Search Results (1,349)

The endoplasmic reticulum (ER) is a central hub of cellular proteostasis, coordinating protein folding, lipid metabolism, calcium signaling, and inter-organelle communication. Disruptions in ER function activate the unfolded protein response (UPR), an evolutionarily conserved signaling network mediated by PERK, IRE1α, and ATF6. Initially viewed primarily as a stress-mitigating mechanism, the UPR is now recognized as a central coordinator of diverse cellular stress-response pathways. This review focuses on mechanistic insights into UPR signaling, with particular emphasis on its crosstalk with oxidative stress regulation, mitochondrial function and mitochondria–ER contact sites, autophagy, inflammatory signaling, and metabolic sensing. The analysis integrates evidence from biochemical and structural studies, genetic and pharmacological perturbation models, and selected in vivo investigations from PubMed and Google Scholar between 2000 and 2025, focusing on mechanistic, experimental and translational studies addressing UPR signaling and ER stress. Together, these studies demonstrate how transient UPR activation promotes cellular adaptation through coordinated transcriptional, translational, and organelle-specific responses. We further discuss how sustained or unresolved ER stress alters UPR outputs, shifting signaling toward maladaptive outcomes such as mitochondrial dysfunction, dysregulated autophagy, oxidative imbalance, and apoptosis. By placing the UPR within a network of interconnected stress pathways, this work provides a framework for understanding how ER proteostasis is linked to cell fate decisions under stress. Full article

Background/Objectives: Rapid DNA systems accelerate STR profiling but often require the consumption of the entire swab, limiting confirmation testing or downstream analyses. We previously validated a simple subsampling protocol for blood swabs on the RapidHIT^TM ID, using a rigid subungual mini-swab (Copan Italia S.p.A). A new version of this instrument has recently been released, featuring redesigned software and consumables. The RapidINTEL^TM Plus sample cartridge now enables two distinct lysis/extraction protocols, expanding analytical possibilities for rich biological traces. We evaluated subsampling performance using the subungual mini-swab and microFLOQ^® swabs (Copan Italia S.p.A), and assessed feasibility for both blood and buccal reference swabs. Methods: Whole blood from four donors was deposited onto regular Copan swabs (10 µL) or microFLOQ^® swabs (1 µL). A comparison was performed between the direct analysis of blood swabs using a RapidHIT^TM ID V1 (RapidINTEL^TM cartridge) and a RapidHIT^TM ID V2 (RapidINTEL^TM Plus cartridge, GENERAL protocol). Subsequently, both the GENERAL and SPECIALIZED protocols were tested after subsampling from primary blood or buccal swabs dried for 24 h using either a subungual mini-swab or a microFLOQ^®. Results: Blood-swab subsampling on the V2 produced usable STR profiles with both the subungual mini-swab and the microFLOQ^®. The subungual mini-swab was compatible with both the GENERAL and SPECIALIZED protocols. For blood applications, microFLOQ^® fiber treatment showed no inhibitory effects. Reference buccal swabs were successfully analyzed with the RapidINTEL^TM Plus cartridge, either directly (regular swab) or via subungual subsampling under both protocols. In contrast, in this feasibility dataset (single analysis per donor per condition), subsampling a reference swab with microFLOQ^® did not yield suitable profiles for RapidINTEL^TM Plus analysis under the tested conditions. Conclusions: This feasibility study indicates that the subsampling strategy can be applied on the RapidHIT^TM ID V2, particularly using subungual mini-swabs, to retain the primary swab for potential downstream testing while maintaining usable STR profile quality for blood and buccal reference workflows under the tested conditions. Full article

The conservation process is iterative and interactive. Periodic updates stratify data across disciplines and time. Still the transition from raw data to structured knowledge is often slowed by procedural gaps and tooling limitations, creating a semantic divide between abundant digital resources and truly intelligible data. This article proposes a methodological and operational approach for managing the continuity of the information flow within a digitalization process functional to a conservation strategy for the Historical Built Heritage. A graph-structured semantic knowledge base was developed and it is fed by data from heterogeneous sources (Building Information Modeling, reality-based annotation platforms and graph databases), organized according to an explicit conceptual model for representing the building’s diachronic evolution. Interaction and querying are mediated by a prototypical multidimensional visualization environment. The experimentation has proven to anticipate contextualization, to rationalize mapping, to harmonize heterogeneous resources, and to formalize knowledge for sharing and querying. Calabrian heritage, which is part of the region’s identity and subject to natural and anthropogenic risks, is the case of interest. Application scenarios are exemplified in the experiment on San Giovannello, Gerace (RC). Full article

