Search Results (244)

This article addresses recent critiques of secularisation as a linear explanatory model for religious change in European societies, proposing that contemporary artistic creation is a fertile site for observing new interrelations between the secular and the religious. Focusing on João Madureira’s Missa de Pentecostes (2010), composed for the ensemble ‘Sete Lágrimas’ and part of a cultural project by the Roman Catholic community of ‘Capela do Rato’ (Lisbon), the study analyses how this work creatively reconfigures the traditional Mass form. By juxtaposing the Ordinary sections (e.g., Kyrie, Gloria) with the Proper sections (e.g., Introitus, Sequentia), which incorporate non-canonical Portuguese poetic texts, the composition creates a hybrid space in which ritual and artistic modes interact and mutually re-legitimise each other. Using a heterological interpretative framework inspired by Michel de Certeau, the article highlights the tensions and exchanges between ritual and aesthetic logics. The analysis draws on key theoretical concepts including Jean Rancière’s notions of consensus and dissensus, Pierre Bourdieu’s theory of ritual and habitus, Paul Ricoeur’s philosophy of translation as hospitality, and Pierre Lévy’s concept of universalism without totality. The findings suggest that Madureira’s work enacts a process of poetic re-signification of religious memory, opening new possibilities for hybrid ritual–artistic practices. These practices transform ritual time-space into an interface that fosters plural and non-totalising forms of spiritual belonging. Full article

G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in gene regulation and genome stability. Among them, the telomeric repeat-containing RNA (TERRA) forms biologically relevant RNA G4s (rG4s) that participate in telomere maintenance and genome stability. Although many ligands targeting DNA G4s have been reported, the recognition and modulation of RNA G4 topologies remain less explored. In this work, we investigated the interaction between TERRA and the spermine-functionalized Zn(II) porphyrin, ZnTCPPSpm4, using UV–vis absorption, fluorescence, resonance light scattering (RLS), and circular dichroism (CD) spectroscopy. In K⁺, where TERRA adopts a parallel G4 conformation, ZnTCPPSpm4 binds through a stepwise mechanism involving external end-stacking, forming discrete supramolecular complexes without altering the native topology. In contrast, under Na⁺ conditions, ZnTCPPSpm4 induces a gradual conformational rearrangement of TERRA from the antiparallel to a parallel-like G4 topology. A CD melting study showed that ZnTCPPSpm4 stabilizes the parallel RNA G4, while slightly destabilizing the antiparallel topology. Overall, our results demonstrate that ZnTCPPSpm4 is not a simple G4 binder, but a topology-selective ligand capable of remodeling TERRA G4 structures, highlighting the potential of metalloporphyrins as RNA G4-targeting scaffolds. Full article

The structural characterization of GG-rich DNA sequences in presence of metal ions provides essential insight into quadruplex stability and ion-dependent conformational specifics. We report the crystal structure of the GG-quadruplex formed by the sequence GGGGTTTTGGGG in the presence of Zn²⁺, K⁺, and Na⁺. It was deposited in the RCSB Protein Data Bank under the accession code 9FTA. The structure was determined by single-crystal X-ray diffraction at a resolution of 2.49 Å in the space group P2₁2₁2₁. It reveals a parallel-stranded, two-G-tetrad stabilized by K⁺ ions within the central channel, while Na⁺ and Zn²⁺ occupy peripheral and groove-associated sites. Zn²⁺ ions are engaged in noncanonical coordination interactions with phosphate oxygens and structured water molecules, contributing to lattice stabilization and subtle adjustments in groove dimensions. The T4 loop forms a compact, ordered motif that contributes to crystal packing rather than intramolecular G4 stabilization. The presence of mixed cations produces a sole lattice architecture mediated by ions that provides structural insight into how bivalent and monovalent metals mutually modulate G-quadruplex topology. These results suggest a basis for understanding the specific ion effects on G4 structures and may direct the design of metal open DNA architectures. Full article

The upregulation of glycolysis and resultant lactate production (hereafter referred to as fermentative glycolysis) even under normoxic conditions has been considered a hallmark of cancer. In recent years, however, it has become clear that fermentative glycolysis in tumors is not as all-inclusive as originally thought. Nevertheless, many tumor types at different stages of progression are characterized by a predominantly glycolytic metabolism. Fermentative glycolysis in tumors supports several different functions: energy production in the form of adenosine triphosphate molecules, the maintenance and amplification of glycolytic metabolism itself, the feeding of oxidative metabolism through the production of lactate, the generation of metabolic intermediates for biomass production, and the execution of non-metabolic, non-canonical, so-called moonlighting functions. This knowledge, however, raises a number of different questions which, by and large, are still unanswered today. Are there different degrees of glycolysis upregulation in order to support the different functions? How is fermentative glycolysis maintained even under normoxic conditions? Why do moonlighting functions exist, given that they are unrelated to the metabolic steps of glycolysis? Moonlighting functions are generally discussed in the context of tumorigenesis, but do they exist also in non-transformed cells? Do they occur in a coordinated manner in all tumor cells or are they activated selectively depending on the tumor type, tumor stage, or on the inducing stimulus? While these issues are mostly unresolved, in this article we propose some tentative answers which, we hope, may promote new research directions which may further our understanding in this field. Full article

