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Mesoionic imines (MIIs) based on a 1,2,3-triazole core have been popularized in the past ca. 5 years. In this review article we discuss the synthesis, coordination ability and the structural and spectroscopic properties of this fascinating class of electronically ambivalent compounds. Apart from this, we also discuss the utility of MIIs and their compounds in directed C–H activation reactions, and in the activation and conversion of small molecules such as alkynes and CO2. Based on the current state of the art, we touch upon possible future developments of the chemistry of these classes of molecules. Show less

A model-agnostic empirical framework is proposed to measure the uncertainty associated with protein embeddings and to assess the biological relevance of these embeddings in order to improve model reliability and performance on downstream tasks. Show less

This study investigates the application of machine learning techniques to predict the toxicity of tetrazole derivatives, aiding in the identification of environmental risks from chemical exposure. Utilizing LD50 data sourced from the scientific literature and the ChemIDplus database, regression models were developed to forecast acute intraperitoneal toxicity in mice. A machine learning regression model for acute intraperitoneal toxicity in mice was constructed and validated on a test dataset, achieving high accuracy (R2 = 0.76 and MSE below 10−4) and surpassing most of the comparable literature models. Molecular descriptors were computed via Mordred software to explore quantitative structure–activity relationships, and additionally, the model's robustness was demonstrated by measuring the acute toxicity of tetrazole derivatives synthesized through the azido-Ugi reaction. Show less

Abstract This article presents the synthesis and detailed structural investigation of a new palladium(II) heteroligand complex trans-[PdCl(CNXyl)2(C{CN(H)Xyl}2)]Cl, containing an acyclic diaminocarbene ligand and two isocyanide ligands. X-ray diffraction and NMR spectroscopy revealed that complex is stabilized both in the crystal and in solution by a system of N–H···Cl– hydrogen bonds formed between one chloride anion and two N–H groups of the diaminocarbene ligand (N–H···Cl–···H–N), with calculated energies of 3.8–5.4 kcal/mol. A Cambridge Structural Database search identified 22 other palladium(II) acyclic diaminocarbene complexes with similar N–H···X···H–N (X = Cl–, Br–, O=C<, O=S<, etc.) hydrogen-bonded systems. The complex demonstrated significant antiproliferative activity against the triple-negative breast cancer cell line MDA-MB-231, with an IC50 value of 5.55 ± 0.45 µM, which is four times higher than that of cisplatin. Show less

Proteomics has matured into a discipline capable of quantifying nearly every protein encoded by the genome, yet it remains largely blind to the true operational units of physiology: proteoforms. Each proteoform—defined by a specific sequence and post-translationally modified state—represents a unique molecular identity with distinct chemical, functional, and structural properties. This review proposes the proteoform functor: a mathematical map between the abstract proteoform state space and the realised physiological space of biological function—and ultimately complex phenotypes. This mapping is not linear or additive. Rather, it is hierarchical, nonlinear, and context-dependent, reflecting the emergent complexity of life. Without resolving proteoforms, proteomics risks describing shadows of biology rather than its material substance. Deciphering complex phenotypes, demands a shift from bulk protein averages to revealing the precise molecular identities—proteoforms—that give rise to physiology. Show less

Ferroptosis is a type of programmed cell death characterized by accumulation of free iron, reactive oxygen species generation and lipid peroxidation and is distinct from other types of regulated cell deaths such as apoptosis, necrosis and autophagy. Ferroptosis is distinct from other programmed cell deaths for its iron dependence and its significant role in tumor suppression. Therefore, harnessing ferroptosis may offer promising avenues for cancer therapy. In the present review, the different pathways that lead to ferroptosis, the genes and transcription factors involved in both iron and lipid metabolism, as well as the impact of small‑molecule alterations on the regulation of ferroptotic cell death, were discussed. Furthermore, the emergence of combination therapies with ferroptosis‑inducing molecules that overcome resistance to conventional chemotherapy, particularly in solid tumors, were highlighted. Show less