The maintenance of endoplasmic reticulum (ER) Ca²⁺ homeostasis is intrinsically linked to the fidelity of protein folding, forming a functional tether that, when disrupted, triggers the Unfolded Protein Response (UPR). This bidirectional axis serves as a critical rheostat for cellular viability, yet its chronic dysregulation underpins the molecular etiology of numerous pathologies, including neurodegeneration, heart failure, and malignant transformation. This review provides a comprehensive interrogation of the Ca²⁺-ER Stress–UPR network, delineating how primary stress sensors—PERK, IRE1alpha, and ATF6—engage in complex feedback loops that either reinstate equilibrium or commit the cell to apoptosis. We specifically examine the PERK-CHOP-SERCA2b inhibitory circuit as a central driver of persistent Ca²⁺ depletion and discuss the role of Mitochondria-Associated Membranes (MAMs) in governing lethal Ca²⁺ transfer. Notably, we move beyond the classical paradigm of CHOP as a terminal apoptotic executioner, incorporating emerging evidence of its context-dependent adaptive functions. By synthesizing mechanistic insights across diverse disease models, this work highlights the transition from adaptive to maladaptive UPR as a universal pathological checkpoint. Ultimately, we evaluate the therapeutic potential of ‘axis-targeted’ interventions, such as SERCA activators and selective UPR modulators, aimed at resolving the underlying Ca²⁺ signaling defects in ER stress-related disorders. Full article

The endoplasmic reticulum (ER) responds to stimuli that disrupts its homeostasis by activating a signalling network known as unfolded protein response (UPR), that restores cellular balance and determines cell fate through three key sensors: inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK). Emerging evidence suggests that UPR regulates the expression of numerous long non-coding RNAs (lncRNAs), which play critical roles in maintaining ER homeostasis. Here we show that expression of lncRNA H19 is downregulated in response to ER stress in (MCF7, T47D and 293T) cells. Using genetic and pharmacological approaches, we demonstrate that H19 downregulation is primarily mediated by the PERK arm of the UPR. Specifically, knockdown or chemical inhibition of PERK compromised the ER stress-mediated H19 repression, while PERK activation significantly reduced H19 expression. H19 overexpression promotes the optimal activation of ATF6 and PERK pathways, while it attenuates the signalling by IRE1-XBP1 axis of the UPR. Furthermore, in triple-negative breast cancer (TNBC) cells MDA-MB-231, ectopic H19 provided resistance to ER stress-induced apoptosis. Bioinformatic analyses across multiple breast cancer cohorts revealed that high H19 expression was associated with poor prognosis, particularly in basal-like subtypes. Collectively, our findings show that H19 is downregulated during UPR in a PERK-dependent manner, where H19 in turn modulates UPR signalling and cell fate during conditions of ER stress. Full article

The unfolded protein response (UPR) is a highly conserved adaptive mechanism that restores endoplasmic reticulum (ER) homeostasis under stress. Beyond its canonical roles in proteostasis, the UPR has emerged as a central regulator of immune responses across diverse contexts, including infection, inflammation, cancer, and autoimmunity. IRE1α, PERK, and ATF6 are three principal UPR sensors that coordinate complex signaling networks to regulate antigen presentation, cytokine production, and immune cell differentiation. This review highlights the molecular mechanisms by which small molecules target the UPR to modulate immune responses. In addition, we highlight stress granules (SGs) and the prevalence of protein–protein interactions mediated by intrinsically low-complexity domains (LCDs) in the UPR as potential new avenues for immune modulation. Finally, we discuss future directions for leveraging UPR modulation in immunotherapy, infectious disease, and chronic inflammatory disorders. Full article

