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ACS Central Science Jun 2024Coacervates formed by liquid-liquid phase separation emerge as important biomimetic models for studying the dynamic behaviors of membraneless organelles and...
Coacervates formed by liquid-liquid phase separation emerge as important biomimetic models for studying the dynamic behaviors of membraneless organelles and synchronously motivating the creation of smart architectures with the regulation of cell fate. Despite continuous progress, it remains challenging to balance the trade-offs among structural stability, versatility, and molecular communication for regulation of cell fate and systemic investigation in a complex physiological system. Herein, we present a self-stabilizing and fastener-bound gain-of-function methodology to create a new type of synthetic DNA membraneless organelle (MO) with high stability and controlled bioactivity on the basis of DNA coacervates. Specifically, long single-strand DNA generated by rolling circle amplification (RCA) is selected as the scaffold that assembles into membraneless coacervates via phase separation. Intriguingly, the as-formed DNA MO can recruit RCA byproducts and other components to achieve self-stabilization, nanoscale condensation, and function encoding. As a proof of concept, photoactivatable DNA MO is constructed and successfully employed for time-dependent accumulation and spatiotemporal management of cancer in a mouse model. This study offers new, important insights into synthetic membraneless organelles for the basic understanding and manipulation of important life processes.
PubMed: 38947212
DOI: 10.1021/acscentsci.4c00380 -
Journal of Extracellular Biology Jun 2024() causes Bacterial Cold Water Disease in salmonids. During host-pathogen interactions, gram-negative bacteria, such as , release external membrane vesicles (OMVs)...
() causes Bacterial Cold Water Disease in salmonids. During host-pathogen interactions, gram-negative bacteria, such as , release external membrane vesicles (OMVs) harbouring cargos, such as DNA, RNA and virulence factors. This study aimed to characterise the potential role of the OMVs' small RNAs (sRNAs) in the -rainbow trout host-pathogen interactions. sRNAs carried within OMVs were isolated from . RNA-Seq datasets from whole-cell and their isolated OMVs indicated substantial enrichment of specific sRNAs in the OMVs compared to the parent cell. Many of the OMV-packaged sRNAs were located in the pathogenicity islands of . Conservation of sRNAs in 65 strains with variable degrees of virulence was reported. Dual RNA-Seq of host and pathogen transcriptomes on day 5 post-infection of -resistant and -susceptible rainbow trout genetic lines revealed correlated expression of OMV-packaged sRNAs and their predicted host's immune gene targets. In vitro, treatment of the rainbow trout epithelial cell line RTgill-W1 with OMVs showed signs of cytotoxicity accompanied by dynamic changes in the expression of host genes when profiled 24 h following treatment. The OMV-treated cells, similar to the -resistant fish, showed downregulated expression of the suppressor of cytokine signalling 1 (SOCS1) gene, suggesting induction of phagosomal maturation. Other signs of modulating the host gene expression following OMV-treatment include favouring elements from the phagocytic, endocytic and antigen presentation pathways in addition to HSP70, HSP90 and cochaperone proteins, which provide evidence for a potential role of OMVs in boosting the host immune response. In conclusion, the study identified novel microbial targets and inherent characteristics of OMVs that could open up new avenues of treatment and prevention of fish infections.
PubMed: 38947174
DOI: 10.1002/jex2.161 -
Journal of Pain Research 2024Chronic peripheral neuropathic pain (PNP) is a debilitating condition that is associated with many types of injury/diseases, including diabetes mellitus. Patients with...
BACKGROUND & OBJECTIVE
Chronic peripheral neuropathic pain (PNP) is a debilitating condition that is associated with many types of injury/diseases, including diabetes mellitus. Patients with longstanding diabetes develop diabetic PNP (DPNP), which is resilient to currently available drugs. The underlying molecular mechanisms of DPNP are still illusive, but K7 channels that have been implicated in the pathogenesis of various types of chronic pain are likely to be involved. Indeed, using the streptozotocin (STZ) rat model of DPNP, we have previously shown that K7 activation with their non-selective activator retigabine attenuated neuropathic pain behavior suggesting that these channels are implicated in DPNP pathogenesis. Here, we evaluated, in the same STZ model, whether the more potent and more selective K7 channel openers flupirtine and ML213 attenuate STZ-induced pain hypersensitivity.