Biomedical research benefits from the rapid growth and diversity of experimentally detected protein–protein interactions (PPIs) by gaining important biological insights. However, increasingly dense PPI networks can be challenging to interpret and apply. The 2025 update of the Integrated Interactions Database (IID) enhances accessibility and utility through several new features. We identify and incorporate network structural components from co-purified protein sets, as well as curated and predicted complexes, enabling users to explore network organization Show less

Biomedical research benefits from the rapid growth and diversity of experimentally detected protein-protein interactions (PPIs) by gaining important biological insights. However, increasingly dense PPI networks can be challenging to interpret and apply. The 2025 update of the Integrated Interactions Database (IID) enhances accessibility and utility through several new features. We identify and incorporate network structural components from co-purified protein sets, as well as curated and predicted complexes, enabling users to explore network organization beyond binary interactions. Functional, pathway, and disease associations of these components can be analyzed, enabling interactions to be grouped into higher-order structures with known or provisional biological roles. Users can now filter interactions by five detection types: pairwise, co-purification, colocalization, proximity, and other evidence. To extend the value and information of predicted interactions, we include interaction interface predictions for 53 647 PPIs, generated using the MEGADOCK docking algorithm, adding molecular detail for structural biology and variant impact studies. Finally, we map PPIs to 15 immune cell types and 12 additional normal tissues, offering tissue-specific views of interaction networks increasingly relevant in disease and immunology research. IID 2025 now includes over 1 million experimentally detected human PPIs, representing an 83% increase from the previous release, alongside expanded non-human networks. The portal remains publicly available at https://ophid.utoronto.ca/iid. Show less

Ferroptosis is a type of programmed cell death characterized by accumulation of free iron, reactive oxygen species generation and lipid peroxidation and is distinct from other types of regulated cell deaths such as apoptosis, necrosis and autophagy. Ferroptosis is distinct from other programmed cell deaths for its iron dependence and its significant role in tumor suppression. Therefore, harnessing ferroptosis may offer promising avenues for cancer therapy. In the present review, the different pathways that lead to ferroptosis, the genes and transcription factors involved in both iron and lipid metabolism, as well as the impact of small‑molecule alterations on the regulation of ferroptotic cell death, were discussed. Furthermore, the emergence of combination therapies with ferroptosis‑inducing molecules that overcome resistance to conventional chemotherapy, particularly in solid tumors, were highlighted. Show less

Artificial intelligence (AI) is being used in oncological drug development to address the high costs, low success rates, and long timelines that characterize traditional drug development pipelines. The use of machine learning (ML) and deep learning (DL) models in computer-aided drug design is constantly growing owing to their capacity to analyze large, heterogeneous datasets, their ability to capture nonlinear biological trends, and their integration of various molecular and clinical characteristics. AI applications accelerate target discovery by predicting protein structures, ranking disease-relevant genes, and assessing target drugability. AI can be used to conduct rapid searches of multiplexed chemical libraries, predict drug-target interactions, and optimize the pharmacological and physicochemical properties of drugs in virtual screening. Advanced neural network designs also aid in de novo drug design, which involves developing new molecular structures with therapeutic properties of interest. This review outlines how AI has been used for target identification, virtual screening, de novo molecular design, and, specifically, in cancer applications. It further discusses the major issues in AI-based drug development, such as data quality, model interpretation, computational constraints, and ethical and regulatory considerations, which remain essential obstacles to broader clinical translation. Show less

Many ligands are structurally rigid and well-defined, e.g. N-heterocyclic carbenes display a fan-like structure with a defined buried volume. Here, we break this dogma by introducing more flexibility around the catalytically active center by using acyclic (diamino)carbene (ADC) ligands. The ADC ligand was constructed in a straightforward protocol on the ruthenium center via methyl isocyanide coordination and subsequent reaction with amines such as pyrrolidine. Ligand flexibility in the formed (pyrrolidine)(methylamine)carbene ruthenium complex Ru-2 was demonstrated both in solution (variable temperature NMR) and in the solid state through crystallographic identification with the protic NH site oriented either distal or proximal to the ruthenium center. In contrast to their cyclic analogues, the Ru-ADC complexes are highly active in base-free transfer hydrogenation, with turnover numbers >1000. The base-free conditions allowed for the transformation of substrates with base-sensitive groups such as esters, amides, acids, and amines, substrates that typically fail to undergo transfer hydrogenation under classical conditions. The absence of base also enabled late-stage hydrogenation of more complex substrates, and it avoids complications such as corrosion attributed to KOH and related strong bases. Show less

