Biochemistry has a strong interest in ion channels, a diverse group of membrane proteins. This group has long remained difficult to study at the structural level, but much progress has been made in recent decades with improvements in biochemical methods and computational procedures. Voltage-gated ion channels undergo conformational changes upon functioning, and multiple models of activation mechanisms were proposed based on experimental data. This review focuses on the structural studies of the functioning of voltage-gated ion channels, which are accompanied by conformational changes in proteins, and the methodological advances that allow their observation. Particular attention is paid to the lipid modulation of ion channels, as well as to the use of various lipids and membrane mimetics to stabilize specific conformations of ion channels. Modern experimental methods that allow obtaining ion channel proteins in specific functional states are discussed, including cryoelectron microscopy and cryoelectron tomography. NMR (Nuclear Magnetic Resonance) spectroscopy approaches and molecular modeling studies of conformational dynamics of ion channels and their isolated domains are also discussed. Finally, new algorithms for studying the conformational mobility of proteins have been recently developed, which help to better understand the mechanisms of ion channel domain movements.

Faithful replication and repair of the genome are essential processes for all life. Genome maintenance is coordinated by a complex suite of proteins, with bacteria evolving intricate systems despite their relatively simplistic genomes. DNA polymerases are a key class of proteins that mediate genome maintenance. DNA polymerases are all capable of extending nascent strands of DNA but contribute to DNA replication and repair in distinct ways depending on their active site and substrate specificity. The first discovered polymerase, bacterial DNA polymerase I (Pol I), has long been considered the primary enzyme responsible for Okazaki fragment maturation and resynthesis in many DNA repair pathways. These conclusions derive primarily from studies using the gram-negative bacterium, Escherichia coli. Given that some bacterial lineages diverged from E. coli over a billion years ago, these assumptions may not account for evolution in functional diversity. In this review, we examine the structural features of bacterial Pol I and discuss how each of its distinct enzymatic activities contribute to genome maintenance. Throughout, we introduce differences that have been discovered between gram-negative and gram-positive species and explore how activity differences may translate to functional adaptations in replication or repair. We focus on evidence from gram-positive bacteria, particularly Bacillus subtilis and Geobacillus stearothermophilus, that challenges the universality of Pol I’s functions and reveals lineage-specific adaptations in replication and repair mechanisms. By synthesizing historical perspectives with recent discoveries, this review underscores both the importance of Pol I and the evolutionary diversification of Pol I in bacterial DNA metabolism.

Human immunodeficiency virus type 1 (HIV-1) negative factor (Nef) is a multifunctional accessory protein that plays a central role in HIV-1 immunopathogenesis by compromising CD4+ T cell integrity and disrupting immune homeostasis. Although dispensable for viral replication in vitro, in vivo studies consistently demonstrate that Nef drives high viral burdens, facilitates immune evasion, and accelerates CD4+ T cell loss. Nef accomplishes these effects through a wide array of host-directed mechanisms, including the targeted downregulation of CD4 and major histocompatibility complex class I (MHC-I) molecules; perturbation of T cell receptor (TCR) signaling via mis-localization of the kinase Lck and disruption of immunological synapse formation; enhancement of cell-to-cell viral transmission by optimizing viral assembly and conditioning target cells for efficient infection; modulation of uninfected bystander cells through extracellular vesicles that amplify inflammatory signaling and promote permissiveness; and interference with CD4+ T cell trafficking by altering cytoskeletal dynamics and polarity, thereby limiting immune surveillance and facilitating viral dissemination. Evidence from non-human primate models, humanized mouse studies, and individuals infected with nef-defective HIV-1 strains underscores the protein’s indispensable contribution to disease progression. Importantly, Nef remains active within tissue reservoirs even under suppressive antiretroviral therapy (ART), sustaining chronic immune dysfunction. Collectively, these features position Nef as an attractive therapeutic target whose inhibition may help restore immune competence and support efforts toward achieving a functional HIV-1 cure.

