👤 Wofford JD

Drug discovery is a complex and expensive procedure involving several timely and costly phases through which new potential pharmaceutical compounds must pass to get approved. One of these critical steps is the identification and optimization of lead compounds, which has been made more accessible by the introduction of computational methods, including deep learning (DL) techniques. Diverse DL model architectures have been put forward to learn the vast landscape of interaction between proteins and ligands and predict their affinity, helping in the identification of lead compounds. Show less

Indexing articles by their publication type and study design is essential for efficient search and filtering of the biomedical literature, but is understudied compared to indexing by MeSH topical terms. In this study, we leveraged the human-curated publication types and study designs in PubMed to generate a dataset of more than 1.2M articles (titles and abstracts) and used state-of-the-art Transformer-based models for automatic tagging of publication types and study designs. Specifically, we trained PubMedBERT-based models using a multi-label classification approach, and explored undersampling, feature verbalization, and contrastive learning to improve model performance. Our results show that PubMedBERT provides a strong baseline for publication type and study design indexing; undersampling, feature verbalization, and unsupervised constrastive loss have a positive impact on performance, whereas supervised contrastive learning degrades the performance. We obtained the best overall performance with 80% undersampling and feature verbalization (0.632 macro-F1, 0.969 macro-AUC). The model outperformed previous models (MultiTagger) across all metrics and the performance difference was statistically significant (p < 0.001). Despite its stronger performance, the model still has room for improvement and future work could explore features based on full-text as well as model interpretability. We make our data and code available at https://github.com/ScienceNLP-Lab/MultiTagger-v2/tree/main/AMIA. Show less

An efficient synthetic protocol was devised for the preparation of five cationic ruthenium-arene complexes bearing imidazol(in)ium-2-dithiocarboxylate ligands from the [RuCl₂(p-cymene)]₂ dimer and 2 equiv of an NHC·CS₂ zwitterion. The reactions proceeded cleanly and swiftly in dichloromethane at room temperature to afford the expected [RuCl(p-cymene)(S₂C·NHC)]Cl products in quantitative yields. When the [RuCl₂(p-cymene)]₂ dimer was reacted with only 1 equiv of a dithiolate betaine under the same experimental conditions, a set of five bimetallic compounds with the generic formula [RuCl(p-cymene)(S₂C·NHC)][RuCl₃(p-cymene)] was obtained in quantitative yields. These novel, dual anionic and cationic ruthenium-arene complexes were fully characterized by various analytical techniques. NMR titrations showed that the chelation of the dithiocarboxylate ligands to afford [RuCl(p-cymene)(S₂C·NHC)]⁺ cations was quantitative and irreversible. Conversely, the formation of the [RuCl₃(p-cymene)]^- anion was limited by an equilibrium, and this species readily dissociated into Cl^- anions and the [RuCl₂(p-cymene)]₂ dimer. The position of the equilibrium was strongly influenced by the nature of the solvent and was rather insensitive to the temperature. Two monometallic and two bimetallic complexes cocrystallized with water, and their molecular structures were solved by X-ray diffraction analysis. Crystallography revealed the existence of strong interactions between the azolium ring protons of the cationic complexes and neighboring donor groups from the anions or the solvent. The various compounds under investigation were highly soluble in water. They were all strongly cytotoxic against K562 cancer cells. Furthermore, with a selectivity index of 32.1, the [RuCl(p-cymene)(S₂C·SIDip)]Cl complex remarkably targeted the erythroleukemic cells vs mouse splenocytes. Show less

Iron is critical for virtually all organisms, yet major questions remain regarding the systems-level understanding of iron in whole cells. Here, we obtained Mössbauer and EPR spectra of Escherichia coli cells prepared under different nutrient iron concentrations, carbon sources, growth phases, and O2 concentrations to better understand their global iron content. We investigated WT cells and those lacking Fur, FtnA, Bfr, and Dps proteins. The coarse-grain iron content of exponentially growing cells consisted of iron-sulfur clusters, variable amounts of nonheme high-spin FeII species, and an unassigned residual quadrupole doublet. The iron in stationary-phase cells was dominated by magnetically ordered FeIII ions due to oxyhydroxide nanoparticles. Analysis of cytosolic extracts by size-exclusion chromatography detected by an online inductively coupled plasma mass spectrometer revealed a low-molecular-mass (LMM) FeII pool consisting of two iron complexes with masses of ∼500 (major) and ∼1300 (minor) Da. They appeared to be high-spin FeII species with mostly oxygen donor ligands, perhaps a few nitrogen donors, and probably no sulfur donors. Surprisingly, the iron content of E. coli and its reactivity with O2 were remarkably similar to those of mitochondria. In both cases, a "respiratory shield" composed of membrane-bound iron-rich respiratory complexes may protect the LMM FeII pool from reacting with O2 When exponentially growing cells transition to stationary phase, the shield deactivates as metabolic activity declines. Given the universality of oxidative phosphorylation in aerobic biology, the iron content and respiratory shield in other aerobic prokaryotes might be similar to those of E. coli and mitochondria. Show less

Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully by tissues via the tricarboxylic acid cycle (TCA cycle) to carbon dioxide. Alternatively, glucose can be catabolized anaerobically via glycolysis to lactate, which is itself also a potential nutrient for tissues and tumours. The quantitative relevance of circulating lactate or other metabolic intermediates as fuels remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice, and find that lactate can be a primary source of carbon for the TCA cycle and thus of energy. Intravenous infusions of 13C-labelled nutrients reveal that, on a molar basis, the circulatory turnover flux of lactate is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice and 2.5-fold in fasting mice; lactate is made primarily from glucose but also from other sources. In both fed and fasted mice, 13C-lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis reveals that during the fasted state, the contribution of glucose to tissue TCA metabolism is primarily indirect (via circulating lactate) in all tissues except the brain. In genetically engineered lung and pancreatic cancer tumours in fasted mice, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumours. Show less

The use of molecular biological methodologies has provided a greater understanding of the cytotoxic effects of cisplatin and the underlying mechanisms of tumour cell resistance. Resistance to cisplatin is often multifocal with plasma membrane, cytosolic and nuclear components. Cisplatin-DNA adducts appear to be recognised by specific damage recognition proteins. Proteins associated with the transport of platinum through plasma membranes and genes associated with cisplatin resistance appear to be close to being elucidated. Current Phase I and Phase II clinical trials with platinum-containing complexes largely focus on the 1,2 diaminocyclohexane (DACH) carrier ligand, the dicarboxylatocyclobutane leaving group and complexes which circumvent cisplatin resistance in murine leukaemia models. At present, the trials are at too early a stage to allow comment on their clinical utility and, consequently, the relevance of the murine leukaemia-based preclinical observations. On the horizon, orally active platinum (IV) ammine/amine dicarboxylate dichloride coordination complexes with preclinical toxicological profiles similar to carboplatin should enter clinical trial in the next year. Show less