Drug-drug interactions (DDIs) are a significant source of morbidity and adverse drug events (ADEs), particularly in situations of polypharmacy and complex medication regimens. While rules-based software integrated in electronic health records (EHRs) has demonstrated proficiency in identifying DDIs present in medication regimens, large language model (LLM) based identification requires thorough benchmarking and performance evaluation using high-quality datasets for safe use. The purpose of this study was to develop a series of performance benchmarking experiments specifically for LLM performance in identification and management of DDIs using a specifically curated clinician-annotated dataset of clinically-relevant DDIs. Show less

We report the facile synthesis of new gold(I) carbene complexes based on a mesoionic cobaltocenylidene metallocarbene via a fluorinative desilylation reaction. The carbene has been characterized by a variety of spectroscopic methods, revealing that it has the highest HEP value reported for a MIC so far, suggesting that the carbene is highly electron donating. The properties of the new class of metallo-mesoionic carbenes is further investigated, revealing also exceptionally low TEP values. Electrochemical studies also suggest the cobaltocenium moiety to be further reducible. In addition, the cell growth inhibitory effects of the new metallocarbene complexes were explored in cancer cells and bacteria. The combination of electrochemical activity, exceptional electron donating properties and their putative application in medicinal chemistry makes these new metallo-MICs a highly interesting new class of ligands. Show less

Four novel gold(I) N-heterocyclic carbene (NHC) complexes were synthesized and characterized; they are tuned in terms of the aromatic extension of the NHC scaffold and two of them contain a thiosugar residue to enhance their cellular uptake. To verify their potential interaction with human serum albumin (HSA), ESI-MS interaction analysis and fluorescence titrations were performed. Biological studies were carried out to evaluate their possible cytotoxic effect on three ovarian cancer cell lines, i.e., A2780 (both sensitive and cisplatin-resistant), and SKOV-3. Confocal microscopy and fluorescence-activated cell sorting tests were also carried out for the four complexes. Thiosugar conjugation proved to be an effective strategy to enhance potency and selectivity, resulting in a considerable improvement compared to the corresponding complexes lacking the thiosugar moiety. Furthermore, six bioconjugates containing targeting peptides were synthesized; in most cases, no significant improvement in either cytotoxic activity or selectivity was observed, except for the LHRH peptide conjugates, which showed a slight enhancement in both cytotoxicity and selectivity compared to the unconjugated complexes. Show less

Combining single-cell parallel profiling of genome conformation, histone modifications, chromatin accessibility and gene expression reveals dynamics and intranuclear spatial clustering of epigenome profiles, enabling sophisticated analysis of the regulatory landscape across cell types and tissues. Show less

While various metal complexes demonstrate immunogenic cell death (ICD)-inducing properties, there is a lack of studies comparing ICD properties in structurally similar complexes with different metal centers. In this study, we synthesized four structurally similar Rh(I) and Ir(I) complexes with redox-active 1,2-bis(arylimino)acenaphthene (Ar-bian) ligands and assessed their anticancer and ICD-inducing properties. Analysis of damage-associated molecular patterns (DAMPs), ROS localization and dying cell populations highlighted the distinct roles of the metal center and the ligands. Specifically, only Rh(I) complexes induced the release of the three essential DAMPs and high levels of late apoptotic cells, while the Ir(I) complexes failed to trigger crucial “eat-me” signals. This work offers valuable insights into structure–activity relationships in metal complexes in the context of ICD. Show less