The ESCRT-III complex is a highly conserved membrane remodeling system known for its essential roles in eukaryotic cellular processes such as endosomal trafficking, multivesicular body (MVB) formation, viral budding, membrane repair, and cytokinesis. These activities are critical for maintaining cellular integrity, and dysfunction in ESCRT-III has been linked to diseases including cancer, viral infection, and neurodegeneration. Recent findings suggest that bacterial homologs such as IM30 and PspA—while structurally simpler—exhibit remarkable functional similarities to their eukaryotic counterparts and play essential roles in membrane remodeling and deformation, particularly under environmental stress. However, the precise mechanisms driving these biological processes remain unclear. This review explores their structural dynamics, membrane-binding behavior, and remodeling activities. Emerging in vitro evidence suggests that PspA and IM30 assemble into high-molecular-weight oligomeric rings and filamentous structures, facilitating membrane interactions and remodeling. In contrast to eukaryotic ESCRT-III, which requires accessory proteins to form functional remodeling complexes, bacterial ESCRT-III proteins are capable of remodeling membranes autonomously. These activities drive a variety of structural transformations, including membrane curvature, elongation, protrusion, double-membrane vesicles (DMVs) formation, and fusion. By integrating recent findings, this review provides a comprehensive overview of current knowledge and highlights key directions for future research into the mechanisms and physiological roles of bacterial ESCRT-III.

Plants have been a part of human health since our very beginnings, and many of our modern pharmaceuticals claim their origins from medicinal plants. The range of specialized metabolites synthesized by plants is highly diverse, and metabolic functions have developed over the millennia to cover roles such as defense, adaptation to environmental stress, and even reproduction. These metabolites subsequently play roles in human health and diseases that are both significant and profound. The importance of plant natural products for the pharmaceutical, cosmetic and nutraceutical industries cannot be overstated. However, the fact that these specialized metabolites may be available only in low quantities from plants that are slow growing, endangered, or from fragile environments due to certain biotic and abiotic stresses makes their commercial use challenging despite the scenario that some stresses can enhance the production of secondary metabolites. Genome editing is a technique or technology that comprises of tools like CRISPR/Cas9, TALEN, ZFN. The following review describes the successful use of CRISPR/Cas9 genome editing in engineering medicinal plants, food crops and commercial crops to modulate metabolic pathways involved in the biosynthesis of valuable compounds to improve natural product identification, development and ultimately, commercial viability.

More than 170 distinct RNA modifications have been identified, playing pivotal roles in regulating development, homeostasis, and adaptive evolution. A recent groundbreaking study in Nature revealed that glycoRNA prevents endogenous RNA from being misidentified as non-self, thereby averting autoimmune responses. This function is astonishingly parallel to that of A-to-I RNA editing, another prevalent RNA modification. Here, we synthesize current knowledge of RNA modifications linked to immune function and highlight an intriguing but intuitive principle: modifications that act within the cell, such as A-to-I editing, must be installed in the nucleus before reaching the cytoplasm where unmodified exogeneous RNAs also prevail. By contrast, glycoRNA, which functions at the cell surface, faces no such spatial constraint, as self/non-self-identity needs not be resolved in the cytoplasm. We also acknowledge the existence of modifications such as C-to-U editing that appear less related to immunity. Future investigations will determine whether immune-associated functions are a dominant property of a broader spectrum of RNA modifications. Overall, this work deepens our understanding of how RNA modifications shape immune homeostasis and self/non-self-discrimination, and prompts broader reflection on how multilayered molecular regulations allow organisms to balance stability with diversity across development, evolution, and adaptation.

Galectins, a family of sugar-binding proteins, play a multifaceted role in human health and disease. They do not only regulate cellular processes but also influence tumor development and progression by promoting tumor growth, angiogenesis, metastasis, and most importantly, immune evasion. Unraveling their role in oncology opens doors for innovative therapies and novel diagnostic tools. Intriguingly, another layer of control emerges with non-coding RNAs, microRNAs, long ncRNAs, and circular RNAs. These RNA molecules act as master regulators in cancer by targeting galectins. This interplay between galectins and non-coding RNAs presents a golden opportunity for targeted control of cancer hallmarks in which galectins are highly involved. Manipulating this interaction can potentially increase the effectiveness of existing cancer therapies, particularly immunotherapy. This exciting avenue holds immense promises for the development of novel and targeted cancer therapies. In this review, the authors explore the complex interplay between ncRNAs and galectin across various types of cancer.

