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Dynamic disorder, trap renormalization, and diffusion on rugged energy landscapes.

Diffusion in rugged energy landscapes is central to chemical physics, with relevance to glasses, disordered solids, and biomolecular motion. Most theories assume quenched disorder, but in many condensed-phase and biological systems, local energies fluctuate because of solvent reorganization, structural relaxation, or conformational change. A region that is strongly trapping at one time may become less confining later. We develop a minimal theory for one-dimensional diffusion on a rugged site-energy landscape containing quenched Gaussian disorder and dichotomic fluctuations. The key objects are

GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.

Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation to metabolic stress is crucial to maintain pancreatic β-cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well-known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms linking GLP-1R signalling with mitochondrial and β-cell functional ada

Effect of PEG-Induced Liquid-Liquid Phase Separation on DNA-Topotecan Interactions.

Understanding the impact of liquid-liquid phase separation (LLPS) on drug and biological molecules is key to advancing drug delivery and biomolecular engineering. This study investigates how polyethylene glycol (PEG)-induced LLPS modulates the photophysical behavior of topotecan (TPT) and the structural organization of calf thymus DNA (ctDNA) in binary (PEG:TPT and PEG:ctDNA) and ternary (PEG:TPT:ctDNA) systems. In the PEG:TPT system, LLPS induced a shift from the emissive Z-form to the more stable C-TPT form, with enhanced fluorescence and a longer ∼4.0 ns lifetime, suggesting reduced water a

The Epichaperome Matrix Theory: A systems-level model of active molecular organization.

BACKGROUND: Epichaperomes are stable, stress-induced supramolecular assemblies formed through extensive integration of molecular chaperones, co-chaperones, signaling proteins, and client proteins. Although increasing evidence indicates that epichaperomes act as organizational hubs that coordinate proteostasis and signaling networks in cancer, neurodegenerative disorders, and chronic inflammatory diseases, their potential physical roles in cellular organization remain largely unexplored. RESULTS: Here, the Epichaperome Matrix Theory, a systems-level theoretical framework that conceptualizes th

LLPS-based classification and a novel prognostic signature reveal NRF1 as a therapeutic target in pancreatic cancer.

BACKGROUND: Aberrant liquid-liquid phase separation (LLPS) can alter biomolecular condensate functions and may influence pancreatic tumorigenesis and progression, but the specific role of LLPS regulators in prognosis and the tumor immune microenvironment (TIME) in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: We integrated transcriptome data of LLPS regulator-related differentially expressed genes (DEGs; n = 298) in a cohort of 176 PDAC patients from TCGA. Three LLPS regulator subtypes (LS1-LS3) were identified through multi-omics analyses, and a prognostic LLPS subtype-re

Electronic structure, DNA-binding, and biological activity correlations in transition metal complexes of a tetradentate Schiff base: experimental and computational studies.

A novel tetradentate Schiff base ligand (L), synthesized by the condensation of 2,6-diaminopyridine and 3,5-dichlorosalicylaldehyde, and its Cu(II), Ni(II), Co(II), Zn(II), and VO(IV) complexes were prepared and characterized by elemental analysis, FT-IR, UV-Vis, NMR, ESI-mass, magnetic susceptibility, thermal, and EPR studies. Spectroscopic evidence indicates coordination of the ligand through an N2O2 donor set. Based on the available spectroscopic, magnetic, and analytical data, the Cu(II), Ni(II), and Co(II) complexes are proposed to adopt predominantly square-planar geometries, while the Z

Conditionally folded disordered regions contribute to adaptation and regulation in Schistosomamansoni.

Schistosoma mansoni, a causative agent of schistosomiasis, has a complex life cycle that requires extensive molecular adaptation to diverse host environments. Intrinsically disordered proteins (IDPs) and regions (IDRs) are highly flexible protein segments that play key roles in cellular regulation, signaling, and host-pathogen interactions. In this study, we conducted a proteome-wide analysis of IDRs and conditionally folded intrinsically disordered regions (CF-IDRs) in the S. mansoni proteome. 10,749 protein sequences were retrieved from UniProt and reduced to 9638 non-redundant proteins. Int

Broken and Reassembled: The Molecular Mechanisms and Clinical Consequences of Structural Genomic Variation.