Zinc is a crucial element in cellular processes, and its homeostasis has intricate relationships with the initiation, progression, and therapeutic intervention of cancer. Activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been proven to be an effective strategy for cancer immunotherapy. Herein, we report four phosphorescent iridium complexes (Ir1–Ir4) with zinc chelating ligands. Among them, Ir1 can bind and image mitochondrial chelatable zinc ions via phosphorescence-lifetime responses, consequently modulating the expression of zinc-regulatory proteins. Furthermore, the in situ formed heteronuclear metal complex Ir1-Zn2 shows nuclease mimetic activities, capable of hydrolyzing mitochondrial DNA (mtDNA) to release mtDNA fragments for the activation of the cGAS-STING pathway. In conclusion, we designed a mitochondria-targeting phosphorescent Ir(III) complex with dual functions in dysregulation of zinc homeostasis and generation of nuclease in situ, which provides an innovative approach to stimulate the cGAS-STING pathway. Show less

Proteomics has matured into a discipline capable of quantifying nearly every protein encoded by the genome, yet it remains largely blind to the true operational units of physiology: proteoforms. Each proteoform—defined by a specific sequence and post-translationally modified state—represents a unique molecular identity with distinct chemical, functional, and structural properties. This review proposes the proteoform functor: a mathematical map between the abstract proteoform state space and the realised physiological space of biological function—and ultimately complex phenotypes. Show less

Hybrid phosphines with anionic hard donor functions can be used to create an adaptable ligand environment for soft late transition metals. Herein, we show that the change of coordination of a diphosphine–phosphinic acid (P3OOH) in response to acid–base interactions or hydrogen bonding results in structural transformations of a disilver complex [Ag2(P3OO)2] (1) to give solvated and protonated derivatives [Ag2(P3OOH)2]2+ (2) and [Ag3(P3OO)3H]+ (3), accompanied by the alteration of the quantum yield of the solid-state photoluminescence from 0.06 up to 0.69. The related diphosphine–phosphide oxide complexes [M2(P3O)2] (M = Ag, Au) are oxidized to phosphinate compounds 2 and non-luminescent [Au2(P3OO)2H]+ (5) in the presence of triflic acid. Alternatively, [Au2(P3O)2] readily accommodates an additional gold(I) ion to yield a trinuclear cluster [Au3(P3O)2]+ (6), which is brightly sky-blue phosphorescent in the crystalline state (Φem = 0.76). The phosphide oxide group −PO in 6 is stable towards oxidation under acidic conditions in solution but undergoes protonation that results in two orders of magnitude (>170-fold) increase of the emission intensity. Complex 6 acts as a guest in the crystalline matrix of 5 due to their structural similarity and affords solid solutions with bright luminescence at a doping content of 1–2%. Show less

Fluorescein isothiocyanate-conjugated Annexin V in combination with propidium iodide (PI) labelling is a widely used flow cytometric assay for quantifying apoptotic and necrotic cells in anticancer studies. However, increasing evidence suggests that double-positive cells, or the Annexin V⁺/PI⁺ fraction, may represent not only late apoptosis but also different modalities of regulated cell death, including necroptosis, pyroptosis, ferroptosis, and cuproptosis. By collating findings from preclinical studies across different cancer cells, this review highlights the need for consensus in interpreting Annexin V⁺/PI⁺ populations. In the absence of molecular and/or microscopy data, this fraction is more appropriately classified as undergoing 'late-stage cell death'. In short, establishing standardised interpretive criteria is crucial to enhance understanding, facilitate cross-study comparability, and improve the translational relevance of anticancer research. Show less

Motivation: Proteins are of great significance in living organisms. However, understanding their functions encounters numerous challenges, such as insufficient integration of multimodal information, a large number of training parameters, limited flexibility of classification-based methods, and the lack of systematic evaluation metrics for protein question answering systems. To tackle these issues, we propose the Prot2Chat framework. Results: We modified ProteinMPNN to encode protein sequence and structural information in a unified way. We used a large language model Show less