In clinical and preclinical magnetic resonance imaging (MRI), image quality is often limited by intrinsic tissue contrast, so paramagnetic agents are used to amplify relaxation differences and improve lesion detectability. Widely used gadolinium-based contrast agents present recognized drawbacks, stimulating interest in nanoscale platforms with tuneable magnetic and biological properties. This review provides a critical analysis on the use of metal-doped carbon nanodots (C-dots) as MRI contrast candidates. We briefly revisit MRI signal formation, spin–lattice ($T_1$) and spin–spin ($T_2$) relaxation, and relaxometric parameters $r_1$ and $r_2$ and outline how pulse-sequence choice favours $T_1$- or $T_2$-dominant agents. We compare approved small-molecule agents with nanostructured systems, highlighting unmet needs in safety, field-strength dependence, multimodality, and organ-specific imaging. A central focus is how nano- and molecular architectures of metal-doped carbon dots govern $r_1$ and $r_2$: the metal species and oxidation state, its location within the carbon matrix, surface chemistry and hydration, and the accessibility for proton and water exchange can shift performance toward $T_1$ or $T_2$. Engineered C-dots with controlled composition and metal dopants have proven to pair improved relaxivity with fluorescence, targeting ligands, or therapeutic payloads. Overall, metal-doped C-dots represent a flexible and potentially safer alternative to classical contrast agents; however, successful clinical translation and market uptake will still require standardized relaxometry at clinical field strengths, scalable and reproducible synthesis, and comprehensive in vivo safety and efficacy validation. Full article

Sympathetic nervous system (SNS) imbalance is a common pathological basis for cardiovascular diseases, non-alcoholic fatty liver disease, and diabetes. This review focuses on these diseases, analyzing two core mechanisms: excessive sympathetic excitation induced by endoplasmic reticulum stress (ERS) or autophagy dysfunction in key central nuclei (e.g., hypothalamus, rostral ventrolateral medulla); and ERS/autophagy abnormalities in peripheral target organs caused by chronic SNS overactivation. Existing studies confirm that chronic SNS overactivation promotes peripheral metabolic overload via sustained catecholamine release, inducing persistent ERS and disrupting the protective unfolded protein response (UPR)–autophagy network, ultimately leading to cell apoptosis, inflammation, and fibrosis. Notably, central ERS or autophagy dysfunction further perturbs autonomic homeostasis, exacerbating sympathetic overexcitation. This review systematically elaborates on SNS overactivation as a critical bridge mediating UPR–autophagy network dysregulation in central and peripheral tissues, and explores therapeutic prospects of targeting key nodes (e.g., chemical chaperones, specific UPR modulators, nanomedicine), providing a theoretical basis for basic research and clinical translation. Full article

This study provides a comprehensive overview of research and advancements on carbon materials with regard to practical targets for hydrogen storage in terms of gravimetric and volumetric capacities. For the sake of clarity, only the most relevant references on hydrogen storage by adsorption are presented, although the study was conducted in the same exhaustive manner as the one initially carried out by Anne C. Dillon and Michael J. Heben in 2001 with a particular emphasis on emerging technologies and potential applications in various sectors. This study also focuses on the importance of carbon-based materials with high specific surface areas and porous structures optimised to maximise adsorption—including at high pressure—while primarily limiting references herein to experimentally validated results. It therefore offers insights into the porous materials, as well as the methodologies—including a fully comprehensive and so-far proven highly transferable intermolecular hydrogen model combining van der Waals’s and Coulomb’s forces—used to improve hydrogen solid storage efficiency. Full article

We analyze the formal equivalence between the electromagnetic energy conservation law derived from Maxwell’s equations in an optical microcavity and the conservation of a probability fluid associated with the de Broglie–Bohm theory for an effective massive particle describing a photon in this cavity. This work is part of a critical analysis of recent experiments by Sharoglazova et al. carried out with a view to refuting the de Broglie–Bohm theory. Furthermore, the consequences of our analysis for microphotonics go far beyond these experiments. In particular, extensions that take into account photon spin and stochastic aspects associated with radiative or absorption losses are considered. From the point of view of symmetries and probability current, here the effective photon behaves like a spin-1/2 particle. Full article