BACKGROUND: Structural variants (SVs) are a major class of genomic variation that profoundly influences human genetic diversity, evolution, … tion and resolving previously intractable rearrangements. Furthermore, recent discoveries regarding biomolecular condensates in DNA repair (e.g., PARP1, MRNIP phase separation) reveal previously unrecognized regulatory layers governing repair pathway choice and SV formation. KEY MESSAGES: (i) SVs are generated by specific DNA lesions and error-prone repair processes, wit …

Establishment and validation of a prognostic model based on liquid-liquid phase separation-related genes in gastric cancer.

BACKGROUND: Growing evidence suggests that the imbalance of liquid-liquid phase separation (LLPS) can alter the spatiotemporal coordination ability of biomolecular condensates, thereby playing an important role in carcinogenesis and cachexia. Gastric cancer (GC), ranking as the fifth most prevalent malignancy globally, remains lacking in systematic analysis at the GC-LLPS level within current research. This study aims to identify differentially expressed LLPS-related genes (LLPSGs) in GC and elucidate the role of LLPS in the initiation and progression of GC. Identifying the role of LLPS in car…

Respiratory Syncytial Virus Sequesters NF-κB Subunit p65 to Cytoplasmic Inclusion Bodies To Inhibit Innate Immune Signaling.

Viruses routinely employ strategies to prevent the activation of innate immune signaling in infected cells. Respiratory syncytial virus (RSV) is no exception, as it encodes two accessory proteins (NS1 and NS2) which are well established to block interferon signaling. However, RSV-encoded mechanisms for inhibiting NF-κB signaling are less well characterized. In this study, we identified RSV-mediated antagonism of this pathway, independent of the NS1 and NS2 proteins and indeed distinct from other known viral mechanisms of NF-κB inhibition. In both human and bovine RSV-infected cells, we demonst

Необоснованные конкретные подписи на структурные воды, выявленные в результате динамической ядерной поляризации с помощью УФ-почитаемых радикалов.

Содержимые молекулы структурной воды стабилизируют белковые сгибы и модернизируют свою функцию, однако по-прежнему трудно наблюдать в растворе, поскольку рецензии на основе обмена благоприятствуют местам, в которых используется растворитель. Здесь мы введем протокол для обнаружения структурных молекул воды в местных условиях с использованием долгоживущей гиперполяризованной воды (HyperW), срабатывающей с помощью ультрафиолетовых, нетерпимых радикалов. В модели белкового ингибитора химотрипсина 2, ГиперВ-усилен two- размерная корреляция NMR-спектра через PD 5.5-8.4 :: выявлять значительные улуч

Functions and Therapeutic Potentials of Long Noncoding RNA in Skeletal Muscle Atrophy and Dystrophy.

Skeletal muscle is the most abundant tissue in the human body and is responsible for movement, metabolism, energy production and longevity. Muscle atrophy is a frequent complication of several diseases and occurs when protein degradation exceeds protein synthesis. Genetics, ageing, nerve injury, weightlessness, cancer, chronic diseases, the accumulation of metabolic byproducts and other stimuli can lead to muscle atrophy. Muscular dystrophy is a neuromuscular disorder, part of which is caused by the deficiency of dystrophin protein and is mostly related to genetics. Muscle atrophy and muscular

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… Recent studies have found dysregulated behaviour of biomolecular condensates in cancer, neurodegeneration and cardiomyopathy [ 108 ]. Therefore, it is also essential to identify the dysregulated condensates associated with muscle atrophy and their key lncRNAs. … A., “Modulating Biomolecular Condensates: A Novel Approach to Drug Discovery,” Nature Reviews. Drug Discovery 21 (2022): 841–862. 109. Coan M., Haefliger S., Ounzain S., and Johnson R., “Targeting and Engineering Long Non‐Coding RNAs for Cancer Therapy,” Nature Reviews. …

Selective molecular inhibition of the HDAC6 ZnF-UBP binding domain impairs multiple myeloma cell function.

Multiple myeloma is a plasma cell malignancy with a poor prognosis despite the recent development of new therapeutic options. Histone deacetylase 6 (HDAC6) is overexpressed in multiple myeloma cells and may be involved in the acquisition of resistance to conventional anti-proteasome treatments. In addition to displaying a deacetylase catalytic activity, HDAC6 plays an essential role in the regulation of autophagy and cell death by recognizing ubiquitinated motifs from misfolded proteins through its C-terminal ZnF-UBP binding domain. These defective proteins are sent to the aggresome to facilit

EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs.

Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss

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… Biomolecular Condensates in the Nucleus. Trends Biochem. Sci. 2020;45:961–977. doi: 10.1016/j.tibs.2020.06.007. 47. Lyon A.S., Peeples W.B., Rosen M.K. A framework for understanding the functions of biomolecular condensates across scales. Nat. Rev. Mol. …

From bench to bedside: the application of cannabidiol in glioma.

Glioma is the most common malignant tumor in central nervous system, with significant health burdens to patients. Due to the intrinsic characteristics of glioma and the lack of breakthroughs in treatment modalities, the prognosis for most patients remains poor. This results in a heavy psychological and financial load worldwide. In recent years, cannabidiol (CBD) has garnered widespread attention and research due to its anti-tumoral, anti-inflammatory, and neuroprotective properties. This review comprehensively summarizes the preclinical and clinical research on the use of CBD in glioma therapy

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… One such emerging mechanism involves the interaction of CBD with stress granules (SGs), a type of biomolecular condensate (BMC), which plays a crucial role in cellular stress responses and has been implicated in anti-glioma activity. … Altering biomolecular condensates as a potential mechanism that mediates cannabidiol effect on glioblastoma. Med Oncol. 2024;41(6):140. doi: 10.1007/s12032-024-02381-x. 60. Kim NY, Shivanne Gowda SG, Lee SG, Sethi G, Ahn KS. …

From undruggable to degradable: A deep learning-enabled framework for precision orthopaedic protein degradation.

BACKGROUND/OBJECTIVE: A fundamental translational impasse in musculoskeletal disorders-from osteoarthritis to bone metastases-is the "undruggability" of critical pathological drivers sequestered within anatomically restricted and avascular skeletal niches. While Targeted Protein Degradation (TPD) offers a revolutionary event-driven modality to eradicate these refractory targets, its clinical translation to orthopaedics is severely hindered by the physicochemical incompatibility of large degraders with dense extracellular matrices and the scarcity of bone-specific E3 ligases. METHODS: In this

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… Furthermore, they are often sequestered within super-enhancer-associated complexes or phase-separated biomolecular condensates, rendering them thermodynamically difficult for small molecules to inhibit and physically inaccessible to antibody-based therapies( Fig. 1 c) [ 12 ]. … A brief guideline for studies of phase-separated biomolecular condensates Nat Chem Biol 18 12 2022 1307 1318 36400991 10.1038/s41589-022-01204-2 13 Ferrari S. Langdahl B. …

Student Summer Research Awards - SSRAAbstracts of the SSRA September 2022 meeting, UCD School of Medicine.

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Unlocking the potential of tumor-targeting peptides in precision oncology.

Targeted cancer therapy has emerged as a promising alternative to conventional chemotherapy, which is often plagued by poor selectivity, off-target effects, and drug resistance. Among the various targeting agents in development, peptides stand out for their unique advantages, including minimal immunogenicity, high tissue penetration, and ease of modification. Their small size, specificity, and flexibility allow them to target cancer cells while minimizing damage to healthy tissue selectively. Peptide-based therapies have shown great potential in enhancing the efficacy of drug delivery, improvi

" Nucleolus in Human Beasons: Ribosome Biogenesis " , " Nucleolar Survey " и " Terrapeutic Opportunities " .

Nucleolus превратился в динамичную и многофункциональную субядерную органилию, интегрирующую рибосомный биогенез с клеточным ростом и сигнализацией стресса. Регулирование нуклеолярной функции все чаще признается в качестве главного движителя человеческих заболеваний, связывающего изменённое рибосомное производство и нуклеолярное наблюдение с раком, рибосомопатиями, синдромами преждевременного старения, нейродегенерацией и иммунными расстройствами. В этом обзоре мы интегрируем структурные, молекулярные и болезнетворные перспективы нуклеолярной биологии для определения того, как рипосомный биоге

Enhancing the Safety of Nanoparticles in Medicine: Highlights of Progress and Critical Objectives.

Nanoparticles have transformed drug delivery, imaging, vaccination, and precision therapeutics, but their clinical translation remains constrained by safety profiles that are inseparable from material design, biological identity, host factors, and manufacturing. This review critically evaluates recent progress, persistent limitations, and priority objectives for safer nanomedicine. Unlike reviews organized primarily by material class or isolated toxicology endpoints, we integrate physicochemical determinants, protein corona formation, immune recognition, organ disposition, preclinical models,