unknown if
these proteins relate to social behavior or if they are uniformly produced across strains. This study aimed to compare proteomes from used nesting material and three
sources (sweat, saliva, and urine) from three strains and compare levels of known protein odors with rates of social behavior. Used nesting material samples from
each cage were analyzed using LC-MS/MS. Sweat, saliva, and urine samples from each cage’s dominant and subordinate mouse were also analyzed. Proteomes were
assessed using principal component analyses and compared to behavior by calculating correlation coefficients between PC scores and behavior proportions. Twentyone
proteins from nesting material either correlated with affiliative behavior or negatively correlated with aggression. Notably, proteins from the major urinary
protein family, odorant binding protein family, and secretoglobin family displayed at least one of these patterns, making them candidates for future work. These
findings provide preliminary information about how proteins can influence male mouse behavior.
Significance: Research on how olfactory signals influence same sex social behavior is primarily limited to those that promote intermale aggression. However, exploring
how olfaction modulates a more diverse behavioral repertoire will improve our foundational understanding of this sensory modality. In this proteome analysis we
identified a short list of protein signals that correspond to lower rates of aggression and higher rates of socio-positive behavior. While this study is only correlational,
it sets a foundation for future work that can identify protein signals that directly influence social behavior and potentially identify new murine pheromones
Directed evolution of the rRNA methylating enzyme Cfr reveals molecular basis of antibiotic resistance.
No full textAlteration of antibiotic binding sites through modification of ribosomal RNA (rRNA) is a common form of resistance to ribosome-targeting antibiotics. The rRNA-modifying enzyme Cfr methylates an adenosine nucleotide within the peptidyl transferase center, resulting in the C-8 methylation of A2503 (mA2503). Acquisition of results in resistance to eight classes of ribosome-targeting antibiotics. Despite the prevalence of this resistance mechanism, it is poorly understood whether and how bacteria modulate Cfr methylation to adapt to antibiotic pressure. Moreover, direct evidence for how mA2503 alters antibiotic binding sites within the ribosome is lacking. In this study, we performed directed evolution of Cfr under antibiotic selection to generate Cfr variants that confer increased resistance by enhancing methylation of A2503 in cells. Increased rRNA methylation is achieved by improved expression and stability of Cfr through transcriptional and post-transcriptional mechanisms, which may be exploited by pathogens under antibiotic stress as suggested by natural isolates. Using a variant that achieves near-stoichiometric methylation of rRNA, we determined a 2.2 Å cryo-electron microscopy structure of the Cfr-modified ribosome. Our structure reveals the molecular basis for broad resistance to antibiotics and will inform the design of new antibiotics that overcome resistance mediated by Cfr