Constructed wetlands (CW) are a low-cost alternative for wastewater treatment, where microbial communities play a key role in the biotransformation of pollutants, including sulfur compounds. This study reports the identification of cultivable bacteria involved in the sulfur cycle (SC) in a subsurface-flow CW located in Tetipac, Mexico. Water, sediment, and rhizosphere samples were collected during four sampling events and plated on a mineral medium with thiosulfate. Colony-forming units were quantified, and 15 isolates were genetically identified by partial 16S rRNA gene sequencing. Bacterial abundance was higher in the rhizosphere, and the cultivable fraction was dominated by Pseudomonadota, particularly Gammaproteobacteria, accompanied by Bacteroidota and several previously uncultured lineages; genera such as Achromobacter, Chitinophaga, Enterobacter, Pseudomonas, Raoultella and Stenotrophomonas were recovered. Biochemical assays revealed heterogeneous metabolic profiles, with several isolates showing activities comparable to canonical sulfur-oxidizing bacteria (SOB). Most isolates oxidized thiosulfate and a substantial proportion oxidized elemental sulfur, with higher metabolic performance in rhizosphere isolates and a positive association with BOD₅ removal. Overall, these results indicate that the Tetipac wetland harbors a cultivable community of largely non-canonical SOB whose mixotrophic versatility and spatial differentiation suggest a key contribution to the SC and organic matter degradation in CW. Full article

Chemotherapeutic agents targeting ribosome biogenesis induce profound reorganization of nucleolar architecture, yet how the tumor suppressor p53 governs these structural responses remains unclear. Here, we show that loss of p53 leads to NF-κB-dependent disappearance of nucleolar caps induced by doxorubicin (DOXO). Under these conditions, fibrillarin (FBL), which is normally confined to the nucleolus, relocates to the nucleoplasm and forms foci that partially associate with G-quadruplex (G4) structures, non-canonical nucleic acid secondary structures enriched at transcriptionally active genomic regions. To examine whether this redistribution is linked to transcriptional changes, we integrated publicly available transcriptomic datasets and identified genes that were upregulated in p53-deficient cells under DOXO treatment and downregulated upon FBL depletion. Given that casein kinase 2 alpha (CK2α) is a nuclear binding partner of FBL, we further analyzed CK2α-dependent gene programs. This analysis revealed that a fraction of FBL-responsive genes overlapped with CK2α-dependent signatures and were enriched for promoter-proximal G4 structures. Among candidate regulators, the G4-binding transcription factor MAZ emerged as a potential mediator linking nucleoplasmic FBL and CK2α to G4-associated transcriptional regulation. Together, our findings identify a mechanism linking loss of p53 to G4-associated transcriptional reprogramming through nucleolar architectural disruption mediated by an FBL–CK2α–MAZ axis during DOXO treatment. Full article

Triplexes (TRX) are a class of flipons that can form due to the interaction of RNA with B-DNA. While many proteins have been proposed to bind triplexes, structural models of these interactions do not exist. Here, I present AlphaFold V3 (AF3) models that reveal interactions between the high-mobility group protein B1 (HMGB1), HNRNPU (SAF-A), TP53, ARGONAUTE (AGO), and REL domain proteins. The TRXs result from the sequence-specific docking of RNAs to DNA via Hoogsteen base pairing. The RNA and DNA strands in apolar TRX are oriented in the opposite 5′ to 3′ direction, while copolar TRX have RNA and DNA strands pointing in the same 5′ to 3′ direction. TRXs can incorporate different RNA classes, including long noncoding RNAs (lncRNAs), short RNAs, such as miRNAs, piRNAs, and tRNAs, nascent RNA fragments, and non-canonical base triplets. Many pathways regulated by TRX formation have evolved to constrain retroelements (EREs), which are both an existential threat to the host and a source of genotypic variation. TRXs help set the boundaries of active chromatin, repressing the expression of most EREs, while depending on other flipons to modulate cellular programs. The TRXs help nucleate folding of intrinsically disordered proteins. Full article