METHODS
Male Sprague Dawley rats (250-300 g) were used. The STZ model involved a single injection of STZ (60 mg/kg, i.p.). Behavioral testing for mechanical and heat pain sensitivity was performed using a dynamic plantar aesthesiometer and Hargreaves analgesiometer, respectively.
RESULTS
STZ rats exhibited behavioral signs of mechanical and heat hypersensitivity as indicated by significant decreases in the mean paw withdrawal threshold (PWT) and mean paw withdrawal latency (PWL), respectively, at 35 days post-STZ treatment. Single injections of flupirtine (10 mg/kg, i.p.) and ML213 (5 mg/kg, i.p.) to STZ rats (35-days after STZ treatment) caused significant increases in the mean PWT, but not PWL, indicating attenuation of mechanical, but not heat hypersensitivity. Both flupirtine and ML213 were as effective as the positive control gabapentin (10/kg, i.p.), and their anti-allodynic effects were prevented by the K7 channel-specific blocker XE991 (3 mg/kg, i.p.).
CONCLUSION
The findings suggest that K7 channels are involved in the mechanisms of mechanical but not heat hypersensitivity associated with DPNP, and that their activation may prove to be effective in alleviating DPNP symptoms.
PubMed: 38947132
DOI: 10.2147/JPR.S467535 -
The Yale Journal of Biology and Medicine Jun 2024Joint hypermobility syndromes, particularly chronic pain associated with this condition, including Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum... (Review)
Review
Chronic Pain and Joint Hypermobility: A Brief Diagnostic Review for Clinicians and the Potential Application of Infrared Thermography in Screening Hypermobile Inflamed Joints.
Joint hypermobility syndromes, particularly chronic pain associated with this condition, including Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorders (HSD), present diagnostic challenges due to their multifactorial origins and remain poorly understood from biomechanical and genomic-molecular perspectives. Recent diagnostic guidelines have differentiated hEDS, HSD, and benign joint hypermobility, providing a more objective diagnostic framework. However, incorrect diagnoses and underdiagnoses persist, leading to prolonged journeys for affected individuals. Musculoskeletal manifestations, chronic pain, dysautonomia, and gastrointestinal symptoms illustrate the multifactorial impact of these conditions, affecting both the physical and emotional well-being of affected individuals. Infrared thermography (IRT) emerges as a promising tool for joint assessment, especially in detecting inflammatory processes. Thermal distribution patterns offer valuable insights into joint dysfunctions, although the direct correlation between pain and inflammation remains challenging. The prevalence of neuropathies among hypermobile individuals accentuates the discordance between pain perception and thermographic findings, further complicating diagnosis and management. Despite its potential, the clinical integration of IRT faces challenges, with conflicting evidence hindering its adoption. However, studies demonstrate objective temperature disparities between healthy and diseased joints, especially under dynamic thermography, suggesting its potential utility in clinical practice. Future research focused on refining diagnostic criteria and elucidating the underlying mechanisms of hypermobility syndromes will be essential to improve diagnostic accuracy and enhance patient care in this complex and multidimensional context.
Topics: Humans; Thermography; Joint Instability; Chronic Pain; Ehlers-Danlos Syndrome; Inflammation; Infrared Rays
PubMed: 38947102
DOI: 10.59249/WGRS1619 -
Frontiers in Nutrition 2024The study highlighted the potential of sesame seed coat (SSC), typically discarded during sesame paste processing, as a valuable resource for valorization through...