Accurate and efficient DNA replication constitutes the most effective safeguard against genome instability. Numerous aspects of replication initiation, elongation, and termination are tightly regulated by post-translational modifications. In this review, we summarize recent advances in elucidating pathways regulated by ubiquitin and the small ubiquitin-like modifier, SUMO, and compare insights gained in yeast with those obtained in vertebrate systems. These reversible modifications play critical roles in both DNA replication and replication-coupled repair processes. When active replisomes encounter obstacles such as nucleotide depletion, DNA secondary structures, or base lesions that impede fork progression, multiple genome surveillance pathways are activated to coordinate the replication stress response. Stalled replication forks undergo remodeling and reversal, thereby stabilizing the fork and facilitating replication restart. In parallel, diverse tolerance mechanisms have evolved to enable lesion bypass or replication traverse, which transiently alters the replication machinery yet permits continuation of DNA synthesis. At the core of these processes are the DNA damage tolerance and Fanconi anemia pathways, whose components collaborate to prevent under-replication during S phase and beyond. Furthermore, ubiquitin and SUMO signaling act synergistically through the activity of SUMO-targeted ubiquitin ligases. These enzymes sequester damaged replication forks at the nuclear periphery and promote recombination-mediated restart under stringent spatiotemporal control of the replication checkpoint. Failure of these mechanisms forces the cell to engage in a final, “do-or-die” attempt to initiate DNA synthesis during mitosis, a process that is also orchestrated by ubiquitin signaling.

Targeted protein degradation is an elegant therapeutic strategy that harnesses the cell’s own degradation machinery to selectively eliminate target proteins. This approach marks a paradigm shift in drug discovery, moving beyond traditional occupancy-based inhibition toward target degradation, thereby silencing proteins that have historically resisted pharmacological intervention. Degrader molecules function by inducing proximity between target proteins and effectors, most commonly E3 ubiquitin ligases, triggering their ubiquitylation and proteasomal degradation. Molecular glue degraders – monovalent small molecules that promote these neo-interactions – have emerged as powerful tools in this space. Serendipity was once synonymous with molecular glue discovery, but increasing mechanistic understanding is now guiding their rational design. In this review, we trace their evolution from chance discovery, explore the biological mechanisms that underpin molecular glue activity, examine key examples that have advanced into the clinic, and discuss the challenges that remain in harnessing these compounds for broader therapeutic impact.

Mitochondrial fatty acid oxidation (mFAO) disorders are caused by genetic variants in mFAO enzymes, their electron transporters, and cofactors. The clinical spectrum is heterogeneous, ranging from multi-organ failure and early death to milder neuromuscular forms that often are triggered or exacerbated during catabolic stress. Advances in genetics and the inclusion of mFAO disorders in newborn screening programs have allowed timely diagnosis and dietary interventions to prevent tissue damage and even death. Current dietary treatment aims to prevent energy deficiency and reduce toxic metabolites, but does not significantly prevent neurological, cardiac, and skeletal muscular abnormalities, including rhabdomyolysis. This review summarizes the present knowledge obtained from human studies showing that disruption of mitochondrial bioenergetics and redox homeostasis may represent relevant mechanisms for understanding long-term tissue damage and the stress-induced disease pathology of mFAO disorders. Sources and mechanisms of reactive oxygen species (ROS) production are discussed, including knowledge gained from mutations in the Electron Transfer Flavoprotein (ETF) and ETF-Ubiquinone Oxidoreductase (ETF-QO) proteins. The ETF/ETF-QO site serves as a biophysical and biochemical linker between mFAO and OXPHOS, and its high capacity for ROS production makes it a key component of the respiratory chain and a source of ROS in mFAO disorders. Understanding mitochondrial disturbances and how secondary disturbances in mFAO cofactors integrate with redox regulation at the ETF/ETF-QO site will advance our understanding of not only mFAO disorders but also the many diseases entailing OXPHOS and mFAO deficiencies, such as neurological and cardiovascular diseases, and as such, be enlightening for mitochondrial medicine in general.