Antimicrobials are common drugs used to treat and prevent infectious diseases in plants, animals, and humans. Since their discovery in the mid-20th century, their use has dramatically increased for the benefit of humanity, and also for animal care. However, antimicrobial resistance soon appeared, which, according to the WHO, will limit or impede their use at the horizon of 2050. Indeed, antimicrobial resistance (AMR), which is a natural phenomenon in bacteria increased dramatically over the last 3 decades mainly due to the overuse and misuse of antibiotics in humans, animals, and plants. Apart from affecting human health, drug-resistant diseases also adversely affect plant and animal health, reduce agricultural productivity, and threaten food security. AMR affects all countries, regardless of economic status, and imposes high costs on health systems and national economies. Therefore, antimicrobial resistance should be studied and analyzed under the One Health paradigm. In mind of the One Health paradigm, to reduce and overcome AMR, we must take at least 3 complementary and integrated actions: (i) monitoring the resistome; (ii) developing protective strategies against antibiotic resistance; (iii) taking curative actions by designing new and original treatments. Moreover, the three actions must be conducted simultaneously due to the continuous adaptation of bacteria. Full article

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s disease represent a major challenge in neuroscience due to their complex, multifactorial nature and the absence of curative treatments. These disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, proteostasis collapse, calcium dyshomeostasis, chronic neuroinflammation, and the prion-like propagation of misfolded proteins. Together, these processes trigger a cascade of cellular damage that culminates in synaptic dysfunction and programmed neuronal death. This review integrates current evidence on the sequential stages of neurodegeneration, emphasizing the convergence of oxidative, inflammatory, and proteotoxic pathways that drive neuronal vulnerability. Moreover, it explores emerging therapeutic strategies aimed at restoring cellular homeostasis, such as Nrf2 activation, modulation of the unfolded protein response (UPR), enhancement of autophagy, immunotherapy against pathological proteins, and gene therapy approaches. The dynamic interplay among mitochondria, endoplasmic reticulum, and glial cells is highlighted as a central element in disease progression. Understanding these interconnected mechanisms provides a foundation for developing multi-targeted interventions capable of halting or delaying neuronal loss and improving clinical outcomes in neurodegenerative disorders. This work provides an integrative and introductory overview of the convergent mechanisms underlying neurodegeneration rather than an exhaustive mechanistic analysis. Full article

Necrosis is a characteristic feature of glioblastoma multiforme (GBM) and is closely associated with tumor-associated inflammation and poor clinical outcomes. However, the molecular consequences of necrotic cell death on endoplasmic reticulum (ER) stress signaling in GBM cells remain unclear. In this study, we examined the effects of necrotic cells on the ER stress signaling and unfolded protein response (UPR) in human glioblastoma cell lines. Exposure to necrotic cells reduced IRE1α phosphorylation and increased unspliced XBP1 (XBP1u) accumulation, without affecting PERK or ATF6 pathways. These changes were accompanied by enhanced IκBα phosphorylation and impaired autophagic degradation. Treatment with ER stress inducers failed to reverse XBP1u accumulation, and reduced phosphorylation of PKAc was observed together with decreased IRE1α activation. Transcriptomic analysis and quantitative reverse transcription PCR (qRT-PCR) revealed that necrotic cell-induced XBP1u was associated with altered expression of XBP1-related genes, while XBP1 knockdown produced similar transcriptional changes and enhanced the effects of necrotic cell treatment. These findings suggest that necrotic cells impair canonical IRE1α-XBP1 signaling and induce transcriptional reprogramming in glioblastoma cells, which may contribute to tumor progression. Full article

A unified digital toolbox is introduced for kinematics analysis and dimension synthesis of parallel robots, addressing challenges in configuration diversity and computational complexity. By integrating hierarchical kinematic modeling with screw theory, the toolbox establishes standardized analytical frameworks for mobility, inverse kinematics and dexterity evaluation. A modular toolbox architecture—comprising interactive, data, external module, database and functional layers—enables systematic design, workspace estimation and dexterity-driven optimization. A hybrid MATLAB-C++ interface ensures computational efficiency and scalability. The efficacy of the toolbox is demonstrated through a case study on a novel 2UPR-2RPS parallel mechanism, achieving optimized dimensional parameters (k₁ = 0.85, k₂ = 1.3, k₃ = 0.85, k₄ = 1.3) with a mean dexterity index of 0.637 and validated workspace symmetry. Results confirm that the toolbox streamlines the design process, ensures computational accuracy and enables rapid adaptation to new robotic configurations. This work provides a robust foundation for advanced parallel robot design, offering significant potential for industrial and research applications requiring high-precision motion control. Full article