The study highlighted the potential of sesame seed coat (SSC), typically discarded during sesame paste processing, as a valuable resource for valorization through extracting bioactive compounds. It examined the phenolic composition and antioxidant activity of SSC, and evaluated its antibacterial properties against foodborne pathogens such as O157:H7, and Typhimurium. Additionally, SSC underwent nanoemulsion coating, analyzed using dynamic light scattering and scanning electron microscopy, to enhance its application as a natural preservative. The research specifically focused on incorporating SSC nanoemulsion into milk to determine its effectiveness as a preservative. SSC demonstrated considerable antioxidant activity and phenolic content, with catechin identified as the predominant polyphenol. GC-MS analysis revealed seven major compounds, led by oleic acid. Notably, SSC effectively inhibited in broth at 100 mg/ml. The application of SSC and its nanoemulsion resulted in changes to bacterial morphology and a significant reduction in bacterial counts in milk, highlighting its potential as an effective natural antibacterial agent. The findings of this study highlight the potential use of SSC as a valuable by-product in the food industry, with significant implications for food preservation.
PubMed: 38946786
DOI: 10.3389/fnut.2024.1405708 -
Evolutionary Ecology 2024Animal and plant colouration presents a striking dimension of phenotypic variation, the study of which has driven general advances in ecology, evolution, and animal...
UNLABELLED
Animal and plant colouration presents a striking dimension of phenotypic variation, the study of which has driven general advances in ecology, evolution, and animal behaviour. Quantitative Colour Pattern Analysis (QCPA) is a dynamic framework for analysing colour patterns through the eyes of non-human observers. However, its extensive array of user-defined image processing and analysis tools means image analysis is often time-consuming. This hinders the full use of analytical power provided by QCPA and its application to large datasets. Here, we offer a robust and comprehensive batch script, allowing users to automate many QCPA workflows. We also provide a complimentary set of useful R scripts for downstream data extraction and analysis. The presented batch processing extension will empower users to further utilise the analytical power of QCPA and facilitate the development of customised semi-automated workflows. Such quantitatively scaled workflows are crucial for exploring colour pattern spaces and developing ever-richer frameworks for analysing organismal colouration accounting for visual perception in animals other than humans. These advances will, in turn, facilitate testing hypotheses on the function and evolution of vision and signals at quantitative and qualitative scales, which are otherwise computationally unfeasible.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s10682-024-10291-7.
PubMed: 38946730
DOI: 10.1007/s10682-024-10291-7 -
Experimental & Molecular Medicine Jul 2024The reciprocal crosstalk between testicular Sertoli and Leydig cells plays a vital role in supporting germ cell development and maintaining testicular characteristics...
The reciprocal crosstalk between testicular Sertoli and Leydig cells plays a vital role in supporting germ cell development and maintaining testicular characteristics and spermatogenesis. Conventional 2D and the recent 3D assay systems fail to accurately replicate the dynamic interactions between these essential endocrine cells. Furthermore, most in vitro testicular tissue models lack the ability to capture the complex multicellular nature of the testis. To address these limitations, we developed a 3D multicellular testis-on-a-chip platform that effectively demonstrates the reciprocal crosstalk between Sertoli cells and the adjacent Leydig cells while incorporating various human testicular tissue constituent cells and various natural polymers infused with blood coagulation factors. Additionally, we identified SERPINB2 as a biomarker of male reproductive toxicity that is activated in both Sertoli and Leydig cells upon exposure to various toxicants. Leveraging this finding, we designed a fluorescent reporter-conjugated toxic biomarker detection system that enables both an intuitive and quantitative assessment of material toxicity by measuring the converted fluorescence intensity. By integrating this fluorescent reporter system into the Sertoli and Leydig cells within our 3D multicellular chip platform, we successfully developed a testis-on-chip model that can be utilized to evaluate the male reproductive toxicity of potential drug candidates. This innovative approach holds promise for advancing toxicity screening and reproductive research.
PubMed: 38945952
DOI: 10.1038/s12276-024-01258-3 -
Biomedicine & Pharmacotherapy =... Jun 2024Adipose-derived mesenchymal stromal cells (AD-MSCs) are an essential issue in modern medicine. Extensive preclinical and clinical studies have shown that mesenchymal...