Atherosclerosis (AS) is a disease characterized by chronic vascular wall inflammation and lipid deposition. Although lipid-lowering drugs such as statins have significantly reduced cardiovascular event rates, “residual inflammatory risk” remains a key factor driving disease progression and plaque rupture. As a central regulator of the inflammatory response, the nuclear factor-κappaB (NF-κB) signaling network comprises both canonical pro-inflammatory pathways and functionally more complex non-canonical pathways. Increasing evidence in recent years indicates that abnormal and sustained activation of the non-canonical NF-κB signaling pathway plays a pivotal role in driving plaque rupture. This review first elaborates on the shift in AS strategies from “lipid-lowering” to “anti-inflammatory” approaches, followed by an in-depth analysis of the molecular activation mechanisms of the NF-κB signaling pathway and its distinctiveness in the AS pathological process, along with its epigenetic regulation. It emphasizes how this pathway drives pathological angiogenesis and regulates vascular smooth muscle cell (VSMC) phenotypic switching and macrophage function, thereby forming a vicious cycle that amplifies inflammation and structural damage, ultimately leading to acute cardiovascular events. Finally, we systematically summarize current progress and challenges in drug development targeting the NF-κB pathway (e.g., targeting key kinases like NIK and IKKα), aiming to provide theoretical foundations and future directions for novel therapeutic strategies to stabilize coronary plaques and prevent acute coronary syndromes. Full article

The role of alternative nucleic acid structures (ANS) in biology is an area of increasing interest. These non-canonical structures include the Z-DNA and Z-RNA duplexes (ZNA), the three-stranded triplex, the four-stranded G-quadruplex (GQ), and i-motifs. Previously, the biological relevance of ANS was dismissed. Their formation in vitro often required non-physiological conditions, and there was no genetic evidence for their function. Further, structural studies confirmed that sequence-specific transcription factors (TFs) bound B-DNA. In contrast, ANS are formed dynamically by a subset of repeat sequences, called flipons. The flip requires energy, but not strand cleavage. Flipons are enriched in promoters where they modulate transcription. Here, computational modeling based on AlphaFold V3 (AF3), under optimized conditions, reveals that known B-DNA-binding TFs also dock to ANS, such as ZNA and GQ. The binding of HLH and bZIP homodimers to Z-DNA is promoted by methylarginine modifications. Heterodimers only bind preformed Z-DNA. The interactions of TFs with ANS likely enhance genome scanning to identify cognate B-DNA-binding sites in active genes. Docking of TF homodimers to Z-DNA potentially facilitates the assembly of heterodimers that dissociate and are stabilized by binding to a cognate B-DNA motif. The process enables rapid discovery of the optimal heterodimer combinations required to regulate a nearby promoter. Full article

Synapses, abundant in the brain, are structures needed for life. Our Introduction, based on the forms of such structures published few decades ago, helped in developing recent concepts of health and diseases. Growing axons govern their growth by cell-to-cell communication, axon guidance, and synapse orientations. The assembly of synapses requires the organization and function of pre-synaptic and post-synaptic neuronal terminals with a liquid–liquid phase, governed by Ca²⁺ responses of thin astrocyte domains. Upon synapse stimulation, the clefts expand up to several folds while pre- and post-synaptic thickness remains unchanged. In additional responses, neurons co-operate with astrocytes and extracellular vesicles (EVs), the latter dependent on extracellular and intracellular spaces. Astrocyte and microglia cells and/or EV secretions induce neurons by various effects including traveling changes. Pre-synaptic responses are defined as canonical if based on neurotransmitter release; non-canonical if they are without release and are discharged by EVs, not neurotransmitters. Health and diseases depend on other general properties, such as those defined molecularly. Among neurodegenerative diseases, attention is specified by various properties of Alzheimer’s and other diagnoses. Critical identifications can be due to astrocyte and microglia cells or multiple effects induced by EVs. At present, the complexity of therapies, although of limited success, is developing innovative initiatives. Full article

Background: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by limited therapeutic options and poor prognosis. Temozolomide (TMZ) remains the standard chemotherapy; however, its effectiveness is often hindered by the development of acquired resistance. Cuproptosis, a recently identified copper-dependent form of regulated cell death, has emerged as a potential therapeutic target. The synergistic effects of TMZ and copper, as well as the molecular mechanisms underlying their combined action, remain unclear. This study aimed to investigate the role of tripartite motif-containing protein 14 (TRIM14) and its downstream effector ATP7A in mediating TMZ- and copper-induced cuproptosis in glioma. Methods: We employed in vitro cellular assays, in vivo xenograft models, bioinformatic analysis, immunofluorescence staining, Western blotting, and co-immunoprecipitation experiments to examine the functional involvement of TRIM14 and ATP7A during combined TMZ and copper chloride (CuCl₂) treatment. Intracellular copper levels and cuproptosis markers, including Dihydrolipoamide S-acetyltransferase (DLAT), were assessed to evaluate copper-dependent cytotoxicity. Results: TMZ combined with CuCl₂ markedly enhanced cuproptosis in glioma cells, as evidenced by increased DLAT expression and elevated intracellular copper accumulation. This combination treatment significantly suppressed TRIM14 expression, downregulated the TRIM14–ATP7A axis, and inhibited non-canonical NF-κB signaling. Co-immunoprecipitation assays further revealed a potential interaction between TRIM14 and ATP7A, suggesting that TRIM14 may modulate ATP7A stability or activity. Conclusions: Our findings indicate that TMZ and copper synergistically induce cuproptosis in GBM by disrupting the TRIM14–ATP7A regulatory axis and promoting intracellular copper accumulation. Targeting TRIM14 or ATP7A to enhance cuproptosis may represent a promising therapeutic strategy to overcome TMZ resistance and improve clinical outcomes in GBM patients. Full article