Colorectal cancer (CRC) remains a significant global health challenge, ranking third in incidence and second in mortality among cancers worldwide. This review addresses the complex landscape of CRC, focusing on incidence, mortality trends, preventive strategies, and the evolving therapeutic approaches, particularly highlighting the role of platinum-based drugs like oxaliplatin (OXP). It also underscores the increasing burden of CRC, with factors such as westernized diets, aging populations, and genetic predispositions contributing to its prevalence. Therapeutically, early detection greatly enhances survival rates, emphasizing the importance of regular colonoscopies and stool tests. For advanced CRC, chemotherapy remains pivotal, with OXP as a cornerstone treatment despite its associated chemotherapy-induced peripheral neurotoxicity (CIPN). The review explores innovative strategies to overcome challenges related to chemotherapy, such as drug resistance and side effects, highlighting recent developments in the field, such as Pt(IV) prodrugs and immunotherapeutic approaches to enhance efficacy while minimizing toxicity. Additionally, this manuscript examines experimental models for drug screening, emphasizing the role of murine models and advanced 3D in vitro systems in CRC research. Overall, the review advocates for a comprehensive approach, integrating prevention, early detection, and personalized treatments to alleviate the global burden of CRC. Show less

Ferroptosis, the non-apoptotic, iron-dependent form of cell death is an unavoidable outcome and byproduct of cellular metabolism. Reactive oxygen species generation during metabolic activities transcends to ­Fe2+-induced lipid peroxidation, leading to ferroptosis. Cancer cells being highly metabolic are more prone to ferroptosis. However, their neoplastic nature enables them to bypass ferroptosis and become ferroptosis-resistant. The capability of cancer cells to reprogram its metabolic activities is one of its finest abilities to abort oxidative damage, and hence ferroptosis. Moreover, the reprogrammed metabolism of cancer cells, also associates with the radical trapping antioxidant Show less

Background: Adverse drug reactions (ADRs) are harmful side effects of medications. Social media provides real-time, patient-generated data, though its unstructured format presents challenges. Natural language processing and transfer learning offer promising solutions. Objective: This study aimed to evaluate whether transformer-based models fine-tuned on a general ADR dataset can effectively classify ADRs from tweets related to glucagon-like peptide-1 (GLP-1) receptor agonists and to benchmark their performance against state-ofthe-art large language models (LLMs). Show less

Mitochondria are the energy production centers in cells and have unique genetic information. Due to the irreplaceable function of mitochondria, mitochondrial dysfunction often leads to pathological changes. Mitochondrial dysfunction induces an imbalance between oxidation and antioxidation, mitochondrial DNA (mtDNA) damage, mitochondrial dynamics dysregulation, and changes in mitophagy. It results in oxidative stress due to excessive reactive oxygen species (ROS) generation, which contributes to cell damage and death. Mitochondrial dysfunction can also trigger inflammation through the activation of damage-associated molecular patterns (DAMPs), inflammasomes and inflammatory cells. Besides, mitochondrial alterations in the functional regulation, energy metabolism and genetic stability accompany the aging process, and there has been a lot of evidence suggesting that oxidative stress and inflammation, both of which are associated with mitochondrial dysfunction, are predisposing factors of aging. Therefore, this review hypothesizes that mitochondria serve as central hubs regulating oxidative stress, inflammation, and aging, and their dysfunction contributes to various diseases, including cancers, cardiovascular diseases, neurodegenerative disorders, metabolic diseases, sepsis, ocular pathologies, liver diseases, and autoimmune conditions. Moreover, we outline therapies aimed at various mitochondrial dysfunctions, highlighting their performance in animal models and human trials. Additionally, we focus on the limitations of mitochondrial therapy in clinical applications, and discuss potential future research directions for mitochondrial therapy. Show less

Proteins are of great significance in living organisms. However, understanding their functions encounters numerous challenges, such as insufficient integration of multimodal information, a large number of training parameters, limited flexibility of classification-based methods, and the lack of systematic evaluation metrics for protein question answering systems. To tackle these issues, we propose the Prot2Chat framework. Show less