Adipose-derived mesenchymal stromal cells (AD-MSCs) are an essential issue in modern medicine. Extensive preclinical and clinical studies have shown that mesenchymal stromal/stem cells, including AD-MSCs, have specific properties (ability to differentiate into other cells, recruitment to the site of injury) of particular importance in the regenerative process. Ongoing research aims to elucidate factors supporting AD-MSC culture and differentiation in vitro. Angiopoietin-like proteins (ANGPTLs), known for their pleiotropic effects in lipid and glucose metabolism, may play a significant role in this context. Regeneration is a complex and dynamic process controlled by many factors. ANGPTL6 (Angiopoietin-related growth factor, AGF), among many activities modulated the biological activity of stem cells. This study examined the influence of synthesized AGF-derived peptides, designated as AGF9 and AGF27, on AD-MSCs. AGF9 and AGF27 enhanced the viability and migration of AD-MSCs and acted as a chemotactic factor for these cells. AGF9 stimulated chondrogenesis and lipid synthesis during AD-MSCs differentiation, influenced AD-MSCs cytokine secretion and modulated transcriptome for such basic cell activities as migration, transport of molecules, and apoptosis. The ability of AGF9 to modulate the biological activity of AD-MSCs warrants the consideration of this peptide a noteworthy therapeutic agent that deserves further investigation for applications in regenerative medicine.
PubMed: 38943988
DOI: 10.1016/j.biopha.2024.117052 -
Cell Reports Jun 2024Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor...
Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor (PAFR). However, drug development targeting the PAFR has been limited, partly due to an incomplete understanding of its activation mechanism. Here, we present a 2.9-Å structure of the PAF-bound PAFR-G complex. Structural and mutagenesis analyses unveil a specific binding mode of PAF, with the choline head forming cation-π interactions within PAFR hydrophobic pocket, while the alkyl tail penetrates deeply into an aromatic cleft between TM4 and TM5. Binding of PAF modulates conformational changes in key motifs of PAFR, triggering the outward movement of TM6, TM7, and helix 8 for G protein coupling. Molecular dynamics simulation suggests a membrane-side pathway for PAF entry into PAFR via the TM4-TM5 cavity. By providing molecular insights into PAFR signaling, this work contributes a foundation for developing therapeutic interventions targeting PAF signal axis.
PubMed: 38943642
DOI: 10.1016/j.celrep.2024.114422 -
EMBO Reports Jun 2024Centrosomes are the canonical microtubule organizing centers (MTOCs) of most mammalian cells, including spermatocytes. Centrosomes comprise a centriole pair within a...
Centrosomes are the canonical microtubule organizing centers (MTOCs) of most mammalian cells, including spermatocytes. Centrosomes comprise a centriole pair within a structurally ordered and dynamic pericentriolar matrix (PCM). Unlike in mitosis, where centrioles duplicate once per cycle, centrioles undergo two rounds of duplication during spermatogenesis. The first duplication is during early meiotic prophase I, and the second is during interkinesis. Using mouse mutants and chemical inhibition, we have blocked centriole duplication during spermatogenesis and determined that non-centrosomal MTOCs (ncMTOCs) can mediate chromosome segregation. This mechanism is different from the acentriolar MTOCs that form bipolar spindles in oocytes, which require PCM components, including gamma-tubulin and CEP192. From an in-depth analysis, we identified six microtubule-associated proteins, TPX2, KIF11, NuMA, and CAMSAP1-3, that localized to the non-centrosomal MTOC. These factors contribute to a mechanism that ensures bipolar MTOC formation and chromosome segregation during spermatogenesis when centriole duplication fails. However, despite the successful completion of meiosis and round spermatid formation, centriole inheritance and PLK4 function are required for normal spermiogenesis and flagella assembly, which are critical to ensure fertility.
PubMed: 38943004
DOI: 10.1038/s44319-024-00187-6