LD-Transpeptidases (LDTs) are a widely conserved class of peptidoglycan (PG) crosslinking enzymes in bacteria. They are sometimes overlooked as they often act secondary to penicillin binding proteins (PBPs) under standard conditions. However, LDTs are essential in key pathogens such as Clostridioides difficile and are responsible for β-lactam resistance in Mycobacterium tuberculosis and Enterococcus faecium due their low affinity for penicillins and cephalosporins, allowing them to form LD-crosslinks when DD-crosslinking PBPs are inactivated. This role makes LDTs a promising target when developing new treatments for these pathogens. LDTs can perform different enzymatic reactions. Most commonly they reinforce the PG with 3,3-LD-crosslinks or, in a few cases, 1,3-LD-crosslinks, during stationary phase or stress responses. Some LDTs also incorporate endogenous and exogenous non-canonical D-amino acids into the PG. In many Gram-negative bacteria, specialised LDTs tether lipoproteins or outer membrane proteins (OMPs) to the PG to maintain cell envelope integrity; in some cases this regulates virulence factors. Specialised LDTs have also been implied to have roles in polar growth, toxin secretion, and symbiotic colonisation. Recent discoveries include novel subgroups of the major YkuD family and the identification of the VanW family; this has opened new research directions surrounding LDTs. We aim to understand LDTs and their roles to expand our knowledge of PG synthesis and modification and how these enzymes can be targeted for antibiotic treatment. Full article

Computational and machine learning approaches play a pivotal role in identifying, characterizing, and targeting noncanonical DNA structures, including G-quadruplexes, Z-DNA, hairpins, and triplexes. These configurations play critical roles in maintaining genomic stability, facilitating DNA repair, and regulating chromatin organization. Although the human genome predominantly adopts the B DNA conformation, evidence indicates that non-B DNA forms exert significant influence on gene expression and disease development. This highlights the need for dedicated computational frameworks to systematically investigate these alternative structures. Machine learning model, encompassing supervised and unsupervised algorithms such as K Nearest Neighbors, Support Vector Machines, and deep learning architectures including Convolutional Neural Networks, have shown considerable potential in predicting sequence motifs predisposed to forming non-B DNA conformations. These predictive tools contribute to identifying genomic regions associated with disease susceptibility. Complementary bioinformatics platforms and molecular docking tools, notably Auto Dock, along with chemical libraries like ZINC, facilitate the virtual screening of small molecules targeting specific DNA structures. Stabilizers of G quadruplexes, exemplified by CX 5461, have demonstrated therapeutic promise in BRCA-deficient cancers, highlighting the translational impact of computational methods on drug discovery. Anticipating DNA structural shifts opens new avenues in personalized medicine for complex diseases, with computational chemistry and machine learning deepening our understanding of DNA topology and guiding smarter ligand design. The integrated approach proposed in this review addresses the previous studies performed in this field and highlights the current limitations in structural genomics and advances the development of precision therapeutics aligned with individual genomic profiles. Full article

In adult cardiomyocytes, within the Mitochondrial Associated Membranes (MAMs), the sarcoplasmic reticulum (SR) and mitochondria juxtapose each other, forming a unique and highly repetitive functional structure throughout the cells. These SR-mitochondria contact sites have emerged as critical structures that regulate various physiological processes, including lipid exchange, calcium (Ca²⁺) communication, control of excitation-contraction bioenergetics coupling, and reactive oxygen species (ROS) production. Over the years, several scientific studies have reported the accumulation of diverse proteins within these SR-mitochondria close contacts. Some proteins strategically accumulate in these areas to enhance their function, such as the mitochondrial Ca²⁺ uniporter, while others perform non-canonical roles, such as DRP1 acting as a bioenergetics regulator. The purpose of this review is to provide a comprehensive compilation of the proteins that have been reported to be enriched in cardiac MAMs. We aim to show how their positioning is crucial for proper cardiac physiology and fitness, as well as how mispositioning may contribute to cardiac diseases. Additionally, we will discuss the gaps in our understanding and identify the necessary components to fully comprehend physiological communication between the sarcoplasmic SR and mitochondria in cardiac tissue. Full article